Neurology Issue Volume 77(2) pgs. 91-203,e7-e11 July 12, 2011 (C)2011 American Academy of Neurology issue June 14, 2011

127 Pages·2011·13.42 MB·English

by  ACN

In Focus
Spotlight on the July 12 Issue
RobertA.Gross,MD,PhD,FAAN
Editor-in-Chief,Neurology®
PosturalimbalanceandfallsinPSPcorrelatewith Prevalence,sensitivity,andspecificityofchronic
functionalpathologyofthethalamus cerebrospinalvenousinsufficiencyinMS
Theauthorsdeterminedhowimbalanceandfallsrelatedto Theauthorsdeterminedprevalenceofchroniccerebrospinal
regionalcerebralglucosemetabolismandfunctionalactivation venousinsufficiency(CCSVI)in289patientswithmultiple
ofthecerebralposturalnetworkin16patientswithprogressive sclerosis(MS),21withclinicallyisolatedsyndrome,26with
supranuclearpalsy(PSP).ImbalanceandfallsinPSPwere otherneurologicdiseases,and163healthycontrols,using
closelyassociatedwiththalamicdysfunctionandmostevident specificproposedDopplercriteria.Anincreasedprevalenceof
whenassessedduringmodifiedsensoryinput. CCSVIinpatientswithMSwasdetected,butwithonlymodest
Seep.101;Editorial,p.92 sensitivityandspecificity,suggestingagainstacausativerole
ofCCSVIinMS.
PreferentialD2orpreferentialD3dopamineagonistsin
Seep.138;Editorial,p.98
restlesslegssyndrome
Inthissingle-blindandpolysomnographicinvestigation,aD3- Breastfeedingisnotrelatedtopostpartumrelapsesin
preferringagonist(pramipexole)wassuperiortoaD2- multiplesclerosis
preferringagonist(bromocriptine)in45patientswith Theinfluenceofbreastfeedingonthecourseofmultiple
restlesslegssyndrome(RLS).Theeffectsofselective sclerosis(MS)hasbeendebated.Thisstudy,on423
dopamineagonistscanspurdevelopmentofnewcompounds pregnanciesinwomenwithMS,showedthatthetime-
forRLSandmayincreaseunderstandingofitspathogenesis. dependentprofileoftherelapseratebefore,during,andafter
Seep.110 pregnancydidnotdifferbetweenpatientswhobreastfed
theirbabiesandpatientswhodidnot.
QuantitativeEEGasapredictivebiomarkerforParkinson
Seep.145
diseasedementia
TheauthorsevaluatedquantitativeEEG(QEEG)measuresas
VIEWS&REVIEWS
predictivebiomarkersforthedevelopmentofdementiainpatients
Encephalitisandantibodiestosynapticandneuronalcell
withParkinsondisease(PD).Lowerbackgroundrhythmfrequency
surfaceproteins
showedthehighestoddsratiofordementiarisk,extending
Thisreviewdiscussesthediagnosisand
predictivepowerbeyondneuropsychologicaltesting.QEEGholds
managementofseveraldisordersthat
promiseforclinicaltrialdesignandstudyingthebiologyof
formanewcategoryofautoimmune
cognitivedeclineinPD.
encephalitismediatedbyantibodies
Seep.118
againstcellsurfaceorsynapticproteins.Althoughthese
FromeditorialistSamuelFrank:“Weneedtofindabiomarkerthat
disordersarepotentiallylethalandarenotrare,theyoften
candiagnoseandtrackPDtomovebeyondthesimplephysical
respondtoimmunotherapy.
examinationfeaturesthatwehavebeenusingsincethedaysof
Seep.179
JamesParkinson.”
Seep.94
NB:ThisissueincludesaResident&FellowSectionTeaching
NeuroImage,“Postictalsubconjunctivalhemorrhagesandskin
Causesofdeathamongpeoplewithconvulsiveepilepsyin
petechiae,”thatappearsinprint(p.194).Tocheckout
ruralWestChina:Aprospectivestudy
otherResident&Fellowfeatures,pointyourbrowserto
Understandingcausesofdeathinepilepsymayaidpreventionof
http://www.neurology.organdclickonthelinktotheResident
prematuremortality.Thisstudyprospectivelyestimatedmortality
andFellowSection.
andascertainedcausesofdeathinconvulsiveepilepsyinrural
China.Accidentaldeath,especiallydrowning,andsudden
unexpecteddeathinepilepsywerethemaincauses;theriskof
deathwas5timesthatofthegeneralpopulation.
Seep.132;Editorial,p.96 Podcastscanbeaccessedatwww.neurology.org
Copyright © 2011byAANEnterprises,Inc. 91
EDITORIAL
Localizing imbalance in progressive
supranuclear palsy
Is the thalamus the “fall guy”?
ChristosSidiropoulos, Gaitimbalanceandfallspresentamajorchallengein ThestudybyZwergaletal.3highlightsthewealth
MD neurologic care. Current therapeutics have little to ofresearchcapabilitiesthatcanbeharnessedforun-
PeterA.LeWitt,MD offerformostproblemsofbalance,especiallyinneu- derstanding neural mechanisms underlying locomo-
rodegenerative disorders like progressive supranu- tion in humans. The key finding was a correlation
clear palsy (PSP). Frequent falling, a hallmark of between resting brain glucose metabolism and both
Addresscorrespondenceand PSP,typicallydevelopsearlyandwithgreaterdisabil- gait disturbance and frequency of falls in PSP: re-
reprintrequeststoDr.Christos ity than in idiopathic Parkinson disease (PD), in gional metabolism was diminished in the thalamus
Sidiropoulos,Departmentof
whichimbalanceisprimarilyretropulsiveratherthan and increased in the precentral gyrus, whereas a pa-
Neurology,HenryFordHospital,
2799WestGrandBoulevard, multidirectional.ThepathologicchangesinPSPare tient’smentalimageryofstandingcausedactivation
Detroit,MI48202
intraneuronal aggregates of tau protein (predomi- of glucose metabolism in the midbrain tegmentum
[email protected]
nantlytheH1haplotype1),butthereislittleknown and thalamus. The authors do not report on their
Neurology®2011;77:92–93 about the circuitry and neurochemistry of specific control group, although the distinctive findings in
motor impairments.2 Fortunately, new insight into thepatientswithPSParenotunexpected.Inaprior
thefunctionalanatomyofPSPcomesfromareport [18F]fluorodeoxyglucosePETstudyofpatientswith
by Zwergal et al.3 in this issue of Neurology®. Their various parkinsonian syndromes (including PSP),
findings argue for thalamic localization of postural Juh and colleagues4 found marked hypometabolism
imbalanceandfallinginPSP.Usingcontrolledmul- inthecaudatenucleus,thalamus,midbrain,andcin-
timodalstudiestocharacterizeagroupof16patients gulate gyrus: Eckert et al.5 demonstrated metabolic
with PSP, this report brings together data from the decreasesinthebrainstemandmedialfrontalcortex
patients’ reported frequency of falls, posturography, forpatientswithPSP.Neitherstudyrevealedanin-
brain [18F]fluorodeoxyglucose PET scanning, and creaseofmetabolicactivityinfrontalbrain,however.
fMRI.Thesophisticatedanalysiswasbasedprimarily Structuralimagingusingvoxel-basedmorphome-
on functional connectivity, without evidence from tryinPSPfoundreducedgraymattervolumeinthe
neurotransmitter or electrophysiologic studies. The frontallobes,6sotheenhancedmetabolismdetected
conclusions should be regarded as tentative, there- by Zwergal et al.3 is not readily understood. As an
fore,althoughsuggestiveofwheretherapeuticinter- explanation for their findings, the authors offer the
ventionsshouldbetargeted. notionof“adaptiveplasticity”forfailingsubcortical
NexttoPD,PSPisthemostcommonparkinso- circuits; whether this is plausible will require addi-
niansyndrome;althoughclinicallyheterogeneous,it tionalstudy.InthefMRIcomponentofthepresent
is typically relentlessly progressive, with impaired study,theauthorsusedanovelresearchparadigmof
verticalgaze,axialrigidity,andimbalance.1,2PSPdif- self-elicitedmentalimageryasapsychicsurrogatefor
fuselyinvolvessubcorticalstructures,includingsub- the gait disturbance. Using this simulation, patients
stantia nigra, pedunculopontine nucleus, corpus with PSP with postural imbalance and falls had the
striatum, and cerebral cortex (particularly frontal intriguingfindingofdecreasedactivationlocalizedto
lobe).Histologically,globoseneurofibrillarytangles, midbraintegmentumandthalamus.Theseresultsare
tuftedastrocytes,andvariableextentofneuronalloss in agreement with several reports underscoring the
and gliosis occur. Several neurotransmitter systems importance of the mesencephalic locomotor area
areaffectedbesidestheprominentlossofnigrostria- (acomplexcomprisedofthepedunculopontine,cunei-
taldopaminergicprojections.Thelimitedtherapeu- form,andsubcuneiformnuclei)atinitiatingandmain-
tic responsiveness to dopaminergic treatment is not taining gait. This localization led to deep brain
wellunderstood. stimulationofthepedunculopontinenucleusforboth
Seepage101
FromtheDepartmentofNeurology(C.S.,P.A.L.),HenryFordHospital;andtheDepartmentofNeurology(P.A.L.),WayneStateUniversitySchool
ofMedicine,Detroit,MI.
Disclosure:Authordisclosuresareprovidedattheendoftheeditorial.
92 Copyright © 2011byAANEnterprises,Inc.
patientswithPSPandpatientswithPDwithfreezingof tics,LundbeckInc.,Novartis,andIpsen;hasservedonscientificadvisory
gait.7Furthermore,asZwergaletal.3pointout,neuro- boardsorasaconsultantforChelseaTherapeutics,IMPAXLaboratories,
Inc.,IntecPharma,NeuroDerm,Ltd.,Neurologix,Inc.,SantheraPhar-
nallossisprominentinboththethalamusandpedun-
maceuticals, and XenoPort, Inc.; serves as Editor-in-Chief of Clinical
culopontinenucleusearlyinPSP.8,9 NeuropharmacologyandontheeditorialboardofJournalofNeuralTrans-
Theimportantcontributionofthalamicfunction mission; has received research support from Allergan, Inc., Boehringer
Ingelheim,Ipsen,ChelseaTherapeutics,Impax,Merz,Neurologix,No-
for gait and balance control is further supported by
vartis,Schering-PloughCorp.,UCB,XenoPort,Inc.,SantheraPharma-
thephenomenonofastasiainpatientswiththalamic
ceuticals,andtheMichaelJ.FoxFoundationforParkinson’sResearch;
lesions. Projections ascending to the thalamus from andhasservedasanexpertwitnessinamedico-legalcase.
the pedunculopontine nucleus occur in the nonhu-
man primate brain.10 Since most of the pedunculo-
REFERENCES
pontineneuronsarecholinergic(andotherevidence
1. Song YJ, Huang Y, Halliday GM. Clinical correlates of
implicatescholinergicdysfunctioninthePSPthala-
similarpathologiesinParkinsoniansyndromes.MovDis-
mus11), enhancing cholinergic neurotransmission
ordEpub2011Jan21.
might improve gait dysfunction in PSP; unfortu- 2. Kaat DL, Chiu WZ, Boon AJ, van Swieten JC. Recent
nately,thishasnotbeeneffective.12Tofurthercom- advancesinprogressivesupranuclearpalsy:areview.Curr
plicate matters, medications with anticholinergic AlzheimerResEpub2011Jan11.
3. ZwergalA,laFouge`reC,LorenzlS,etal.Posturalimbal-
properties (amantadine and amitriptyline) may pro-
anceandfallsinPSPcorrelatewithfunctionalpathologyof
vide symptomatic benefit for patients with PSP.13
thethalamus.Neurology2011;77:101–109.
Differential involvement of the various cholinergic
4. JuhR,KimJ,MoonD,ChoeB,SuhT.Differentmeta-
receptor subtypes or of other neurotransmitter sys- bolicpatternsanalysisofParkinsonismonthe18F-FDG
tems (especially GABA and glutamate) may explain PET.EurJRadiol2004;51:223–233.
thevariableresultsofmedicationtrialsinPSP. 5. EckertT,TangC,MaY,etal.Abnormalmetabolicnet-
Zwergaletal.3havetakenanimportantfirststep works in atypical parkinsonism. Mov Disord 2008;23:
727–733.
forlocalizingthesourceofimpairedbalanceinPSP,
6. PadovaniA,BorroniB,BrambatiSM,etal.Diffusionten-
buttheresultsrequirevalidationandfurtherexplora-
sorimagingandvoxelbasedmorphometrystudyinearly
tion. [18F]fluorodeoxyglucose PET and fMRI have
progressive supranuclear palsy. J Neurol Neurosurg Psy-
relativelypoorspatialresolution,soarenotidealfor chiatry2006;77:457–63.
smallareasofinterest,suchasthepedunculopontine 7. Brusa L, Iani C, Ceravolo R, et al. Implantation of the
andthalamicnuclei.Furthermore,thetemporalres- nucleus tegmenti pedunculopontini in a PSP-P patient:
safe procedure, modest benefits. Mov Disord 2009;24:
olutionoffMRIislimitedanddoesnotpermitaccu-
2020–2022.
rate activation sequences of the brain structures
8. Henderson JM, Carpenter K, Cartwright H, Halliday
controllinggait.Thelackofneurotransmitterimag-
GM. Loss of thalamic intralaminar nuclei in progressive
ing options limits inferences about neurochemical supranuclear palsy and Parkinson’s disease: clinical and
systemsindisordersofgaitandbalance.Invivoauto- therapeuticimplications.Brain2000;123:1410–1421.
radiography and postmortem histochemistry might 9. Zweig RM, Whitehouse PJ, Casanova MF, Walker LC,
provide more detail of thalamic pathophysiology in JankelWR,PriceDL.Lossofpedunculopontineneurons
in progressive supranuclear palsy. Ann Neurol 1987;22:
PSP.Anotherinvivotechnique,diffusiontensorim-
18–25.
aging and detailed tractography, might be used to
10. MatsumuraM,NambuA,YamajiY,etal.Organizationof
createanintegratedfunctionalatlasofthemidbrain
somaticmotorinputsfromthefrontallobetothepedun-
tegmentum-thalamicloop. culopontine tegmental nucleus in the macaque monkey.
Sinceimbalanceandgaitdisordersarecommonfea- Neuroscience2000;98:97–110.
turesofneurodegenerativedisordersandofnormalag- 11. Warren NM, Piggott MA, Perry EK, Burn DJ. Cholin-
ergic systems in progressive supranuclear palsy. Brain
ing,furtherresearchintotheoriginsoftheseproblems
2005;128:239–249.
witheffectivescreeningtoolsisapriority.Thepresent
12. LitvanI,PhippsM,PharrVL,HallettM,GrafmanJ,Sala-
study3offersapracticalrouteandvaluableinsightsfor
zarA.Randomizedplacebo-controlledtrialofdonepezilin
intensivestudyofpatientsatriskforfalls. patients with progressive supranuclear palsy. Neurology
2001;57:467–473.
DISCLOSURE 13. KompolitiK,GoetzCG,LitvanI,JellingerK,VernyM.
Dr.Sidiropoulosreportsnodisclosures.Dr.LeWitthasreceivedspeaker Pharmacologicaltherapyinprogressivesupranuclearpalsy.
honorariafromAllergan,Inc.,BoehringerIngelheim,ChelseaTherapeu- ArchNeurol1998;55:1099–1102.
Neurology77 July12,2011 93
EDITORIAL
Seize the day
Quantitative EEG as a biomarker for dementia in Parkinson disease
SamuelFrank,MD James Parkinson described “the shaking palsy” as a line;further,theynotedanincidenceofdementiafor
disease with “involuntary tremulous motion, with the aggregate group, within 5 years of the baseline
lessened muscular power, in parts not in action and EEG examination, of 34%. As expected, those with
Addresscorrespondenceand evenwhensupported;withapropensitytobendthe PD-MCI showed a significant hazard ratio (HR) of
reprintrequeststoDr.Samuel
trunkforwards,andtopassfromawalkingtoarunning 4.3. The most notable QEEG finding was in the
Frank,BostonUniversitySchool
ofMedicine,72EastConcord pace: the senses and intellects being uninjured.”1 The background rhythm frequency (BRF). When sub-
StreetC3,Boston,MA02118 motorsignsweredescribedwell,butdementiawasno- jects with a BRF lower than the median of 8.5 Hz
[email protected]
tably and actively omitted in the original description. were compared with those with a BRF greater than
For patients with Parkinson disease (PD) today, the the median, the HR was 13. The incidence of de-
Neurology®2011;77:94–95
questionofwhethertheywilldevelopdementiaremains mentia was 66% for those with lower than median
difficulttoaddressearlyinthecourseofthedisease,and BRF vs 8.1% for those with higher than median
theopenquestioncontributestoanxiety.Almostallpa- BRF. There was also an increased risk of dementia
tientswithPDexhibitsubcorticalcognitivedysfunction forthosewithhigherthanmedianthetabandpower
andupto80%ofpatientswithPDdevelopsignificant (51%vs21%)withaHRof3.
enoughcognitivedeficitstomeetthecriteriafordemen- The authors did not state whether subjects were
tia.2InthisissueofNeurology®,Klassenetal.3describea screened for depression, which can affect neuropsy-
potential biomarker for identifying dementia in PD, chologic testing results, but the larger study from
possiblybringingusclosertoaddressingoneofourpa- whichthisanalysiswasderiveddidscreenfordepres-
tients’majorworries. sion. QEEG is not routinely used clinically because
Asampleof117dementia-freesubjectswerepro- theacquisitionofdataisnotnecessarilysimple,butit
spectivelyevaluatedovera9-yearperiod.Duringthis can be done by a trained technician. Group data of
time, an extensive clinical neuropsychologic battery thissortdonotyetsupportusingQEEGtopredict
was administered, including the Folstein Mini- dementiainPDonanindividualbasis,butthework
Mental State Examination, Auditory Verbal Learn- presentedinthisstudymaybeusefultostratifyrisk
ingTest(long-termmemoryscore),ControlledOral inpotentialstudycandidatesbeforeentryintoclinical
WordAssociationTest,StroopInterferenceTrailsB, trialsoftreatmentsintendedtopreventordelaydemen-
Wechsler Adult Intelligence Scale III, Digit Span, tiainPD.Thislow-cost,reliabletestmaycomplement
andJudgmentofLineOrientationTest.Inaddition, neuropsychologic testing in the future, but cannot be
quantitative EEG (QEEG) was performed at least usedasasubstituteforclinicaljudgment.
twiceduringthestudy.QEEGisanoldtechnology Work to identify biomarkers for the onset and
that dates back to the 1920s. Data can be obtained progression of PD is ongoing, with many potential
onstandardequipmenttorecordadigitalEEGand promisingcandidates.5Fromascientificstandpoint,
analyzedwithspecialsoftware,buttheQEEGmust amoreobjectivemarkerofthediseasestatewillprob-
beobtainedwhilethepatientisawake,notdrowsy,and ablyreducevariabilityintrials,therebyreducingthe
withoutmuscleartifact.TheuseofQEEGindementia necessarysizeandlengthoftimeofclinicaltrials(and
hasbeenproposedforsometime,includinganAmeri- also the cost). Although biomarkers will never replace
can Academy of Neurology practice parameter from theclinicalexamination,objectivetestingmayprovidea
1997,whichstatesthattheuseofQEEGindementia measureofreassurancetopatientsabovethatprovided
“maybeausefuladjuncttointerpretationoftheroutine bythehistoryandphysicalexamination.
EEGwhenusedinexperthands.”4 Weneedtofindabiomarkerthatcandiagnoseand
Klassenetal.3foundthat23%ofsubjectshadPD trackPDtomovebeyondthesimplephysicalexamina-
and mild cognitive impairment (PD-MCI) at base- tionfeaturesthatwehavebeenusingsincethedaysof
SeePage118
FromtheBostonUniversitySchoolofMedicine,Boston,MA.
Disclosure:Authordisclosuresareprovidedattheendoftheeditorial.
94 Copyright © 2011byAANEnterprises,Inc.
JamesParkinson.WithQEEG,SPECT,orPETimag- LundbeckInc.;servesasaconsultantforGenzymeCorporation;andre-
ing,andotherpotentialbiomarkersofprocessesinPD, ceivesresearchsupportfromtheMichaelJ.FoxFoundation.
wemaybeabletopredictPDprogressionandcompli-
cations,includingdementia,perhapsyearsbeforeonset.
REFERENCES
Early detection and prediction may help patients and
1. Parkinson J. Essay on the Shaking Palsy. London: Sher-
theirfamilieswithplanningforthefuture.Evennow, woodNealy&Jones;1817.
therearetherapiestousewhentheprocessofdementia 2. Aarsland D, Andersen K, Larsen JP, Lolk A, Kragh-
becomesclinicallyevidentinPD.6 SorensenP.Prevalenceandcharacteristicsofdementiain
Untilthereareclearteststoaidinthediagnosisof Parkinsondisease:an8-yearprospectivestudy.ArchNeu-
PD, monitor the progression, predict complications rol2003;60:387–392.
3. KlassenBT,HentzJG,ShillHA,etal.QuantitativeEEG
suchasthedevelopmentofdementia,andpotentially
asapredictivebiomarkerforParkinsondiseasedementia.
prevent PD from developing, biomarker develop-
Neurology2011;77:118–124.
ment in PD and other neurodegenerative diseases
4. NuwerM.AssessmentofdigitalEEG,quantitativeEEG,
willcontinuetobeahighresearchpriority.Inaddi-
andEEGbrainmapping:reportoftheAmericanAcademy
tiontoneuropsychologictesting,Klassenetal.3have ofNeurologyandtheAmericanClinicalNeurophysiology
madesubstantialstridestowardfindingdementiabe- Society.Neurology1997;49:277–292.
foreourpatientsandtheirfamiliesdo. 5. WuY,LeW,JankovicJ.PreclinicalbiomarkersofParkin-
sondisease.ArchNeurol2011;68:22–30.
DISCLOSURE 6. EmreM,AarslandD,AlbaneseA,etal.Rivastigminefor
Dr.FrankservesonthedatasafetymonitoringboardfortheHuntington dementia associated with Parkinson’s disease. N Engl
Study Group; has received speaker honoraria from Allergan, Inc. and JMed2004;351:2509–2518.
Neurology77 July12,2011 95
EDITORIAL
The geography of epilepsy
A fatal disease in resource-poor settings
GretchenBirbeck,MD Physicianswhocareforpeoplewithepilepsy(PWE) In a population of 3,568 PWE receiving care as
DaleHesdorffer,PhD are all too familiar with their risk of seizure-related part of a WHO/International League against Epi-
injuries. For more severely affected patients, brain lepsydemonstrationproject,thecasefatalitywas3%
injuryordeathduetostatusepilepticusisofconcern, over28monthsofobservation.Theoverallstandard-
Addresscorrespondenceand particularly during periods of medication adjustments izedmortalityratioforPWEcomparedwiththatfor
reprintrequeststoDr.Gretchen
orpoorantiepilepticdrug(AED)adherence.Morere- the general rural Chinese population was 4.92,
Birbeck,InternationalNeurologic
andPsychiatricEpidemiology cently, the realities and risks of sudden unexplained whereas among PWE younger than 35 years, the
Program,MichiganState deathinepilepsyhavebecomeanadditionalcausefor mortalitywasmorethan50timesthatofsimilaraged
University,#324WestFeeHall,
EastLansing,MI48824 anxiety.1 Are PWE at increased risk of early death? individuals in the rural Chinese population. Com-
[email protected] StudiesintheUnitedStateshaveshownthatthemor- mon causes of death included drowning (45%),
tality risk for PWE is (cid:1)2–3 times that of the general otheraccidentaldeaths(14%),andstatusepilepticus
Neurology®2011;77:96–97
population,2 withtheriskbeinghighestinthosewith (7%). As devastating as these numbers are, they
refractoryepilepsyanddecreasingovertime.Butwhat probablyunderestimatethemortalityrisk.Bythena-
about PWE who live in settings with more inherent tureofthepopulationstudied,weassumethatevery-
physicalrisksandwithpooreraccesstotreatment? onehadaccesstotreatment.Previousstudiesinother
Reports from resource-poor countries have long regions of rural China, on the other hand, have
suggested that seizure-related deaths from falls, shown that only 3% of PWE are receiving treat-
burns,anddrowningsaswellasfromstatusepilepti- ment,5 and, not surprisingly, the risk of seizure-
cus (often related to lapses in AED availability) are relatedinjuriesincreasesintheabsenceoftreatment.6
disturbinglyfrequent.3Ofcourse,clinic-orhospital- ThenewinsightsprovidedbyMuetal.suggesta
based reports may be biased toward more severe ill- reappraisalofestimatesofthecontributionthatepi-
ness. Epidemiologic studies from resource-poor, lepsy makes to the global burden of disease. Data
non-Western settings have shown higher than ex- fromthe2005GlobalBurdenofDiseases,Injuries,and
pectedincidencerates(meaningthenumberofnew RiskFactorsStudy7willbeusedtoguideprogrammatic
casesofepilepsyper100,000populationoveraspe- prioritiesinpublichealthandhealthpolicyandplan-
cificperiodoftime)relativetotheprevalenceofepi- ning.Withoutreasonableestimatesoftheearlymortal-
lepsy(meaningthenumberofactivecasesofepilepsy ity associated with epilepsy in resource-poor settings,
per 100,000 population at a single point in time), epidemiologic studies underestimate the contribution
suggesting either that PWE in such settings com- ofepilepsytotheglobalburdenofdisease.Forregions
monly experience early death or that they benefit withahighincidenceofepilepsy,thismayrepresenta
fromhigherremissionratesthanareobservedinthe considerableoversight.
West.Establishingtherelativemortalityrisksforep- The clinical implications for policy makers and
ilepsy in resource-poor settings is challenging, how- health care workers providing epilepsy care services
ever, because studies require mortality data from a inresource-poorsettingsareclear.Caremustinclude
populationofPWEinadefinedcommunityaswell consistent and reliable access to AEDs in adequate
asmortalityratesfromcomparableindividualsinthe dosesforallPWE,aswellascounselingregardingthe
same or a similar community, preferably over the riskofseizure-relatedinjuriesandadviceondecreas-
sametimeperiod.InthisissueofNeurology®,Muet ingsuchrisksthroughlifestylechangesorreorganiza-
al.4 provide alarmingly high population-based, tion of domestic and work responsibilities. Because
epilepsy-specificmortalityestimatesforpeopleresid- mosthealthcareservicesindevelopingcountriesare
inginruralWestChina. deliveredbynonphysicianhealthcareworkers,these
Seepage132
FromtheInternationalNeurologicandPsychiatricEpidemiologyProgram(G.B.),MichiganStateUniversity,EastLansing;EpilepsyCareTeam,
ChikankataHospital(G.B.),Mazabuka,Zambia;andGertrudeH.SergievskyCenterandDepartmentofEpidemiology(D.H.),Columbia
University,NewYork,NY.
Disclosure:Authordisclosuresareprovidedattheendoftheeditorial.
96 Copyright © 2011byAANEnterprises,Inc.
recommendations need to be included in the CDC,theAUCD,theNIH(NINDS/NICHD),theMaternalandChild
evidence-based guidelines for care under develop- HealthBureau,andtheEpilepsyFoundationofAmerica.
mentbytheWHO.8Ministriesofhealthalsoneedto
bealertedtothepotentialriskofseizure-relatedmor-
REFERENCES
tality when AED drug supplies are erratic or unsus- 1. HitirisN,MohanrajR,NorrieJ,BrodieMJ.Mortalityin
tained. The epilepsy treatment gap must be epilepsy.EpilepsyBehav2007;10:363–376.
addressed globally, not only to improve the lives of 2. GaitatzisA,SanderJW.Themortalityofepilepsyrevis-
PWEbutalsotopreventsenselessdeaths. ited.EpilepticDisord2004;6:3–13.
3. DiopAG,HesdorfferDC,LogroscinoG,HauserWA.Ep-
Epilepsy is acknowledged to be one of the most
ilepsy and mortality in Africa: a review of the literature.
cost-effective treatable chronic conditions world-
Epilepsia2005;46(suppl11):33–35.
wide9 and yet the treatment gap (number of people
4. Mu J, Liu L, Zhang Q, et al. Causes of death among
with active epilepsy who require treatment yet are peoplewithconvulsiveepilepsyinruralWestChina:a
not receiving it) remains at (cid:1)75% in low-income prospectivestudy.Neurology2011;77:132–137.
countriesandapproaches100%insomeregions.10If 5. ZhaoY,ZhangQ,TseringT,etal.Prevalenceofconvul-
billions of dollars and seemingly boundless political siveepilepsyandhealth-relatedqualityoflifeofthepopu-
lation with convulsive epilepsy in rural areas of Tibet
willcanbeharnessedandusedtoprovidehealthcare
AutonomousRegioninChina:aninitialsurvey.Epilepsy
services and medications for HIV/AIDS at $147.50
Behav2008;12:373–381.
per person per year (first-line therapy),11 what must
6. BirbeckGL.SeizuresinruralZambia.Epilepsia2000;41:
be done to move epilepsy treatment, at (cid:2)$6.00 per 277–281.
year,12 to the top of the global health agenda? As 7. MurrayC,LopezA,BlackR,etal.Globalburdenofdis-
noncommunicablechronicdiseasesbegintogainthe ease 2005: call for collaborators. Lancet 2007;370:109–
attentiontheydeservefromhealthcareandpublic 110.
8. WorldHealthOrganization.MentalHealthGapAction
health authorities worldwide, epilepsy care must
Programme. Available at: www.who.int/entity/mental_
be brought to the forefront of clinical conditions
health/mhgap_final_english.pdf. Accessed February 2,
forprioritization.
2011.
9. WorldHealthOrganization.NeurologicalDisorders:Pub-
DISCLOSURE licHealthChallenges.Geneva:WHOPress;2006.
Dr.BirbeckistheEpilepsyCareTeamDirectorforChikankataHospital 10. MeyerA,DuaT,MaJ,SaxenaS,BirbeckG.Globaldis-
inMazabuka,Zambia;servedastheNeurologyExpertTeamLeaderfor paritiesincareforepilepsy:asystematicreviewandanaly-
theGates-funded2005GlobalBurdenofDiseases,Injuries,andRisk sisofvariationoftheepilepsytreatmentgap.BullWorld
FactorsStudy,whichincludedthegroupevaluatingepilepsy;servesasa HealthOrgan2010;88:260–266.
consultantfortheWorldHealthOrganizationMentalHealthGapAction
11. ClintonFoundation.Antiretroviral(ARV)pricelist(No-
Programme’sGuidelinesDevelopmentGroupforEpilepsyCareGuide-
vember2010).ClintonHealthAccessInitiative;2010.
lines;andhasreceivedresearchsupportfromtheNIH.Dr.Hesdorfferhas
12. ChombaE,HaworthA,MbeweE,etal.Thecurrentavail-
servedonascientificadvisoryboardforPfizerInc;hasreceivedfunding
fortravelfromUCBandGlaxoSmithKline;servesasanEditorofEpilep- abilityofantiepilepticdrugsinZambia:implicationsfor
sia,EpilepsyResearch,andEpilepsyandBehavior,andasaContributing the ILAE/WHO “out of the shadows” campaign. Am J
EditorofEpilepsyCurrents;andhasreceivedresearchsupportfromthe TropMedHyg2011;83:571–574.
Neurology77 July12,2011 97
EDITORIAL
Chronic cerebrospinal venous insufficiency
Have we found the cause and cure of MS?
RobertJ.Fox,MD Multiple sclerosis (MS) has traditionally been con- Following the reports from Zamboni and col-
AlexRae-Grant,MD sidered an autoimmune disorder—an abnormal im- leagues, several other groups performed small
mune system attacking an otherwise healthy brain, CCSVI studies and came to different conclusions.
spinal cord, or optic nerve. But even in its original One study evaluated 56 patients with MS and 20
Addresscorrespondenceand descriptionbyCharcot,theperivenularpredilection controls using ultrasound and found that none met
reprintrequeststoDr.RobertJ.
ofMSlesionssuggestedapotentialvascularetiology. criteriaforCCSVI.8Anotherstudyevaluated21pa-
Fox,9500EuclidAvenue,
ClevelandClinicFoundation, In 1935, Tracy Putman1 reported an animal model tients with MS and 20 controls with phase-contrast
Cleveland,OH44195 ofMSbasedoninjectingobstructingagentsintothe magnetic resonance angiography and found no dif-
[email protected]
venoussinuses.Onthebasisofthismodelhetreated ference in IJV outflow or the presence of IJV reflux
Neurology®2011;77:98–100 74patientswithMSwiththeanticoagulantdicuma- between patients with MS and controls.9 These re-
rol,withmixedresults.2Afterlyingdormantforover sults challenged the hypothesis that CCSVI plays a
halfacentury,thevasculartheoryofMSre-emerged role in MS. Furthermore, CCSVI does not explain
withaseriesofpublicationsledbytheItalianvascu- thegenetic,ethnic,orgeographicpreferentialoccur-
larsurgeonPaoloZamboni.Heusedultrasoundand renceofMS,althoughCCSVIhasnotbeenstudied
catheter-basedvenographytodescribevenousinsuf- inrelationtothesefactors.
ficiencyintheinternaljugularveins(IJV),vertebral In this issue of Neurology®, Zivadinov and col-
veins,anddeepcerebralveinsofpatientswithMS, leagues10 report the results of the largest CCSVI
coining the term chronic cerebrospinal venous in- study to date. Using a single, unblinded ultrasound
sufficiency (CCSVI).3 Five ultrasound criteria technicianwhostudied499subjects,theyfoundthat
wereproposed(figure),althoughthesehaveyetto 56%ofpatientswithMSmetcriteriaforCCSVI,as
be validated against a criterion standard. Using did 23% of healthy controls and 46% of subjects
these criteria, Zamboni and colleagues reported a with other neurologic diseases. A post hoc analysis
surprisinglyhigh100%sensitivityand100%spec- suggested that CCSVI was more prevalent in pro-
ificity in discriminating patients with MS from gressive MS than relapsing forms of MS. Together,
controls. The same group reported clinical im- these observations demonstrate an increased preva-
provements in an open-label study of catheter- lenceofCCSVIinpatientswithMS,butwithacon-
based venoplasty,4 later provocatively named the siderably lower prevalence than reported by
liberationprocedure. Zamboni et al. and with substantial proportions of
The public response to these reports was pro- healthy controls and patients with other diseases
found.5Websites,blogs,Facebookpages,andother demonstratingthesameultrasoundchanges.
socialnetworkmediapromotedtheCCSVItheoryas ThisstudysuggeststhatCCSVI,asdefinedusing
salvation for patients with MS. Around the world, ultrasound of the intracranial and extracranial ve-
WebsitessprangupadvertisingtreatmentsforCCSVI. noussystem,isnotlikelytobeaprimarycausalpro-
InCanada,politiciansdebatedwhethertopayfortest- cessinMS.Anincreasedprevalenceinprogressiveas
ingandtreatmentforthiscondition.Somevascularsur- comparedwithrelapsingdiseaseleavesopenthepos-
geons treated CCSVI in patients with MS using sibility that CCSVI may be playing a contributory
endovascularstents,withreportsoffatalconsequences rolein,orbeaconsequenceof,thedisease,ormaybe
in2patientsandnear-fatalconsequencesinanother.6,7 age-related.
ItbecameclearthattheCCSVItheorywentfarbeyond Wheredowegofromhere?Severalissuesneedto
the traditional clinical research enterprise and had be- beaddressedinordertomoveforward.Manyfacets
comeamedia-drivenphenomenon. ofCCSVIultrasoundstudiesareuntestedorunclear.
Seepage138
FromtheMellenCenterforMultipleSclerosis,NeurologicalInstitute,ClevelandClinicLernerCollegeofMedicine,ClevelandClinic,Cleveland,OH.
Studyfunding:SupportedbyRC1004-A-5andRG4103A4/2fromtheNationalMSSociety.
Disclosure:Authordisclosuresareprovidedattheendoftheeditorial.
98 Copyright © 2011byAANEnterprises,Inc.
Figure Illustrationofthevascularabnormalitiescomprisingtheproposedentitychroniccerebrospinal
venousinsufficiency
The5boxesdescribethe5abnormalitiesincludedintheproposedultrasounddiagnosticcriteria.3Reprintedwithpermis-
sion,ClevelandClinicCenterforMedicalArt&Photography©2010.Allrightsreserved.
Thewithin-rater,between-rater,andcross-centerre- chosen clinical endpoints and appropriate patient
producibility and the effects of hydration are un- safetyoversight.
known. The relationship between ultrasound It behooves the clinical research community to
findings and both normal anatomic variation and carefullypursueCCSVItoitsend;weshouldneither
true venous insufficiency is not well-understood. jump on the bandwagon as it passes through town,
Validated magnetic resonance venography criteria norassiduouslymisstheparade.IfCCSVIisauseful
for CCSVI are lacking. The relationship between clinicalorresearchendeavorforsomeproportionof
CCSVIandotheraspectsofMSisunknown,includ- the MS population, we should acknowledge its im-
ingMRImeasures,diseaseduration,anddiseasepro- portance.IfCCSVIisnotfoundtobelinkedtoMS,
gression. Pathologic evaluation of cervical and efficientanddefinitivestudieswillletusredirectpre-
azygousveinsisneededtounderstandthehistologic ciousresourcestowardresearcheffortsmorelikely
correlatesofultrasound-definedCCSVI. to advance the understanding and treatment of
To help address the conflicting reports, in June thisdisease.
2010theUnitedStatesandCanadianMultipleScle-
rosis Societies awarded 7 research awards totaling ACKNOWLEDGMENT
$2.4milliontostudyCCSVI.Together,theseproj- TheauthorsthankDrs.JeffreyCohenandRichardRudick,Cleveland
ectswillevaluateover500patientswithMSand600 Clinic,fortheirdiscussionandreviewofthismanuscript.
controls using ultrasound, magnetic resonance an-
DISCLOSURE
giography, catheter-based venography, and patho-
Dr.FoxhasreceivedspeakerhonorariafromBiogenIdecandTevaPhar-
logic studies from autopsy tissue. In addition, the
maceuticalIndustriesLtd.;hasservedasaconsultantforBiogenIdec,
Canadian Institutes of Health Research commis- Genentech,Inc.,andNovartis;hasservedonclinicaltrialadvisorycom-
sioned a standing Scientific Expert Working Group mitteesforBiogenIdec;hasreceived/receivesresearchsupportfromthe
NationalMultipleSclerosisSociety(RG4091A3/1;RG4103A4/2;RC
tomonitorandanalyzeresultsfromtheseandother
1004-A-5),whichincludesfundingtostudyCCSVI;andservesonthe
ongoing CCSVI studies. Given the uncertainties of editorialboardsofNeurology®andMultipleSclerosis.Dr.Rae-Granthas
the relationship between CCSVI and MS and the receivedspeakerhonorariafromBiogenIdec,EMDSerono,Inc.,and
potentialrisksofintervention,anyCCSVIinterven- Teva Pharmaceutical Industries Ltd.; receives publishing royalties for
HandbookofMultipleSclerosis(SpringerHealthcare,2010);servesonthe
tion such as balloon venoplasty should be restricted
speakers’bureauofBiogenIdec;andhasreceivedresearchsupportfrom
to a blinded, controlled clinical trial using carefully theNationalMultipleSclerosisSociety(RC1004-A-5).
Neurology77 July12,2011 99
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