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Ростовский Государственный Медицинский Университет
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Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_186_библиотеки_им_акад_М_И_Перельмана

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(A)AnMRIofapatientwithfrontotemporaldementia(FTD),showingextensiveatrophymostpronounced inthefrontalcortex.(B)AmicroscopicsectionofalargePickbodyjustbesidethenucleus.(A,reprinted fromvonSchulthessGK.MolecularAnatomicImaging.3rded.WoltersKluwer;2015;andB,reprinted fromRubinR,StrayerDS.Rubin’sPathology.5thed.WoltersKluwer;2007.)
Box7.4FTDandAmyotrophicLateralSclerosis(ALS)
In2011,aspecificgenemutationwasidentifiedthatcouldcausebothFTDandamyotrophic lateralsclerosis(ALS).Severalothermutationsthatcancausebothdiseaseshavesince beendiscovered.AlthoughFTDisthoughtofasapurelycognitivedementiaandALSasa movementdisorder,thereactuallycanbeconsiderableclinicaloverlapbetweenthetwo (approximately50%ofpatientswithALS,forexample,ultimatelyexhibitsomedegreeof cognitiveimpairment).TheprecisegeneticsandclinicalfeaturesthatcharacterizetheFTD- ALSspectrumremainanareaofactiveresearch.SeeChapter11forareviewofALS.
https://t.me/med1917
Histology.Pickbodies,whichareroundintracellularaggregatesoftauprotein,arefoundin approximatelyhalfofallcasesofFTD.
Diagnosis.DependingonthespecificformofFTD,thediagnosisisprimarilyaclinicalone,whichcan besupportedbyneuroimaging(CTorMRIwillshowfrontaland/ortemporalatrophy)and histopathologicalanalysis(toprovideadefinitivediagnosis,althoughrarelynecessary).
Treatment.Thereisnospecifictreatment.Supportforthepatient’scaregiversmaybethemostimportant intervention,asthebehavioralchangescanbeasourceofterribledistresstothepatient’sfamily.Genetic counselingshouldalsobeoffered.
PrionDiseasesandCreutzfeldt-JakobDisease
Priondiseasesareneurodegenerativediseasescausedbytheaccumulationinthebrainofinsolubleand infectiousprionprotein,amisfoldedvariant(PrPSC)thatreplacesthenormalprionprotein(PrPc)(see Box7.5).Histologically,thesediseasesarecharacterizedbyintraneuronalcytoplasmicvacuolesthatgive thebraintissueaspongiformappearance(spongiformencephalopathyisanothertermforthese diseases),alongwithneuronallossandtheabsenceofinflammation.Therearefourmajorvariantsof priondisease:
Creutzfeldt-JakobDisease(CJD) FatalFamilialInsomnia Gerstmann-Straussler-Scheinkersyndrome Kuru
Creutzfeldt-JakobDisease.WewillfocusonCJDbecause—althoughrare(approximately1newcaseof sporadicCJDoccursper1,000,000peopleperyearworldwide)—itisthemostcommonoftheprion diseases.CJDisalwaysfatal,with90%ofpatientsdyingwithin1yearofdiagnosis.Thepatient’scourse isdominatedbyrapidcognitive,motor,andbehavioraldecline.Therapidityofprogressiondistinguishes CJDfromtheotherdementiaswehavediscussed.Psychiatricsymptoms(includinganxietyandapathy) andcognitivesymptoms(memoryloss,aphasia,apraxia)oftendominatetheclinicalpictureearlyinthe course,followedbymyoclonus(presentin∼90%ofpatients),ataxia,andweakness.Patientseventually lapseintocoma,anddeathmostoftenistheresultofasuperimposedrespiratoryinfection.
CJDcanbeinheritedasanautosomaldominanttrait,butinthemajorityofcasesitarisessporadically. Itcanalsobetransmittedandacquiredinvariousotherways—viacontaminatedneurosurgical instrumentsandcadavericmaterial(e.g.,cornealtransplants,duramatertransplants)andcontaminated pituitaryderivedgrowthhormone.Rarely,itcanbecausedbyexposuretobovinespongiform encephalopathy(thisisreferredtoasnewvariantCJD,or,colloquially,asMadCowDisease).
Box7.5Prions
PrionsareproteinparticlesthatarisefrommutationsofthePRNPgeneontheshortarmof chromosome20.TheprecisefunctionofthePRNPgeneisnotunderstood;itisexpressed throughoutthebodybutpredominantlyinthebrain,suggestingthatitprobablyhassome neurologicfunction.Thediseaseprogressessorapidlybecausetheprionscanusenormal PrPCproteinasatemplatetoreplicate,bypassingthemorecomplexmechanicsof replicationviacellularDNA.
https://t.me/med1917
Thediagnosisisusuallymadebyacombinationoftheclinicalpicture,MRIfindings(seebelow),EEG abnormalities(showinggeneralizedperiodicsharpwavecomplexes;thesearenotseeninthenewvariant form),andCSFanalysisforthe14-3-3protein(aneuronalproteinpresentintheCSFindicativeof neuronalinjury;elevatedlevels,however,arenotspecifictoCJD).Anewertest(knownasreal-time quaking-inducedconversion,orRT-QuIC),whichdetectsmisfoldedprionproteinswithintheCSF,looks promising.However,atpresentdefinitivediagnosiscanbemadeonlybymeansofneuropathologic analysisperformedatautopsy.Treatmentispurelysupportive.
https://t.me/med1917
MRIfindingsthatcanbeassociatedwithCreutzfeldt-Jakobdisease(CJD)includediffusecorticalgyral hyperintensities(arrows;thisisreferredtoas“corticalribboning”andcanalsobeseeninthecontextof statusepilepticus)aswellassignalhyperintensitiesinthebilateralbasalgangliaandthalami(not pictured).(ReprintedfromLouisED,MayerSA,NobleJM.Merritt’sNeurology.14thed.WoltersKluwer;
2021.)
FatalFamilialInsomniaisinheritedasanautosomaldominantdisease(sporadiccaseshavebeen reported,butthesearerare)andischaracterizedbysevereinsomniaassociatedwithanexaggerated
https://t.me/med1917
startleresponseandsympathetichyperactivity.LikeCJD,progressionisrapid,anddeathusuallyoccurs within1yearofdiagnosis.
Gerstman-Straussler-ScheinkerSyndromeisalsoinheritedinanautosomaldominantfashion. Cerebellarsymptomssuchasataxiaandgaitincoordinationdominatetheclinicalpicture,followedby weaknessandvaryingdegreesofmemoryloss.Thecourseisabitmoregradual,withmostpatients survivingfor4to5yearsafterdiagnosis.
KuruwasthefirstpriondiseasetobeidentifiedandwasendemicamongtheForetribesinPapuaNew Guineaintheearly-to-mid1900s.Kuruisacquiredviacannibalism(i.e.,eatingbraintissueofaninfected human;deceasedfamilymembersweretraditionallyeateninordertohelpfreetheirspirits).Itwas thoughtthatithadbeeneradicateddecadesagowiththecessationofcannibalism,butahandfulofcases havesincebeenreported.Symptomsincludeearlyandprominenttremors(thewordkuruderivesfroma Forewordmeaning“toshake”),ataxia,andmyoclonus,followedbydementiaanddeathusuallywithin1 to2yearsofdiagnosis.
Box7.6DifferentialDiagnosisofRapidlyProgressiveDementias
Thereisalonglistofdiseasesandsubstancesthatcancauserapidlyprogressivedementia, butallofthese,likeCJD,onlyrarelypresentasrapidlyadvancingdementiainthisway. Thesediagnosesareimportanttokeepinmind,however,becauseunlikeCJD,mostare potentiallyreversible:
Infections(HIV,Lymedisease,herpessimplexvirus,neurosyphilis) Toxins(alcohol,drugs,heavymetals) Paraneoplasticsyndromes Autoimmunediseases(systemiclupuserythematosus[SLE],Sjogrens,Hashimotos) Granulomatousdiseases(Behcets,sarcoidosis) Vasculitis
Table7.2WhatYou’veLearnedsoFar,ParedDowntotheBasics
TypeofDementia MostChara cteristicFea tures
Alzheimerdementia Memorydeficitispredominant Vasculardementia Progressesstepwise DementiawithLewyBodies Parkinsonianfeatures,visualhallucinations,fluctuatingcognitivefunction Frontotemporaldementia Behaviorchanges Creutzfeldt-Jakobdisease Veryrapidprogression,myoclonus
ReversibleDementias
Thereareseveralreversibledementiasthat,becausetheycanbetreated,areimportantdiagnosesnotto miss.
Psychiatricdisorders.Variouspsychiatricdisorders,suchasmajordepression,canmasqueradeas dementia.Whendementiaoccursasaconsequenceofmentalillness,itisreferredtoasdementia syndromeofdepression,previouslypseudodementia.Treatmentwithantidepressantswillusuallyresolve thecognitivesymptoms.
https://t.me/med1917
MetabolicDisorders.CognitiveimpairmentassociatedwithHashimotothyroiditiscanevolveacutelyor subacutely.VitaminB12deficiency(whichcanbeacauseofperipheralneuropathy[page281]or subacutecombineddegenerationofthespinalcord[page269])canalsocausereversiblemildcognitive impairmentanddementia.Long-standingalcoholabuseresultinginWernicke-Korsakoffsyndrome(page
380)isanotherexample.
NormalPressureHydrocephalus(NPH).Thisdisorderisdiscussedfarmoreoftenthanitisseen;NPH israre.Itclassicallypresentswiththetriadofcognitivedecline,gaitdisturbance,andurinary incontinence(‘wet,wobblyandwacky’isacommonwaytorememberthis).Youcanunderstand, therefore,whyitcomesupsooftenindiscussion,sinceallthreeofthesefeaturesarecommoninthe elderly.
MostcasesofNPHareidiopathic,theresultofanimbalancebetweentheproductionandabsorptionof CSF.TheCSFpressureisnormaloronlyslightlyelevated.Secondarycausesincludeinfections, inflammatoryconditions,andhemorrhagicstrokesthatimpairCSFabsorption.TheincreasedCSFvolume inbothidiopathicandsecondaryNPHleadstoventricularenlargementandcompressionofadjacentbrain tissue.
AnMRIofapatientaffectedbynormalpressurehydrocephalus(NPH),withventriculomegalyoutof proportiontothedegreeofgeneralizedbrainatrophy.However,keepinmindthatNPHisfirstandforemost aclinicaldiagnosis.Youwilloftenseeradiologyreportsthatcommentonventriculomegaly(oftenfollowed by“maybeconsistentwithNPH”)butyouneedto“correlateclinically;”ifthepatientdoesnotpresentwith featuresconsistentwithNPH,thediagnosisisnotNPH,regardlessoftheimagingfindings.(Reprinted fromLouisED,MayerSA,NobleJM.Merritt’sNeurology.14thed.WoltersKluwer;2021.)
NPHprogressesslowly.Thepatient’scognitiveimpairmentcantakealmostanyformandcanmimic AlzheimerDisease.Urinaryincontinenceistheleastcommonofthethreeclassicfeatures(about50%of patients).Thetypicalgaitdisturbanceisoftendescribedasshuffling,andcancloselymimictheshuffling gaitassociatedwithParkinsondisease.
SuspectNPHinanypatientwithdementiaandagaitdisturbancewithorwithouturinaryincontinence.
https://t.me/med1917
ThefirstdiagnostictestisanMRIorCTscan,andifthisshowsenlargedventriclesoutofproportionto thedegreeofgeneralizedbrainatrophy,proceedwithalumbarpuncture,whichhasbothdiagnosticand
therapeuticimplications.IfremovalofasmallamountofCSFleadstoanimprovementinthepatient’s symptoms,thenthepatientmaybeacandidateforashunt.Gaitshouldimprovequickly,withinminutesof CSFremoval,butsomepatientsmayimproveaslongas24hourslater.CSFdrainageisnotaperfecttest; ithasarelativelylowsensitivityforpredictingwhowillbenefitfromashunt,sosomepatientswhomight benefitwillbemissed.
Themostcommonshuntusedtodayisaventriculoperitonealshunt,andanadjustablevalveallowsfor carefultitrationoftheCSFpressure.Complicationsfromshuntplacementrequiringneurosurgical interventionoccurinapproximately25%ofpatientsandincludesubduralhematomasandtheneedfor shuntrevision.MostpatientswiththeclassicpresentationofNPHwhoshowimprovementwithCSF removalwillimprovewithshunting;gaitshowsthemostimprovement;cognitivefunctionislesslikelyto improve.
TransientGlobalAmnesia(TGA).Afavoriteofbooks,televisionandmovies,amnesiamaybeagreat plotdevicebutcanbeaterrifyingreality.Transientglobalamnesia(TGA)isnotadementiaatall— neitherisitaneurodegenerativedisorder—butwewanttodiscussitherebecauseofitssudden,dramatic memorydeficit.
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MRIwithasmallfocusofrestricteddiffusionintherighthippocampusinapatientwithtransientglobal amnesia.(ReprintedfromCuelloOderizC,MiñarroD,DardikD,etal.TeachingNeuroImages: hippocampalfociofrestricteddiffusionintransientglobalamnesia.Neurology.2015;85(20):e145.)
TGAisareversibleamnesia.Theneurologicexaminationisnormalexceptforthesuddendevelopment oftheinabilitytocreatenewmemories.Patientswillkeepaskingthesamequestionsoverandoveragain: WhereamI?Whoareyou?andsoon.Theywill,however,remainorientedtoselfandbefullycapableof carryingoutcomplexcognitivetasks.Thedegreeofretrogradeamnesia—theinabilitytorememberthings
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priortotheevent—isvariable.
Symptomstypicallylast1to24hours,althoughsomepatientsmayexperienceverymildresidual memoryimpairmentthatpersistsforweeks.
TGAoccursmostofteninpatients50to70yearsofageandcanaffectbothmenandwomen.Thecause isnotknown.PatientswithTGAdonotappeartohaveanincreasedriskofstrokeorseizure,orof developingdementialaterinlife.
PatientswithTGAshouldbeobserveduntiltheyreturntobaselinementalstatus.AnMRIisoften obtainedtoruleoutstrokeoranunderlyingseizurefocusandcanshowincidentalsmalldiffusion­restrictinglesionsinthehippocampi(seeimageonpage200).Ifanyneurologicabnormalitiesare present,orifthememorydeficitpersistsbeyond24hours,thenimagingaswellasanEEGaredefinitely indicated.
Notreatmentisrequiredbeyondreassurance.Recurrenceisrarebutcanoccur,andforunclearreasons ismorecommoninpatientswithapersonalorfamilyhistoryofmigraine.
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https://t.me/med1917
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