Sie sind auf Seite 1von 11

24/02/2016

TheEvaluationofRapidlyProgressiveDementia

Neurologist.AuthormanuscriptavailableinPMC2012May20.
Publishedinfinaleditedformas:

PMCID:PMC3356774
NIHMSID:NIHMS373979

Neurologist.2011Mar17(2):6774.
doi:10.1097/NRL.0b013e31820ba5e3

TheEvaluationofRapidlyProgressiveDementia
MichaelHenryRosenbloom,MD1,*andAlirezaAtri,MD,PhD1,2
1
BedfordVAHospital,GeriatricResearchandEducationClinicalCenter(GRECC),Bedford,MA
2
DepartmentofNeurology,MassGeneralHospital,Boston,MA
CorrespondingAuthor:MichaelHenryRosenbloom,MD,AttendingNeurologist,CenterforDementiaandAlzheimersDisease,HealthPartnersSpecialty
Clinic,401PhalenBoulevard,St.Paul,MN55130,Phone:6512547900,Fax:6512543123,Email:Michael.H.Rosenbloom@HealthPartners.comEmail:
mrosenbloom@memory.ucsf.edu
CopyrightnoticeandDisclaimer

Thepublisher'sfinaleditedversionofthisarticleisavailableatNeurologist
SeeotherarticlesinPMCthatcitethepublishedarticle.

Abstract

Goto:

Background

Rapidlyprogressivedementia(RPD)isauniquesetofdisordersresultingincognitive,behavioral,andmotordecline
within2years.AvarietyofetiologiesmaycontributetoRPDincludingneurodegenerative,inflammatory,infectious,and
toxicmetabolicconditions.JakobCreutzfeldtdisease(CJD)isfrequentlythemostconcerningdiagnosisonthe
differential.Thechallengefortheneurologistisdistinguishingpriondiseasefromreversibleprocessesthatresultin
dementia.
ReviewSummary

ThisreviewdiscussestheclinicalaspectsandthediagnosticworkupofRPD.ParticularfocusisgiventobothCJDand
thepotentiallytreatableinflammatoryconditionsthatmaycauseasimilarpresentation.Furthermore,astandardizedstep
wiseapproachisoutlinedforpatientspresentingwithRPD.
Conclusion

NeurologistsshouldadoptastandardizedapproachtotherapidlypresentingdiseaseprocessesthatmaymimicCJDin
theirclinicalandradiologicalfeatures.
Keywords:Rapidlyprogressivedementia,JakobCreutzfeldtdisease,Immunemediateddementia,Paraneoplastic
syndrome,HashimotosEncephalopathy
Introduction

Goto:

Dementiaisachronicprogressive,irreversibleneurodegenerativeprocesscompromisingcognitive,behavioral,andmotor
functionandultimatelyleadstofunctionalimpairment.Typicalexamplesofchronicneurodegenerativediseasesinclude
Alzheimersdementia(AD),vasculardementia(VD),dementiawithLewybodies(DLB)andfrontotemporaldementia
(FTD).However,acertainsubsetoftheseconditionsmayalsopresentwithamoreaccelerateddeclineinfunctionand
warrantclassificationasarapidlyprogressivedementia(RPD).
Rapidlyprogressivedementia(RPD)isdistinguishedfromthemoretypicaldementiasbyasubacutetimecourseandan
acceleratedrateofdeclinethatdevelopsinfewerthan2years.Furthermore,avarietyofunderlyingcausesmay
contributetoaRPDpresentation,includingneurodegenerative,autoimmune,infectious,andtoxicmetabolicprocesses.
ThemostconcerningdifferentialdiagnosisinanypatientpresentingwithRPDisJakobCreutzfeldtDisease(CJD),afatal
prionrelatedneurodegenerativeillness.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356774/

1/11

24/02/2016

TheEvaluationofRapidlyProgressiveDementia

Whereastheprognosisisrelativelywelldefinedforthechronicdementias,theprognosisinRPDisvariabledependingon
theunderlyingcauseofthesymptoms.Forinstance,infectiousorautoimmuneprocessesmaybeslowedorreversedwith
appropriatetreatmentwhereasaneurodegenerativeconditionsuchasCJDmayleadtorapidprogressiontodeathwithin
6monthstime.IdentificationofareversibleRPDisparticularlyimportantconsideringthatdelayintreatmentmayleadto
permanentfunctionalimpairmentordeath.
Thus,thetaskoftheclinicianevaluatingRPDisdistinguishinganirreversibleneurodegenerativeprocesssuchasCJD
frompotentiallyreversibleprocessessuchasparaneoplasticdisease(PND)orHashimotosEncephalitis(HE).Dueto
thebroaddifferentialdiagnosisthatmayleadtoaRPDpresentation,theclinicalevaluationrequiresamoreextensive
diagnosticworkupcomparedtotypicaldementias,involvingacomprehensivehistoryandphysicalexam,magnetic
resonanceimaging(MRI),electroencephalography(EEG),andcerebrospinalfluid(CSF)analysis.
Thepurposeofthisreviewistoprovideinsightintothedifferentialdiagnosis,clinicalapproach,andpotentialtreatments
forRPD.ThereisparticularemphasisonCJD,oneofthemostcommoncausesofRPD.
PrionDiseasePresentingasCJD
JakobCreutzfeldtDisease(CJD) CJDisdividedintosporadicCJD(sCJD),familialCJD(fCJD),andvariantCJD

(vCJD).sCJDisbythefarthemostcommonvariation,occurringin85%ofpatientswithCJD.GeneticCJD,definedas
priondiseasesassociatedwithanunderlyingmutationoftheprionproteingene(PRNP)onchromosome20,occursin
approximately1015%ofpriondiseasewhereasvCJDaccountsfor1%ofcases1.
sCJDusuallypresentsbetweentheagesof50and702.sCJDcarriesoneofthegravestprognoseswithinthefieldof
neurologywithamediansurvivalof5monthsand85%ofpatientsdyingwithin1yearofonset2.InWesterncountries,
CJDoccursatarateof12million/year1.
VariantCJD(vCJD)isanacquiredpriondiseasethatpredominantlyaffectsyoungadultswithameanageof29years
andarangefrom1274years.vCJDoftenpresentswithapsychiatricprodromelastingmorethan6months,and
frequently,thesepatientsmaybemisdiagnosedashavingaprimarypsychiatricillness.SimilarlytosCJD,patientspresent
withacombinationofneurologicalsignsincludingataxia,cognitiveimpairment,andextrapyramidalmotorfindings.
NeuroimagingischaracterizedbythepulvinarsignonMRIdemonstratinghyperintensitiesaffectingthepulvinarnucleus
onT2andFLAIRsequences3.
FamilialgeneticCJDisinheritedinanautosomaldominantfashionandresultsfrompointmutationsandinsertions
affectingPRNP4,5.ThemostcommonmutationisapointmutationaffectingE220K4.InsertionsinPRNP,suchas
ins24bp,leadtorepeatedexpansionsinwhichtherepeatnumberandsizeoftheinsertiondirectlycorrelateswithclinical
phenotypeandseverity(asinHuntingtonsdisease).4Otherinheritedformsofpriondiseaseincludefatalfamilialinsomnia
(FFI),characterizedbyprogressivesleepandautonomicdisturbances,andGerstmannStrauusslerScheinkerdisease
(GSS),whichpresentsasaprogressivecerebellarataxia.
SporadicCJDcanhaveavarietyofpresentationsthatresultincognitive,behavioral,sensory,ormotordysfunction.The
diseasehasbeendescribedasagreatmimicker,compromisingcortical,extrapyramidal,andcerebellarfunction.The
accuracyofdiagnosingCJDcanbequitevariable.Approximately,1520%ofRPDreferralsforsuspectedCJDarea
resultofnonprioncauses.6
Whenperformingtheclinicalinterview,theclinicianshouldinquireaboutinitialsymptomsasthisinformationmaybe
diagnosticallyrelevantintermsoffunctionallocalization.ThemostcommoninitialsymptomsinsCJDincludecognitive
(39%),cerebellar(21%),behavioral(20%),consititutional(20%),sensory(11%),motor(9%),andvisual(7%).7.
TheWorldHealthOrganization(WHO)(seetable1)hasdefinedcriteriabasedonclinicalsymptomsforpossible,
probable,anddefiniteCJD.1ThediagnosisofdefiniteCJDrequireseitherpathologicalconfirmation(byautopsyor
biopsy)ordemonstrationofthediseasecausingformoftheprionprotein.1
Table1
CriteriaforProbableSporadicJakobCreutzfeldtDisease(WHO1998)

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356774/

2/11

24/02/2016

TheEvaluationofRapidlyProgressiveDementia

InordertomeettheWorldHealthOrganization(WHO)criteriaforprobableCJD,patientsmusthaveeitheran
electroencephalogram(EEG)positiveforperiodicepileptiformdishargesorpositive1433proteinaswell2ofthe
followingsymptoms:1.myoclonus,2.pyramidal/extrapyramidalfindings,3.visualorcerebellardeficits,or4.akinetic
mutism.Furthermore,routineinvestigationsshouldnotsuggestanalternativediagnosis.
Unfortunately,thecriteriaforprobableCJDsufferfrombothalackofsensitivityandspecificity.Akineticmutismandan
EEGshowingperiodicepileptiformdischargesareclinicalfeaturesthatcharacterizethelaterstagesofCJD.Furthermore,
thecriteriafailtoincludesignsofcorticaldysfunctionsuchasaphasia,apraxia,andalienlimbphenomenon.Themotor
signsofmyoclonus,parkinsonism,cerebellarataxia,and/orspasticitylackspecificityandcanbefoundinavarietyof
otherneurodegenerativeprocesses.Forinstance,myoclonuswithextrapyramidalfindingsisseenin70%ofDLBpatients
and50%ofADpatients.8
AllpatientswithsuspectedCJDshouldundergospinalfluidanalysis,EEG,andmagneticresonanceimaging(MRI)ofthe
brain.
Thetypicalcerebrospinalfluid(CSF)profileinapatientwithCJDshowsamildlyelevatedproteinandnormalglucose
withoutleukocytosis.2Anysignsofinflammationmaybeindicativeofanautoimmunemediatedencephalopathy.1433
(Gambetti)protein,tau,andneuronspecificenolase(NSE)areallrecognizedCSFbiomarkersforCJD.Despiteroutine
assessmentof1433proteinlevelsinthesepatients,recentstudieshaveshowedthatthisbiomarkerhaslimited
sensitivity.Inacohortof32pathologicallyconfirmedcases,only17(53%)showedelevatedCSF1433protein
levels.9Unfortunately,the1433protein,tau,andNSEareallindirectindicatorsofneuronalinjuryandfailtoaddress
theunderlyingneedforaprionspecificbiomarker.
EEGisausefuldiagnostictoolforlookingatcorticalirritabilityinthispatientpopulation.Studiesinpatientsduringthe
earlystagesofthediseasemayshowfocalordiffuseslowingandonlyinthelaterstagesoftheillnesswillthe
characteristic12Hzperiodicsharpwavesbepresent.However,suchfindingsmayalsooccurinDLBandHE2.The
sensitivityandspecificityofEEGforCJDisvariable,rangingfrom5066%and7491%respectively.2
RecentliteraturehasshownbrainMRItobearelativelysensitiveandspecificdiagnostictoolforCJD.Themostuseful
sequencesincludefluidattenuatedinversionrecovery(FLAIR),diffusionweightedimaging(DWI),andapparentdiffusion
coefficient(ADC).Inastudyof26patients,thedetectionofDWIhyperintensitieswithinthecorticalandsubcorticalgray
matterwas92.3%sensitiveand93.8%specificandconsideredsuperiortobothEEG,NSEand1433proteininthe
detectionofsCJD.10Inanotherneuroimagingstudy,twoneuroradiologists,blindedtodiagnosis,retrospectively
evaluatedDWIandFLAIRimagesfrom40patientswithprobableordefiniteCJDand53controlsubjectswithother
formsofdementiaandratedthelikelihoodofCJDonthebasisoftheimagingfindings.TheuseofbothDWIandFLAIR
sequenceswas91%sensitiveand95%specificforCJD.Furthermore,hyperintensitiesinthesesequenceswasmost
commonlyfoundintheneocortexand/ordeepgraymatter(thalamus,striatum,orboth)11.Thus,thetypicalMRIfindings
inapatientwithsCJDincludeFLAIRandDWIhyperintensitiesinvolvingcorticalandsubcorticalstructures.Recent
workhasshownthatthepresenceofacorrespondingapparentdiffusioncoefficient(ADC)hypointensityisfurther
supportiveofsCJD.Ofnote,patientswithsCJDrarelypresentwithpredominatlysubcorticalinvolvement.Whilethe
presenceofcorticalDWIhyperintensitieshasahighsensitivityforCJD,itshouldbenotedthatsuchfindingsmaybe
presentinotherconditionssuchasvasculitisorseizures.
ThemechanismbehindincreasedcorticalandsubcorticalDWIsignalmayberelatedtovacuolation.Acasestudy
involvingapatientwhounderwentMRIimaging15dayspriortodeathandwassubsequentlyautopsiedshowedthatthe
DWIhyperintensitiescorrelatedbestwithvacuolation(r=0.78P=0.0005),followedbyPrPload(r=0.77P=0.0006),
andastrogliosis(r=0.63P=0.0008).12.
ThediagnosisofdefiniteCJDrequirespathologicalconfirmationbybrainbiopsyorautopsy.ConfirmationofCJDby
biopsypresentsadifficultchallengefromaninfectiousdiseasestandpointgiventhatprionproteinsarenotremovedby
standardsurgicalsterilizationmethods.1
Grossexaminationofthebrainusuallyshowsdiffuseatrophywithoutanyfurtherspecificfindings.Therearethree
histologicalfeaturesthatcharacterizeCJDthatinclude1.)neuronalloss(particularlyincorticallayersIIIV)2)
Spongiformchangeand3)accumulationofabnormalprionprotein.1ThespongiformchangeinCJDischaracterizedby
round,2050micronsizedvacuoleslocatedwithinneurons.WhilespongiformchangesaremostcommonlyseeninCJD,
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356774/

3/11

24/02/2016

TheEvaluationofRapidlyProgressiveDementia

thishistologicalfindingisbynomeansuniquetopriondiseaseandcanbefoundinDLB,hypoxicischemic
encephalopathy,andfrontotemporaldementia.1
Demonstrationofthepresenceofabnormalprionproteinbyimmunohistochemistryisanotherkeyelementinthe
neuropathologicalconfirmationofCJD.Theprionproteinhasavarietyofdistributionsincludingperivacuolar,diffuse
synaptic,andplaquearrangements.TheplaqueconfirmationismostcommonlyseeninvCJD,Kuru,andGerstmann
StrasslerScheinkersyndrome.1
ChronicNeurodegenerativeDiseasesPresentingasRPD

AttheUCSFRPDunit,neurodegenerativedisease(nonprionrelated)wasresponsiblefor14.6%ofallpatientsreferred
forsuspectedCJDandrepresented39%ofthenonprioncases.2.Furthermore,aretrospectivestudyof22patients
diagnosedwithRPDshowedthat23%ofthecasesconsistedoffrontotemporaldementiamotorneurondisease(FTD
MND),18%consistedofeithercorticobasaldegeneration(CBD)orprogressivesupranuclearpalsy(PSP),14%
consistedofdementiawithLewybodies(DLB),and9%consistedofAlzheimersdisease(AD).13.
Possiblefactorsrelatingtothemisdiagnosisofthesetypicallychronicdementiasincludeatypicaltimecourseand
multisystemneurologicalfindings.Forinstance,patientswithFTDMNDweremostcommonlymisdiagnosedwithCJD,
andthisdiseaseprogressesrelativelyrapidlywithanaveragesurvivalof2.3yearsfromdiagnosis.14.Inaddition,these
patientsmaypresentwithdiffusesymptomsaffectingcognitive,bulbarfunction,andmotorfunction,acombinationthat
canbeseeninCJD.Typically,chronicdementiassuchasCBDandDLBmayoccasionallypresentwithanaccelerated
timecourseaswellaswithmyoclonusandextrapyramidalfindings,bothofwhicharecommonsignsinCJD.Whenever
consideringaRPDdiagnosisinapatientsufferingfromachronicdementia,itisimportanttokeepinmindthatsuch
patientsaremoresusceptibletometabolicandinfectiousdisturbances.Forinstance,therapidlydeterioratingADpatient
inthesettingofaUTIordehydrationmaybemisinterpretedassufferingfromaRPD.
NonprionneurodegenerativediseaseisfrequentlyadiagnosisofexclusionandrequirescomprehensiveserumandCSF
analysesandneuroimagingtoruleoutvascular,toxicmetabolic,infectious,andinflammatoryconditions.Forreasons
mentionedabove,CSFbiomarkers(1433protein,tau,NSE)andEEGfindingsofperiodicspikeandwavedischarges
mayoccurinanydiseasethatresultsinrapidcorticalinjury,andpositivefindingsarenotconclusiveevidenceforCJD.
Theclinicianshouldfirstconfirmtheabsenceofametabolicorinfectiousprocesssuperimposeduponthe
neurodegenerativedisease.Thus,ametabolicpanellookingatelectrolytes,BUN,creatinine,andliverfunctiontestsis
essential.Mentalstatuschangemaybetheonlysignofinfectioninthedementedpopulation,andthus,ascreenfor
pneumonia(chestxray)andurinarytractinfection(urineanalysisandculture)isessential.Finally,athoroughreviewof
centrallyactingmedications,includingnonprescriptiondrugs,mayprovidecluesintocontributingfactorstoabrupt
changesinmentalstatus.
NeuroimagingishelpfulindistinguishingprionrelatedfromnonprionrelatedRPD.Firstofall,CJDistheonly
neurodegenerativeconditionresultinginDWIandFLAIRhyperintensities,andtheabsenceofthesefindingsissuggestive
ofanonprionrelatedprocess.Furthermore,theassessmentofatrophypatternsonMRIcandistinguishvariouscauses
ofdementia.Recentworkhasshownthateachneurodegenerativesyndromeisassociatedwithatrophywithinaspecific
intrinsicfunctionalconnectivitynetwork.15Thus,definedstructuresareinherentlymoresusceptiblefordifferent
neurodegenerativediseases.Forexample,ADpatientswilltypicallyhaveatrophyinvolvinghippocampal,precuneus,and
posteriorcingulatestructures.Ontheotherhand,apatientwithCBDwillhaveanatrophypatterninvolvingdorsal
frontalparietalnetworks.
ImmuneMediatedDementiasPresentingasRPD
LimbicEncephalitis Limbicencephalitis(LE)isaninfectiousandautoimmuneprocessthepredominantlyinvolvesthe
anteromedialtemporalcortex,hippocampus,andamygdalaandoccasionallythehypothalamusandinsularcortex.16For

thepurposesofthisreview,wewillbediscussinginflammatorycausesofLE.Inflammatorycausesoflimbicencephalitis
includeparaneoplastic(PNS)LEandantivoltagegatedpotassiumchannelassociatedencephalopathy(VGKCE),both
ofwhicharecharacterizedbyamoresubacutetimecourse.
PNSisaninflammatorygroupofconditionsthatresultinantibodiesproducedwithintheCSFandserumresultinginfocal
neurologicalsymptoms.17,18Theseantibodiesreactagainstproteinsexpressedbythetumorandwillprecedethe
16

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356774/

4/11

24/02/2016

TheEvaluationofRapidlyProgressiveDementia

neoplasmin70%ofcases.16Patientswithparaneoplasticantibodiesagainstcellsurfaceantigensgenerallyhaveabetter
prognosisthanpatientsproducingintraneuronalantibodies.19Themostcommonparaneoplasticantibodiesassociated
withcognitiveandbehavioralsymptomsincludeantiHu,CV2,Ma2,andVGKCantibodies,whichmayormaynotbe
associatedwithanunderlyingtumor.Ofalltheparaneoplasticantibodies,antiHuismostcommonlyassociatedwith
limbicencephalitisandismostfrequentlyfoundinpatientswithsmallcelllungcancer(SCLC).18.Thesepatients
frequentlyhaveahistoryofsmoking.OthersyndromesassociatedwithHuantibodiesincludecerebellardegeneration,
myelitis,sensoryneuronopathy,epilepsiapartialiscontinua,andcentralhypoventilationsyndrome20.CV2antibody(also
referredtoasanticollapsinresponsemediatedprotein5[CRMP5])isfoundinpatientssufferingfromeitherSCLCor
thymoma.InadditiontoLE,CV2antibodyisassociatedwithcerebellardegeneration,uveitis,chorea,opticneuropathy,
myelitis,andperipheralneuropathy.18AntiMa2isassociatedwithtesticulargermcelltumors,breastcancer,andnon
smallcelllungcancerandfrequentlyreactsagainstlimbic,diencephalic,andbrainstemstructures.21.Common
presentationsinadditiontocognitiveandbehavioralchangesincludeverticalgazepalsy,limbrigidity,hypokinesis,and
orofacialdystonia.21,22.Furthermore,thesepatientstendtodevelopsleepdisorderssuchasdaytimesomnolence,
narcolepsy,andREMsleepdisorder.Ma2antibodysyndromeisrelativelyresponsivetotreatmentwith30%ofpatients
experiencingresolutionofsymptomsfollowingorchiectomy,immunotherapy(corticosteroidsandIVIG),and
chemotherapy.21AmorerecentlydescribedPNSresultinginreversibleLEhasbeenassociatedwithantibodiestothe
alpaamino3hydroxy5methyl4isoxazolepropionicacidreceptor(AMPAR)andisfurthercharacterizedby
confusion,hypersomnia,visualhallucinations,andcombativenessinpatientswithbreastadenocarcinoma.23
VGKCEresultsinalimbicencephalitisthroughtheproductionofantivoltagegatedpotassiumchannelantibodiesthat
reactagainstthemolecularlayerofthehippocampus.24Voltagegatedpotassiumchannelautoantibodieshavebeen
reportedinacquiredneuromyotonia,Morvanssyndrome,andautoimmunedysautonomia.2527Thereisatemporal
relationshipbetweenadropinantibodylevelsandclinicalimprovement.Thepresenceofhyponatremiaisfrequently
foundinVGKCEpatientsandaidsinthediscriminationofthisdiseasefromothercausesofLE.
Duetoinvolvementoflimbicstructuressuchasthehippocampusandparahippocampalcortex,patientstypicallypresent
withshorttermmemoryloss.Othercognitiveandbehavioralsymptomssuchasexecutivedysfunction,personality
changes,panicattacks,delusions,andhallucinationshavebeendescribed.28,29Furthermore,patientswithLEfrequently
sufferfromgeneralizedtonicclonicseizures,apossibleresultofanisolatedhippocampallesion.
Duetotherapidlyprogressivecoursecombinedwiththeabruptonsetofcognitive/behavioralimpairment,thiscondition
maypresentsimilarlytoCJD,andshouldalwaysbeconsideredinthedifferentialofRPD.Acaseseriesshowedthat15
patientswereerroneouslygivenadiagnosisofCJD,butweresubsequentlyfoundtohaveelevatedVGKCantibodies28.
SixtypercentofpatientssatisfiedtheWHOdiagnosticcriteriaforCJD.30Furthermore,onepatientsMRIshowed
increasedDWIandFLAIRsignalinvolvingextralimbicstructuressuchastheanteriorcingulategyrusandinsula,which
wouldbemorecharacteristicoffindingsinCJD30as94%ofpatientswithsporadicCJDshowedDWIhyperintensities
involvingthelimbiccortex.31Biopsyoftheaffectedregionwasnegativeforvacuolationorpriondeposition.Allpatients
presentedwithsubacuteshorttermmemorydeficitswithamajoritypresentingwithmyoclonus,seizures,andbehavioral
and/oraffectivedisturbances.
TheevaluationofLErequiresdistinguishingbetweeninfectiousandautoimmunecauses.AninfectiousLEistypically
associatedwithfever,elevatedwhitebloodcount,andnuchalrigidity.Suchgeneralizedsymptomswithaccompanying
encephalopathytypicallypromptspinalfluidanalysis.HSVencephalitiswillshowbothelevatedproteinandleukocytosis.
ThediagnosisisconfirmedbyHSVPCR,whichcarriesasensitivityof>90%.
AutoimmuneLErelatedtoPNSshowsarelativelymilderleukocytosiswithelevatedprotein.Dependingonthe
underlyingneoplasm,patientsmaymanifestelevatedHu,CV2,orMa2antibodiesinserumandCSF.Finally,patients
mayhaveregionsofincreasedglucoseuptakeonfullbodyPETscanorstructuraltumorsdetectedbyCTscanofthe
chest,abdomen,andpelvis.VGKCEmayormaynotbeassociatedwithanunderlyingthymoma.Thissyndromeis
distinguishedbycoexistinghyponatremiadetectedonserumchemistry.VGKCEisdefinedbyelevatedVGKC
antibodiesdetectedinserumorCSF.
ThetreatmentforautoimmuneLEfurthervariesdependingontheunderlyingcause.Inparaneoplasticdisease,the
hallmarkoftreatmentshouldfocusonaddressingtheunderlyingtumorresponsiblefortheparaneoplasticsyndrome.For
instance,theoptimalinterventionforapatientwithsmallcelllungcancerandantiHuLEshouldfocusonsurgicaland
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356774/

5/11

24/02/2016

TheEvaluationofRapidlyProgressiveDementia

chemotherapeutictreatmentforthetumor.
TreatmentforVGKCEwithoutanunderlyingtumorinvolvesimmunosuppressivetherapyconsistingofplasmaexchange
and/orIVIGfollowedbyoralcorticosteroids.Apriorcaseserieshasshownthatsomecombinationoftheseagents
resultedinvariablefallsofVGKCAbtovaluesbetween2and88%aswellasmarkedimprovementof
neuropsychologicalfunctioningin6patients,slightimprovementin3,andnoneinone.32
SteroidResponsiveorHashimotosEncephalopathy(SRE/HE/SREAT)

Goto:

Differentnames(HashimotosEncephalopathy(HE),SteroidResponsiveEncephalopathy(SRE),SteroidResponsive
EncephalopathyAssociatedwithAutoimmuneThyroiditis(SREAT))havebeenusedtorefertoaheterogeneous,sub
acutetochronicautoimmunerelated,encephalopathysyndromethatmaypresentasadementingdisorderassociated
withabnormallyhighlevelsofthyroidantibodiesandwhich,bydefinition,respondstotreatmentwithcorticosteroids,
plasmapheresisorimmunosuppressivetherapy.Hashimotosencephalitis,firstdescribedinasinglecaseofa48yearold
manwithhypothyroidism,elevatedthyroidantibodiesandrecurrentepisodesofstrokelikeencephalopathybyBrainet
al33isanencephalopathythatisassociatedwithalymphocyticthyroiditisandtypicallyinvolveswoman(85%of
cases).34Patientsmayhavecoexistingautoimmuneconditionssuchastype1diabetes,systemiclupuserythematosus,
andSjogrensdisease.Individualsmaybeeuthyroid,hyperthyroid,orhypothyroid,butthediagnosisofHEshouldonly
bemadeoncethepatienthasreturnedtoaeuthyroidstate.34WhileHEmaypresentwithamyriadofsymptoms
includingconfusionandcognitive,psychiatric,moodandbehavioralsymptoms,twomaintypesofpresentationshave
beenproposed:oneinvolvingarelapsingremittingcoursewithstrokelikeepisodes(2530%ofpatients)andasecond
consistingofinsidiousonsetofseizures(7080%ofpatients).34Othersymptomsincludetremor,myoclonus,visual
hallucinations,ataxia,headache,psychosis,andsleepdisturbance.34
ContrarytoCJD,theMRIfindingsinHEarerelativelynonspecificandvaryfromgeneralizedatrophy,periventricular
whitematterchanges,anddiffuseincreasedT2signalwithinsubcorticalandcorticalregions.34,35
Diagnosisinvolvestestingforelevatedantithyroidperoxidase(antiTPO)andthyroglobulin(antiTG)antibodies.TPO
antibodiesaremorefrequentlyelevatedthanTGantibodies.34,35Whileelevatedthyroidantibodiesinthesettingof
encephalopathyissuggestiveofHE,theclinicianshouldkeepinmindthatthyroidantibodylevelsmaybeelevatedinup
to10%ofthepopulation,andthepathogenicroleoftheseantibodiesinHEremainsunclear.36Furthermore,these
biomarkersarenonspecificforHEandmaybefoundinotherautoimmunediseasessuchasrheumatoidarthritis,type1
diabetes,andeveneuthyroidpatients3739Spinalfluidproteinisfrequentlyelevated(78%ofpatients).EEGmost
frequentlyshowsnonspecificdiffuseslowing,andtriphasicorperiodicsharpwavessuggestiveofCJDmayalsooccur.40
Inacaseseriesof6patientscomparedwith14patientsdescribedpreviouslyintheliterature,upto90%ofpatients
respondedfavorablytosomeformofimmunosuppressionthatmostcommonlyconsistedofhighdoseintravenous
corticosteroidsfollowedbyaslowtaperoforalprednisone.41Unfortunately,therearenocontrolledstudiesorevidence
basedguidelinesthatdefineindication,choiceofimmunosuppressiveagent,andtheoptimaldurationoftherapy.Atour
institution,werecommendgivingatrialofhighdosecorticosteroidstopatientswhopresentwithasignificantsubacute
deteriorationinmentalstatus,elevatedantithyroidantibodies,andinwhomotherextensiveclinicalandlaboratory
investigations(seeFigure5)havefailedtorevealalikelycause.Inadditionaltotheclinicalprofile,othernonspecific
findingsthataresupportiveofHEincludethyroidabnormalities(e.g.elevatedTSH),elevatedESRorhsCRP,mildly
inflammatoryCSF(noninfectiousandnonneoplastic),mildormoderate(relativetoageandcerebrovascularrisk
factors)T2subcorticalwhitematterhyperintensitiesonbrainMRIwithminimalatrophy,andabnormalEEGfindings
includingslowing(generalizedorfocal)andsharpwaves(oftenbifrontalorbitemporal).Dependingontheindividuals
riskbenefitprofile,weusuallybegintreatmentwith1gramIVSolumedrolfor35daysfollowedbyaprednisonetaper
(startingat60mg).InitialsteroidtapershouldbeslowaspatientswithHEmayexperiencefrequentrelapseswithsteroid
withdrawal.Patientswhoremainasymptomaticdonotrequireongoingtreatmentwithimmunosuppressiveagents.
However,incasesofrecurrentorsevererelapsesasdemonstratedbyworseningsymptomsandobjectivefindingson
neuropsychologicalorclinicaltests,patientsmayrequiremorefrequentandrepeatedsteroidinfusions(eg.every36
months)andtheadditionoffurtherimmunosuppression.Acasestudyhassuggestedthatplasmapharesismayalsobean
effectivetreatmentinpatientswithsuboptimalresponsetosteroids42.Inmanycases,abnormallaboratoryfindings,
includingveryhighlevelsofantithyroidantibodies,EEG,andinflammatoryCSFandserummaynormalize(or
substantiallyimprove)afterclinicalresponsetotreatment.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356774/

6/11

24/02/2016

TheEvaluationofRapidlyProgressiveDementia

ApproachtotheEvaluationofRPD

AvarietyofetiologiesmayresultinRPD(seetable2).TheevaluationofanyRPDpresentationrequiresacombinationof
history,neurologicalexam,neuroimaging,andspinalfluidanalysis.
Table2
DifferentialDiagnosisofRPD

Step1:TheHistory TheworkupofeachRPDpresentationbeginswithacomprehensivehistoryfocusingonthetime

course,natureofsymptoms,andpotentialcontributingfactors.
Firstly,itisimportanttoassessthepatientspremorbidbaselineandeducationalhistory.Asinanydiseaseprocess
resultingincognitivesymptoms,asupplementaryhistoryfromareliableinformantsuchasafriendorfamilymemberis
critical.Suchprecautionsarehelpfulinavoidinghistoricalinconsistenciesregardingtimecourseandprogression,which
arenecessaryfordistinguishinganatypicalfromatypicaldementia.
RPDshouldbesuspectedinanypatientpresentingwithdeteriorationofcognitivefunctioninfewerthan2years.In
addition,thecourseofthediseasemayprovidefurthercluestoanunderlyingcause.Forexample,Hashimotos
EncephalopathymayhavearelapsingremittingcoursewithstrokelikesymptomswhereasthecourseofsCJDis
fulminant,leadingtodeathwithin1yearstimein85%ofpatients.
Thequalityofsymptomsmayprovidefurtherinsightsintopossibleunderlyingdiseaseprocesses.Giventhatallpatients
withRPDhaveprimarycognitiveorbehavioraldysfunction,adetailedhistoryoftheaffectedcognitivemodality,
specificallymemory,executivefunction,language,orvisuospatialabilitymayhelpnarrowthedifferentialdiagnosis.In
addition,patientswithRPDfrequentlycomplainofmotordysfunctionandinquiriesshouldbemadetodeterminewhether
theproblemisrelatedtocorticospinaltract,basalganglia,orcerebellardisease.
ConsiderationofpotentialcontributingfactorsandsystemicsymptomsisespeciallyhelpfulforreversiblecausesofRPD.
Assessmentoftoxicexposuresisaparticularlyhelpfulpartofthehistory.Theclinicianshouldaskaboutalcoholor
recreationaldruguse.Furthermore,centrallyactingmedicationsespeciallythoselistedunderBeersList(defines
medicationsthataregenerallyconsideredinappropriateintheelderly)mayresultinacutesubacutementalstatus
changes.43Anticholinergicagentscommonlyprescribedforurinarycomplaintssuchastolterodinehavebeenshownto
resultinsubacute,reversiblehallucinationsandverbalmemoryimpairment.44Evenoverthecountermedicationssuchas
PeptolBismolcancauseaclinicalpresentationofapathy,myoclonus,dysarthria,confusion,andseizuresresemblingCJD
throughbismuthpoisoning4.AconsiderationofundiagnosedneoplasmisimportantwhenconsideringpotentialPNSand
inquiriesshouldbemaderegardingtobaccouseandweightloss.Smallcelllungcancer,thymoma,andbreast,ovarian,
andtesticularcancershavebeenassociatedwithcentrallyactingparaneoplasticantibodies.Patientswithceliacdisease
andWhipplesdiseasemaypresentwithamalabsorptionsyndromepriortodevelopmentofcognitivesymptoms.Finally,
sleepimpairmentisacontributingfactortocognitiveimpairmentandintheappropriatecontext,theclinicianshould
inquireintosymptomsofsleepapneaandsimilardisturbances.Acomprehensivefamilyhistoryisimportantforrulingout
potentialinheritedcausesofRPDsuchasfCJD,HD,mitochondrialencephalopathy,andleukoencephalopathy.
Constructingafamilytreeisausefulaidfordeterminingthepatternofinheritance(eg.autosomalrecessive,autosomal
dominant,Xlinked).
Finally,inquiryintothedegreeoffunctionalimpairmentwithregardstoactivitiesofdailyliving(takingmedications,doing
thefinancesbathing,dressing,etc)ishelpfulforanappreciatingtheseverityofthecognitiveandbehavioral
consequences.Thefunctionalassessmentquestionnaire(FAQ)isaquicksurveyassessingbasicdailyfunctionsthatcan
becompletedwiththeassistanceofacaregiver.45
TheneurologicalexamservesasthesecondstepintheevaluationofRPD.Patientswith
CJDfrequentlyhavecorticalrelateddeficitsincludingapraxia,aphasia,orneglectdependingonthecorticalregion
affectedbythepriondisease.ObservationofaffectisimportantasmultiplediseasesassociatedwithRPDincludingCJD,
VGKCE,FTDMND,antiNMDAparaneoplasticdisease,syphilis,etcmaybeassociatedwithdepression,anxiety,
apathy,and/orhallucinations.Theneuropsychiatricinventory(NPI)servesasameansofquantifyingneuropsychiatricand
behavioralsymptoms.ThecranialnerveexammayshowoculomotorabnormalitiessuggestiveofPSPorCBD.A
Step2:TheNeurologicalExam

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356774/

7/11

24/02/2016

TheEvaluationofRapidlyProgressiveDementia

funduscopicexamshouldbeperformedtoruleoutincreasedintracranialpressure.Importantinitialmotorobservations
includerestingasterixis,afindinginmetabolicencephalopathy,andmyoclonus(withorwithoutstartle),whichis
commonlyfoundinvariousneurodegenerativeconditionsuchasCBD,DLB,orCJD.Extrapyramidalsignsincluding
restingtremor,cogwheelrigidity,dystoniaandbradykinesiacanbefoundinbothmetabolic(ie.WilsonsDisease)aswell
asneurodegenerative(ie.CJD,DLB,PSP,CBD)lesionsinvolvingthebasalganglia.
PatientswithRPDwillfrequentlyhaveprominentfrontalreleasesigns(eg.grasp,palmomentalis,rooting,snout,andsuck
Myersonssignmaybefoundinfrontalorextrapyramidaldisease).Consequently,theelicitationoftheBabinskireflex
maybecomplicatedbyalowerextremitygrasp,andthus,alternativetechniquessuchastheChaddock(irritationofthe
skinattheanklejointaroundthemalleolus)andOppenheim(strokingdownwardonthemedialtibia)arerecommended
forassessingpathologicaltoeextension.
IntheevaluationofRPD,neuropsychologicaltestingshouldbeconsideredanextensionoftheneurologicalexam.Insuch
cases,itisrecommendedthatformalneuropsychologicaltestingbeperformedtoassessmemory,executivefunction,
language,andvisuospatialfunction.Theneuropsychologicaltestingwillservetosubstantiatethemedicalhistory,aidin
neuroanatomicallocalization,andnarrowthedifferentialdiagnosis.Ifformaltestingisnotpossible,werecommendan
expeditedcognitiveassessmentusingtheMontrealCognitiveAssessment(MOCA).46
Step3:DiagnosticStudies Serumchemistryandhematologicalstudiesareahelpfulfirststepforrulingoutreversible

causesofencephalopathy.Dramaticshiftsinelectrolytessuchaswithsodium(hyperorhyponatremia)andglucose
(hyperorhypoglycemia)canresultinsuddenmentalstatuschanges.Furthermore,anelevatedwhitebloodcellcountmay
beaharbingerofasystemicinflammatoryprocess.AreversibledementiapanelincludingTSH,vitaminB12,
homocysteine,methylmalonicacid,andurineanalysis/cultureareallusefultolookforcontributingfactorstoapatients
dementia.AnRPRisnotroutinelyorderedinpatientswithsuspecteddementia,butishelpfulforanyatypical
presentationsofcognitiveimpairment.Ifahepaticencephalopathyissuspected,itisrecommendedtocheckaserum
ammonia.ParaneoplasticantibodiesincludingantiVGKCshouldbeorderedbasedontheclinicalpresentationandcan
beobtainedfromeithertheserumorCSF
OneofthemostimportantstepsinevaluatingRPDisthespinaltapandcerebrospinalfluidanalysis.Thisdiagnostictest
notonlyprovidesinitialdataabouttheinflammatorynatureofthediseaseprocess,butalsoallowsforthemeasurementof
variousCSFbiomarkersrelatingtoneuronalinjuryorinfectiousdisease.Anopeningpressureshouldalwaysbe
measuredtoaddressthepotentialforelevatedintracranialpressure.InflammatorymarkersincludeCSFprotein,
leukocytecount,CSFIgG(tobecomparedwithserumIgGforanIgGindex),andoligoclonalbands,allofwhichmay
beelevatedineitherautoimmuneorinfectiousdisease.TheCSFprovidesinfectiousdiseasemarkersincludingbacterial
gramstainandculture,fungalculture,acidfastbacilli(AFB)staining,VDRL,andWhipplesPCR.Oneoftheimportant
CSFlaboratorystudiesincludes1433protein,neuronalspecificenolase(NSE),andtau,allofwhicharebiomarkersof
neuronalinjury.AnelevatedCSFpyruvateandlactatearesuggestiveofmitochondrialdisease.Finally,aCSFsample
maybehelpfulforinvestigatinganeoplasticprocesssuchaslymphomainwhichabnormalcellscanbemeasuredthrough
cytologyandflowcytometry.
BrainMRIimaging,adiagnosticinterventionthatwillprovidefurtherinformationregardingvascular,infectious,
autoimmune,andneurodegenerativeprocesses,isrecommendedforallpatientspresentingwithRPD.Anypatient
suspectedofhavingavascularrelatedRPDsecondarytoischemicstrokeshouldhaveaccompanyingvascularimaging
eitherthroughmagneticresonanceangiography(MRA)orCTangiography.Expectedfindingsinthesepatientsinclude
focalhyperintensitiesthatobeyavasculardistributiononT2,FLAIR,andDWIsequences.MRIshowingfocalmedial
temporallobeT2andFLAIRhyperintensitesmayindicatealimbicencephalitis,whichhasbothautoimmune(anti
VGKCEandparaneoplasticdisease)andinfectiouscauses.Occasionally,theneuroimagingmayonlyshownonspecific
whitematterhyperintensities,whichisfrequentlythecaseinHashimotosEncephalopathy.InCJD,patientshave
characteristicDWI,FLAIR,andADCfindingsinbothsubcorticalandcorticalregions.Finally,aCNSlymphomamay
manifestitselfeitherasamassoccupyinglesionorasdiffusewhitematterdiseaseandshouldalwaysbeevaluatedwith
andwithoutIVcontrast.
Electroencephalography(EEG)isadiagnostictoolwithhightemporalresolutionthatishelpfulindeterminingthefocality
ofalesionsandassessingthepresenceofcorticalirritability.EEGisparticularlyhelpfulinthepatientwhomayhave
subacutecognitiveimpairmentrelatedtofocalepilepsyorcomplexpartialseizures.Thismethodisusefulforuncoveringa
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356774/

8/11

24/02/2016

TheEvaluationofRapidlyProgressiveDementia

hepaticencephalopathythroughthedemonstrationoftriphasicwavesorthecharacteristicfindingofthe1Hzspikeand
wavepatternassociatedwithCJD.Ofnote,nonspecificthetaanddeltaslowingonEEGcanbefoundinearlyCJDas
wellasintheotherneurodegenerativediseases.
Finally,brainFDGPETisanadditionalfunctionalimagingmodalitythatmayfurtherhelpnarrowthedifferential
diagnosis.Thisimagingisparticularlyusefulfordistinguishingafrontalanteriorprocessfromatemporoparietalposterior
process.Additionally,thepresenceofregionalPETbrainhypometabolisminapatientsuspectedofmalingeringishelpful
forconfirminganorganicillness.
Step5:BrainBiopsy Inextremecaseswherediagnosiscannotbeconfirmedbyhistory,exam,neuroimaging,

electrophysiologicalstudies,orspinalfluidanalysis,abrainbiopsymaybeindicatedtodeterminetheetiology,whetherit
beneurodegenerative,neoplastic,inflammatory,orinfectious.
Conclusion

Duetotheirrelativelyinfrequentincidenceandthesudden,diffuseonsetofsymptoms,therapidlyprogressivedementias
representoneofthemostchallenginggroupsofdiseasesfacingtheneurologist.Consequently,diagnosticevaluationof
anypatientwithRPDistypicallymorecomprehensivethanwithchronicneurodegenerativeconditionssuchasAD.The
overwhelminglybroaddifferentialrequiresthecliniciantotakeastandardizedmethodtoanypatientpresentingwiththe
rapidonsetofdementingsymptoms.Suchanapproachwillenablethecliniciantoefficientlydiagnosepotentiallytreatable
conditionssuchasHashimotosEncephalopathy,antivoltagegatedencephalopathy,andparaneoplasticlimbic
encephalitisanddistinguishtheseconditionsfromdiseasessuchasCJD,whichcarryamoregraveprognosis.Increased
awarenessoftheRPDsthroughouttheprimarycare,geriatrician,andneurologistcommunitiesshouldfostermoreefficient
diagnosticandtreatmentstrategiesforthiscomplexsetofdisorders.
Acknowledgments

Goto:

SourcesofSupport:
GeriatricResearchEducationandClinicalCenterFellowship
PIATRI:NIAK23AG0217
References

Goto:

1.MillerBBB,editor.TheBehavioralNeurologyofDementia.1.Cambridge,UK:CambridgeUniversityPress2009.
2.GeschwindMD,ShuH,HamanA,SejvarJJ,MillerBL.Rapidlyprogressivedementia.AnnNeurol.2008
Jul64(1):97108.[PMCfreearticle][PubMed]
3.ZeidlerM,SellarRJ,CollieDA,etal.ThepulvinarsignonmagneticresonanceimaginginvariantCreutzfeldtJakob
disease.Lancet.2000355(9213):14121418.[PubMed]
4.KnightRS,WillRG.Priondiseases.JNeurolNeurosurgPsychiatry.2004Mar75(Suppl1):i3642.
[PMCfreearticle][PubMed]
5.GambettiP,KongQ,ZouW,ParchiP,ChenSG.SporadicandfamilialCJD:classificationandcharacterisation.Br
MedBull.200366:213239.[PubMed]
6.GeschwindMD,HamanA,MillerBL.RapidlyProgressiveDementia.NeurolClin.200725(3):783807.
[PMCfreearticle][PubMed]
7.RabinoviciGD,WangPN,LevinJ,etal.FirstsymptominsporadicCreutzfeldtJakobdisease.Neurology.2006Jan
2466(2):286287.[PubMed]
8.TschampaHJ,SchulzSchaefferW,WiltfangJ,etal.DecreasedCSFamyloidbeta42andnormaltaulevelsin
dementiawithLewybodies.Neurology.2001Feb2756(4):576.[PubMed]
9.GeschwindMD,MartindaleJ,MillerD,etal.Challengingtheclinicalutilityofthe1433proteinforthediagnosisof
sporadicCreutzfeldtJakobdisease.ArchNeurol.2003Jun60(6):813816.[PubMed]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356774/

9/11

24/02/2016

TheEvaluationofRapidlyProgressiveDementia

10.ShigaY,MiyazawaK,SatoS,etal.DiffusionweightedMRIabnormalitiesasanearlydiagnosticmarkerfor
CreutzfeldtJakobdisease.Neurology.2004I63:443449.[PubMed]
11.YoungGS,GeschwindMD,FischbeinNJ,etal.Diffusionweightedandfluidattenuatedinversionrecoveryimaging
inCreutzfeldtJakobdisease:highsensitivityandspecificityfordiagnosis.AJNRAmJNeuroradiol.2005Jun
Jul26(6):15511562.[PubMed]
12.GeschwindMD,PotterCA,SattavatM,etal.CorrelatingDWIMRIwithpathologicandotherfeaturesofJakob
Creutzfeldtdisease.AlzheimerDisAssocDisord.2009JanMar23(1):8287.[PMCfreearticle][PubMed]
13.JosephsKA,AhlskogJE,ParisiJE,etal.Rapidlyprogressiveneurodegenerativedementias.ArchNeurol.2009
Feb66(2):201207.[PMCfreearticle][PubMed]
14.JosephsKA,KnopmanDS,WhitwellJL,etal.Survivalintwovariantsoftaunegativefrontotemporallobar
degeneration:FTLDUvsFTLDMND.Neurology.2005Aug2365(4):645647.[PubMed]
15.SeeleyWW,CrawfordRK,ZhouJ,MillerBL,GreiciusMD.Neurodegenerativediseasestargetlargescalehuman
brainnetworks.Neuron.2009Apr1662(1):4252.[PMCfreearticle][PubMed]
16.LawnND,WestmorelandBF,KielyMJ,LennonVA,VerninoS.Clinical,magneticresonanceimaging,and
electroencephalographicfindingsinparaneoplasticlimbicencephalitis.MayoClinProc.2003Nov78(11):13631368.
[PubMed]
17.PittockSJ,KryzerTJ,LennonVA.Paraneoplasticantibodiescoexistandpredictcancer,notneurologicalsyndrome.
AnnNeurol.2004Nov56(5):715719.[PubMed]
18.DalmauJ,RosenfeldMR.ParaneoplasticsyndromesoftheCNS.LancetNeurol.2008Apr7(4):327340.
[PMCfreearticle][PubMed]
19.BatallerL,KleopaKA,WuGF,RossiJE,RosenfeldMR,DalmauJ.AutoimmuneLimbicEncephalitisin39
Patients:ImmunophenotypesandOutcomes.JNeurolNeurosurgPsychiatry.2007Apr178(4):381385.
[PMCfreearticle][PubMed]
20.GrausF,DalmauJ.Paraneoplasticneurologicalsyndromes:diagnosisandtreatment.CurrOpinNeurol.2007
Dec20(6):732737.[PubMed]
21.DalmauJ,GrausF,VillarejoA,etal.ClinicalanalysisofantiMa2associatedencephalitis.Brain.2004Aug127(Pt
8):18311844.[PubMed]
22.CastleJ,SakonjuA,DalmauJ,NewmanTokerDE.AntiMa2associatedencephalitiswithnormalFDGPET:a
caseofpseudoWhipplesdisease.NatClinPractNeurol.2006Oct2(10):566572.quiz573.[PubMed]
23.BatallerL,GalianoR,GarciaEscrigM,etal.Reversibleparaneoplasticlimbicencephalitisassociatedwith
antibodiestotheAMPAreceptor.Neurology.Jan1974(3):265267.[PMCfreearticle][PubMed]
24.SchottJM.Limbicencephalitis:acliniciansguide.PracticalNeurology.20066:143153.
25.ViallardJF,VincentA,MoreauJF,ParrensM,PellegrinJL,EllieE.Thymomaassociatedneuromyotoniawith
antibodiesagainstvoltagegatedpotassiumchannelspresentingaschronicintestinalpseudoobstruction.EurNeurol.
200553(2):6063.[PubMed]
26.BarberPA,AndersonNE,VincentA.MorvanssyndromeassociatedwithvoltagegatedK+channelantibodies.
Neurology.2000Feb854(3):771772.[PubMed]
27.HartIK,WatersC,VincentA,etal.AutoantibodiesdetectedtoexpressedK+channelsareimplicatedin
neuromyotonia.AnnNeurol.1997Feb41(2):238246.[PubMed]
28.McKeonA,MarnaneM,OConnellM,StackJP,KellyPJ,LynchT.Potassiumchannelantibodyassociated
encephalopathypresentingwithafrontotemporaldementialikesyndrome.ArchNeurol.2007Oct64(10):15281530.
[PubMed]
29.ParthasarathiUD,HarrowerT,TempestM,etal.Psychiatricpresentationofvoltagegatedpotassiumchannel
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356774/

10/11

24/02/2016

TheEvaluationofRapidlyProgressiveDementia

antibodyassociatedencephalopathy.Casereport.BrJPsychiatry.2006Aug189:182183.[PMCfreearticle]
[PubMed]
30.GeschwindMD,TanKM,LennonVA,etal.Voltagegatedpotassiumchannelautoimmunitymimickingcreutzfeldt
jakobdisease.ArchNeurol.2008Oct65(10):13411346.[PMCfreearticle][PubMed]
31.VitaliPlME,HamanA,etal.ImprovingMRIcriteriaforJakobCreutzfeldtdisease(CJD)bythepatternofgray
matterinvolvementonFLAIRandDWIMRI.Neurology2008.200870(suppl1):A8.
32.VincentA,BuckleyC,SchottJM,etal.Potassiumchannelantibodyassociatedencephalopathy:apotentially
immunotherapyresponsiveformoflimbicencephalitis.Brain.2004Mar127(Pt3):701712.[PubMed]
33.BrainL,JellinekEH,BallK.Hashimotosdiseaseandencephalopathy.Lancet.1966Sep32(7462):512514.
[PubMed]
34.ChongJY,RowlandLP,UtigerRD.Hashimotoencephalopathy:syndromeormyth?ArchNeurol.2003
Feb60(2):164171.[PubMed]
35.CastilloP,WoodruffB,CaselliR,etal.Steroidresponsiveencephalopathyassociatedwithautoimmunethyroiditis.
ArchNeurol.2006Feb63(2):197202.[PubMed]
36.HollowellJG,StaehlingNW,FlandersWD,etal.SerumTSH,T(4),andthyroidantibodiesintheUnitedStates
population(1988to1994):NationalHealthandNutritionExaminationSurvey(NHANESIII)JClinEndocrinolMetab.
2002Feb87(2):489499.[PubMed]
37.AtzeniF,DoriaA,GhirardelloA,etal.Antithyroidantibodiesandthyroiddysfunctioninrheumatoidarthritis:
prevalenceandclinicalvalue.Autoimmunity.2008Feb41(1):111115.[PubMed]
38.WalikonisJE,LennonVA.Radioimmunoassayforglutamicaciddecarboxylase(GAD65)autoantibodiesasa
diagnosticaidforstiffmansyndromeandacorrelateofsusceptibilitytotype1diabetesmellitus.MayoClinProc.1998
Dec73(12):11611166.[PubMed]
39.ZophelK,SallerB,WunderlichG,etal.Autoantibodiestothyroperoxidase(TPOAb)inalargepopulationof
euthyroidsubjects:implicationsforthedefinitionofTPOAbreferenceintervals.ClinLab.200349(1112):591600.
[PubMed]
40.PoserS,MollenhauerB,KraubetaA,etal.HowtoImprovetheClinicalDiagnosisofCreutzfeldtJakobDisease.
Brain.1999Dec122(Pt12):23452351.[PubMed]
41.KothbauerMargreiterI,SturzeneggerM,KomorJ,BaumgartnerR,HessCW.Encephalopathyassociatedwith
Hashimotothyroiditis:diagnosisandtreatment.JNeurol.1996243(8):585593.[PubMed]
42.BoersPM,ColebatchJG.Hashimotosencephalopathyrespondingtoplasmapheresis.JNeurolNeurosurg
Psychiatry.2001Jan70(1):132.[PMCfreearticle][PubMed]
43.FickDM,CooperJW,WadeWE,WallerJL,MacleanJR,BeersMH.UpdatingtheBeerscriteriaforpotentially
inappropriatemedicationuseinolderadults:resultsofaUSconsensuspanelofexperts.ArchInternMed.2003Dec8
22163(22):27162724.[PubMed]
44.TsaoJWKH.TranisentMemoryImpairmentandHallucinationsAssociatedwithTolterodineUse.NEJM.2003Dec
4349:22742275.[PubMed]
45.PfefferRI,KurosakiTT,HarrahCH,Jr,ChanceJM,FilosS.Measurementoffunctionalactivitiesinolderadultsin
thecommunity.JGerontol.1982May37(3):323329.[PubMed]
46.NasreddineZS,PhillipsNA,BedirianV,etal.TheMontrealCognitiveAssessment,MoCA:abriefscreeningtool
formildcognitiveimpairment.JAmGeriatrSoc.2005Apr53(4):695699.[PubMed]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356774/

11/11