Acute Limb Ischemia

Thisoccurswhenthereisblockageofaperipheral
artery,eitherfromathromboembolism,or
sometimesfromanembolicplaque:

Thrombusinsitu40%

Emboli38%

Angioplastyocclusion15%

Trauma

Compartmentsyndromerare

SignsandSymptoms

Classically,theSIXPs
Pulseless
Parasthaesia
Painmusclesalsobecometendertopalpationafter
AneurysmandAAA
about68hours
Paralysis
Ananeurysmisanarterythathasalocalised
Pallor
dilation,withapermanentdiameterof>1.5xthat
Perishingcold
expectedoftheparticularartery.
Fixedmottlingoftheskinimpliesirreversibility
TrueAneurysmthewallofthearteryformsthe
BEWAREhotredlegmaysometimesbepresent,
walloftheaneurysm
whichcanresultinmisdiagnosisofgoutorcellulitis

Diagnosis
Youcanroughlylocalisetheblockagebylocating
thebifurcationdistaltothelastpalpablepulse.
Diagnosisisclinical
Treatment

Comfortableafter5mgmorphine(relativelysmall
dose)
BP110/40probablyslightlylow
HR80irregular
RR16
Heartsoundsnormal
Apyrexic
Wholeleftlegiswhiteandcold
Somemottlingfromfoottojustaboveknee
Calfisverytender
Canbarelymoverightleg,butcanwiggletoes.
Cannotmoveleftlegatall.
Pulsesontherightarenormal.
Nopalpableaorticaneurysm
Noobviousswellingoftheleg.

ItisanEMERGENCY!
1
22%ofcasesarefatal
2
16%ofcasesresultin
amputation
Thrombolyticagente.g.tissueplasminogenactivator
(tPA)mosteffectivewhengivenvialocalarterial
catheter(FogartyCatheter),particularlyfor
occlusions<2weeks.Therapyisusuallygivenvia
thecatheterfor824hr
Opensurgery/angioplastyDON'TBEAFRAID
TODOTHESE!equally,dontbeafraidtodo
angiographyincasesofanunsurediagnosis.
Thedecisiontooptforthrombolysisoversurgery
dependsonriskassessmentonanindividualpatient
basis(i.e.risksofsurgeryvsrisksofthrombolysis)
Youshoulduseheparinanticoagulationafterboth
surgeryandthrombolysis!

Afterinitialtreatment
Lookforasourceofembolie.g.ultrasoundsof
aorta,poplitealandfemoralarteriesforsignsof
aneurysm
Watchoutforreperfusioninjurywhichcanleadto
compartmentsyndrome

CaseExample
92yearoldnursinghomepatient
Painfulleftleg,suddenonset
Deafanddementia

Themostfrequentlyinvolvedarteriesare;in
decreasingincidence:abdominalaorta,iliac,
popliteal,femoralandthoracicaorta
Falseaneurysmakapseudoaneurysmother
surroundingtissuesformthewalloftheaneurysm
Thesemostcommonlyoccurinthefemoralartery
followingfemoralarterypuncture.Ifthereis
inadequatepressuretotheentrysiteofthepuncture,
thenbloodcanspilloutandformahaematoma.
Eventuallythesurroundingsofttissuewillformthe
walloftheaneurysm.
Ithinkthedifferencebetweenthisandatrue
haematomaisthatinapseudoaneurysmthereisstill
communicationbetweenthelumenandthefluid
collection,butinahaematoma,thereiseitherno
connection,orjustaoneway'leakage'offluid..

Aneurysmscaneitherbefusiformorsaclike.
Fusiformdescribesashapethatistaperedatboth
ends(abitlikearaindropwithapointybitatboth
ends),whilstsaclikedescribesamorerounded
characteristic.

Wheninspectingananeurysmyoushouldfeelfor
thembeingexpansile.Thismeanstheyexpandand
contract.Swellingsthatarepulsatilearedifferent
thesedonotexpandandcontractbutjusttransmitthe
pulsee.g.nodesoverlyingarteries.
Etiology
Despitethedifferentpathologybetweenaneurysmal
andatheromatousdisease,theriskfactorsforboth
aresimilar,andinclude:
Hypertension
Smoking
Age
Diabetes

Obesity
HighLDLlevels
Sedentarylifestyle
Geneticfactorsaremoreimportantinaneurysmal
diseasethaninatheroscleroticdisease,althoughthey
havearoleinboth.
1
10%ofcaseshaveafirstorder
relativealsowiththecondition

Specificaetiologicalfactorsforaneurysminclude:
Coarctationoftheaorta
Marfanssyndrome,andotherconnectivetissue
disorders
Previousaorticsurgery
Pregnancy(particularly3rdtrimester)
Trauma
Incidenceincreaseswithage5%ofmenover60
haveone
Occur35xmoreofteninmenthanwomen
Complications
Aneurysmsinthemselvesdonotoftenconstitutea
primaryproblem.Theymaycausealocal
obstruction(e.g.ofIVC),andtheycanalsocause
impairedbloodflowtothelowerlimbs.Theyarealso
ariskfactorforthrombosisandembolism.However,
themainriskcomesfromthetendencyofaneurysms
todissectandrupturemostcommonlyanaortic
aneurysmwillruptureintotheretroperitonealspace.
Electiverepairofaneurysmsbeforeruptureis
comparativelysafe
Repairafterrupturehasveryhighmortality

40%ofAAApatientsalsohaveiliacartery
aneurysms,and15%havepoplitealaneurysms.

GeneralfeaturesofAorticAneurysm
Oftensymptomless,anddiscoveredincidentally
(examination,AXR,ultrasound,CT)

Meanageofpresentation65
OftendiscoveredonAXRabout65%ofcasesare
sufficientlycalcifiedtoshowuponradiograph
Ultrasoundisusuallyusedtostagetheaneurysm.It
isaccurateatassessingthesiteoftheaneurysm,and
easytofollowupcasestoassesdevelopment.CTis
moreaccurate,andparticularlyusefulatlookingat
thesurroundstructures(e.g.toseeifthereisany
compression)butmoreexpensive,thusisusually
usedonlyforpreopassessment.
Riskofdissection(bursting).Riskincreaseswiththe
diameteroftheaneurysmAsourceofthrombus
formation,whichcanembolisetothelowerlimbs
Rarely,maybecompletelyoccludedbythrombus
ManagementofAorticaneurysm
Theniceguidelinesstatethatanaorticaneurysmof
greaterthan5.5cmindiametershouldbetreated.
Belowthissize,theriskofdissectionisoutweighed
bytheriskofsurgery.

At5.5cmtheannualriskofruptureis25%
At6.5cmitis35%
At>7cmitis75%
Insomecases,symptomaticaneurysmsofsmaller
sizemaybeoperatedon.
Painisthoughttobeariskfactorforrupture
Thromboembolusisalsoanindicationforsurgery
andcanpreventlimbloss.
Sugeryisthetreatmentofchoice.Therearetwo
options:OpenLaparotomytheaffectedsegmentof
aortamaybeclampedandreplacedbyaprosthetic
segment,(mostcommonaDacrongraft).Graft
failureisrare.Inavariationofthetreatment,the
affectedarterysegmentisbypassed.
Complicationsaregenerallyrare.Theremaybe
kidneyproblems,andsometimesparaplegiaor
ischaemiccolitis.fistulaformationwiththesmall
bowelcanalsooccurbutisrare.Infectionisalso
rare.
Mortality
See58%inelectiveasymptomaticAAA
1020%forsymptomaticemergencyAAA
50%forrupturedAAA
Longtermsurvivalformostpatientsisalmost
identicaltothegeneralpopulation
EndoluminalsurgeryEVAREndovascular
aneurysmrepairanaorticgraftisinsertedthrough
thefemoralartery,andupintotheabdominalaorta.
Thismethodisgenerallypreferred(lowermortality
1.2%)butmanypatientsarenotsuitable.Theremust
beatleast2.5cmnormalaortabetweentheaneurysm
andtherenalarteriestosecurelyfixthegraftin
place.
complicationswiththeactualgraftaremore
commonwiththeendoluminaltechniquethanwith
opensurgery.thegraftcanfail,oritmaybemoved,
allowingbloodtorefilltheaneurysm.Although,the
risksoftheprocedureitselfarefarlessthanopen
surgery.
Generally,rupturecannotbetreatedbythe
endoluminalmethod,althoughthereareongoing
trials.

Backtotop
Dissection and Rupture of AA
Deathratesfromthisriseswithage:
Age5559deathrateis12.5per100000
Age80+deathrateis273per100000
>75%witharupturedAAAdieusuallybefore
gettingtohospital.Ofthosethatdoreachhospital,
surgeryhasa50%mortalityrate.Thusonlyaround
10%ofthosewitharupturedAAAwillsurvive.

Ruptureisessentiallywherethewalloftheaorta
completelyfails,andbloodescapesfreelyintoa
bodycavity(e.g.abdominalcavity).
Thisisdifferentfromdissection!However,
dissectionoftenleadstorupture.
Dissectioniswherebloodescapesthroughthe
innermostlayerofthewalloftheartery,andprises
apartthemedia,creatinganewlumen.Sometimes,
thislumenisabsorbedbackintothemainlumen,
creatingadoublebarrelledaorta.Thismaybe
stable,butmayrupture.Ifitisclosetotheaortic
valve(thoracicaorticaneurysm)itmaycompromise
valvefunction.
Thedissectionissometimesabletotrackbackallthe
waytothepericardium,andcancause
haemopericardium.
Dissectionisamedicalemergencyandhastobe
treatedasap.Ifthebloodmanagestoescapethrough
allthelayersofthewalloftheaorta,thenruptureis
theresult.
ClassificationofDissectingAA

SeeTypeA2/3ofcases.Theseinvolvethe
ascendingaorta,andmayalsoincludethe
descendingaorta
TypeBaffectthedescendingaortaonly
Symptoms
Pain

endoluminally,althoughopensurgeryisoftenstill
thetreatmentofchoice.
AbdominalAorticAneurysm
Usuallyintheinfrarenalsegmentoftheaorta(80%)
Thesemostcommonlyoccurbelowthelevelofthe
renalarteryFeaturesofpain:
Rapidexpansionorrupturewillcauseepigastricpain
radiatingtotheback.Painmayalsobepresentinthe
groin,iliacfossaeandtesticles.
Canbeaconstantorintermittentpain
Becarefulnottodismissitasrenalcolic!
ThoracicAorticAneurysm
Asymmetricalbrachial/radial/carotidpulsesifthe
dissectioninvolvestheaorticarch.Variablepattern
dependingonwherethedissectionis.
BPmaybedifferentineacharmundersimilar
circumstancestotheabove.
PathologyofAneurysm
Ananeurysmisapermanentdilationofthevessel
wall.Thefactthatitispermanentimpliesthatthe
vesselwallitselfisalteredinsomeway.
Atheromatousdegenerationisthemostcommon
causeoftrueaneurysm.Thustheriskfactorsarethe
sameasforCHD:
Smoking
Familyhistory
Diabetes
Hypertension
Age
Hyperlipidaemia

Suddenonset,severepain.Oftendescribedas
tearingandusuallyradiatestotheback.

Painusuallyfollowsthelineofthedissection

Ascendingaortapainwillbeinthechest

Descendingaortapainoftenintheback
Collapse(duetohypotension)Expansile(not Mostprobablypathology
pulsatile)massintheabdomenShockHypotension
Thereisischaemiaoftheaorticmediawherethereis
TachycardiaProfoundanaemiaSuddendeathOther
anatheroscleroticplaque.Thisisasaresultof
signsmayinclude:
releaseofmacrophageenzymes(releasedwhen
macrophagesbecomeactivatived)thatbreakdown
theelasticfibres(collagenandelastin)

Testicularpain
Thereisevidencethatvariousgeneticvariantsof

Symptomssimilartorenalcolic
collagenaremoresusceptible,andthisprobably

Symptomssimilartodiverticulitis
accountsforthefamilialaspectofaneurysms.

Nonspecificbackpainthisresultsfromgradual
Wherethisischaemiaoccursthereislossofthe
erosionofthevertebralbodiesinpatientswithlong
normalelasticnatureofthemedia,allowingitto
standinganeurysm.
expand.

Ifindoubtaboutthediagnosis;assumerupturedAA!

Investigation
Marfans syndrome
Aconnectivetissuedisorder,andissometimes(but
Diagnosisisusuallyclinical,andneedstobemade
notalways)inheritedinanautosomaldominant
quickly!
manner.Itiscausedbymutationsofthefibrinin

Mortalityindissectionisabout1%perhour
geneonchromosome15.Itisverycommon,andis

Thisismuchhigherifitprogressestorupture!
thoughttoaffectabout1in5000individuals,25%of
Treatment
whichwillbetheresultofanewmutation.
Malesandfemalesareequallyaffected.

TypeArequireEmergencysurgeryusuallyby
Fibrillin1genemutationscanbeseenin80%of
opensurgery(DacronGraft).forfurtherdetailssee
cases,andaiddiagnosis.Testingforthiscanalsobe
above:Managementofaorticaneurysm
usedtoscreenotherfamilymembersinknowncases.

TypeBoftennotquiteasurgentastypeA

dependingontheindividualcase.Possibilitytotreat

Themostcommonclinicalfeaturesareinthe
musculoskeletalsystem:
Arachnodactylyabnormallylongandthinfingers
incomparisontothepalm.Fingersmayalsobebent
backwardsattheMCPto180insomecases.
Jointhypermobility
Scoliosislateralcurvatureofthespine
Chestdeformity
Higharchedpalate
Dislocationoflensintheeye
Patientsareusuallytallandthin,withlonglimbs
Thesearegenerallymild,features,butthedisease
canalsohaveseriouscomplications,including:
HeartvalvedefectsPredisposestoaneurysms

Cardiovasculardisordersaretheleadingcauseof
deathinwesternsociety
InEnglandandWales,theyaccountfor40%ofall
deaths:
1
Ischaemicheartdiseaseis27%
2
Cerebralvasculardisorders13%
Atherosclerosisisbyfarthemostimportantcause
Inthedevelopedworldtheincidencehasincreased
massively
IntheUSandsomeEuropeancountries,incidence
hasactuallypeakedandindeclining
IntherestofEurope,andinthemiddleandfareast,
incidenceisrisingrapidly

Thereisweakeningofthemedialayeroftheaorta,
leadingtodilation.Inthesecases,thedilatation
typicallyoccursintheascendingaorta.Theremay
alsobevalvedefects(e.g.aorticregurg)which
complicatetheissue.
InMarfansSyndrome,therootoftheaortais
typicallyaffected
Lungdisorders

Atherosclerosiscanhave3maintypesof
manifestation:
Coronaryheartdiseaseangina,MI,suddendeath
Cerebrovasculardiseasestroke,TIA
Peripheralvasculardiseaseclaudication,critical
limbdisorder
Thesesituationsoftencoexist,andthepathologyis
verysimilar.Forexample,patientspresentingwith
strokeorclaudicationwillverylikelyhavecoronary
arterydiseaseandthiscoexistingdiseaseisan
importantcauseofmortality.

Normalarterystructure:
Thereare3layersofarterialtissue:
TunicaIntimathisistheinnermostlayer,andhasa
singlelayerofendothelium,withasparsesupportive
tissue.Thislayerisveryverythin!
TunicaMediathisisseparatedfromtheintimaby
theinternalelasticlamina.Themediaismadeupof
smoothmuscleandelastictissue.Intheheart,the
elastictissueismostpredominant,butinmost
arteries,thislayerismostlymadeupofsmooth
muscle.
TunicaAdventitiathisisafibrousconnective
tissue.Theexternalelasticlaminaseparatesthis
fromthemedia.Verysmallbloodvesselscanbe
foundinthislayercalledvasavasorumandthese
filterdowntosupplythemedia.
1
Theintimaandinnermostmedia
receivetheirnutrientsfromthe
arteriallumenviadiffusion.

Normalagerelatedchanges
Thesewillusuallybeinconsequentialbyage40,and
verycommonbyage70.Theyareoftentermed
arteriosclerosis.thechangesaffectallbloodvessels,
rightdowntothearterioles.Theyinclude:
Progressivefibrousthickeningoftheintima
Fibrosisandscarringofthemuscularandelastic
media
Accumulationofmucopolyysaccharideground
substance
Fragmentationoftheelasticlaminae

Ultimatelythesechangesreducethestrengthand
elasticityofthevascularwall.Clinically,thiswill
meanthereisdilationoftheaortaandcoronary
arteriesandthisfindingiscommon.

Duradisorders
Itisthoughtthataswellasthefibrindefects,there
arealsoproblemsinTGF(transforminggrowth
factor).Thisisthoughttoaccumulateinheart
valveandbloodvessels,andaltertheirunderlying
structure,leadingtothecomplicationsmentioned
above.
TreatmentofMarfans
blockertherapyhasbeenproventoreducethe
rate/riskofdilatationoftheaortaMonitoringofaortic
dilatationviaXRay,Echo,MRIorCTcanbe
usefulinpatientswithknownMarfans.Usually
patientsarefollowedupwithyearlyechotoassess
thesizeoftheaorta.Insomecases,elective
replacementoftheascendingaortamaybe
recommended,topreventdissectionbuthasa
mortalityof510%.Avoidanceofendurancesports/
activitiesInpregnancyasbothpregnancyand
MarfansareriskfactorsforAA,thenduring
pregnancy,theaortaiscloselymonitoredby6
weeklyechos.

Iftheaorticroot>4cm,ceasariansectionshouldbe
considered
blockertherapyissafetocontinueduring
pregnancy

Atherosclerosis
Epidemiology

Pathology

Intheaortathiscanleadtostretchingoftheaortic
ringresultinginvalveincompetence
Dilationoftheaorticarchandthoracicaortacanalso
leadtounfoldingoftheaortawhichcanbeseen
inchestxraysasalossoftheaorticnotch,anda
widenedappearanceofthecentralvascularcolumn
inthexray.

Tocompensateforthesechanges,thereisoften
smoothmusclehypertrophyandproductionofextra
layersofcollagenintheinternalelasticlaminae.

Atherosclerosis
Thisisadiseaseofthemediumandlargesized
arteriesonly.Itisveryuncommoninarteriesofless
than2mmdiameter.Itiscausedby3typesoflesion:
Fattystreaks
Fibrolipidplaques
Pathology
Complicatedlesions

Themajorriskfactorsare:
Age
Malegenderpremenopausalwomeninparticular
seemtobeaverylowriskbeingpremenopausalis
apreventativefactor.Afterthemenopause,gender
differencesdisappearrapidly.HRTalsohasnorole
inreducingtheriskinfactoestrogentherapy
appearstoincreasetherisk.
Hypertensionantihypertensivetherapyreduces
coronarymortality,strokeandheartfailure.
Smokingthislinkisalsodoserelated
Diabetes
HighlevelsofLDL
LowlevelsofHDL
Obesity
Sedentarylifestyle
IncreasedlevelsofbloodcoagulationfactorVII
Lowbirthweightthisisthoughttobeparticularly
important.Thosewithalowbirth/infantweightare
athigherriskofadultobesity.Thosewithalowbirth
weightandasubsequentlevelofobesityin
adulthoodare23xmorelikelytodiefromheart
diseasethanthosewithahighinfantweight.Alow
infantweightisoften(inthepastatleast)associated
withlowsocioeconomicstatus.
Lowsocioeconomicstatus
Geneticfactorsoftenthingslikehypertension,
hyperlipiedaemiaanddiabetesruninfamilies,and
aremultigenetic.HOWEVERitisalsoimportant
torememberthanfamiliesoftensharethesame
environmentandenvironmentalfactorsmaybe
involvedintheapparentfamilyhistorylink.
Clinicallywesayasignificantfamilyhistoryis
presentwhenfirstdegreerelativeshavehadacute
eventsat<50yearsformenand<55yearsfor
women.

Howeveritisimportanttonotethattherearewide
variationsintheseverityofthedisease,evenwithin
similarpopulations.Thesevariationsarepossibly
duetogeneticfactors.Forexample;
Thereisaninheritedgeneticabnormalitywherebyan
individualhasalackofLDLreceptorsfamilial

hyperlipidaemia?about1in500caucasiansare
heterozygousforthisabnormalitytocopewiththeir
reducednumberofreceptors,theyproduceincreased
amountofLDLs.Thesepeopledevelopcoronary
heartdiseaseintheir40sor50s.
Somepatientsmayevenbehomozygousforthis
geneinthiscasethesepatientswilloftendiefrom
coronaryheartdiseaseintheirinfancyorteens.

Theeffectofriskfactorsismultiplicative,rather
thanadditive.Alsorememberthedifferencebetween
relativeandabsoluterisk.Forexampleamaninhis
30swithhighcholesterolwhosmokes,isfarmore
likelytohaveanacuteeventinthenext10years
thansomeoneofhisagewhodoesntsmokewitha
normalcholesterolBUThisabsoluteriskisstill
verylow.

Inatherosclerosis,thereisinflammationofthe
arterialwall,characterisedbylipidrichdepositsof
atheroma.Thesedepositsdonotcauseaproblem
untiltheybecomelargeenoughtooccludetheartery,
oruntiltheyulcerate,oruntiltheybecomedisrupted
andathrombosisformsontheirsurface.

Signsofatherosclerosisappearearlyinlife,for
instancefattystreaksinthearteriesofchildren
havebeennotedasyoungastheageof7.However,
theseareasymptomatic.

Thediseaseisbasicallycharacterisedby:
Fibrosis
Lipiddeposition
Chronicinflammation

Intheearlystagesofthedisease,theremaybemany
separatestreaksanddeposits,butinlatedisease,
theseallmaybeconfluent.
Progression
Earlyatherosclerosis
Fattystreaks:
Thesewilloccuratareasofturbulentflow,suchas
bifurcations,andtheyareassociatedwithabnormal
endothelialfunction.
Theythemselvesareofnoclinicalsignificance,and
occurinallpopulations
Theyarebasicallyayellowlinearelevationofthe
intimallining.
Pathogensis
Endothelialcellswillbegintoshowunusual
adhesionmolecules(e.g.ICAM1andEselectin).
Thesemaybesimilartothoseseeninacute
inflammation.
Thisattractsmonocytes(macrophages)tothesite
andthesecanbeseenbothenteringandleavingthe
endothelium.
Atthesametime,highlevelsofLDLintheblood
willbegintoaccumulateinthearterialwall.Itmay
bethattheselipiddepositionsetsoffan

inflammatoryreaction,andthemacrophagesare
attractedliketheywouldbetoanytypeof
inflammation.
Themacrophagesenteringthearterialwallwillcome
intocontactwiththeselipidcores,andwilltakeup
theoxidizedLDL,becomingfoamcells.The
macrophageswillalsobeactivatedbythe
inflammatoryproductsreleasedbythearterialwall.
Thefoamcellscandie,andtheyreleasetheir
products,causingtheformationofapooloflipid.
Thispooliscalledalipidcore.
Theactivatedmacrophageswillreleaselotsoftheir
ownproducts.Theseincludecytokinesandgrowth
factors,particularlyPDGF.Thesegrowthfactors
leadtoproliferationofthesmoothmusclelayer.It
willproliferatetowardsthelipidpool,andinan
attempttorepairandstabilisethelesion,itmayform
alayeraroundthepool.Thesmoothmusclecells
changetheirphenotypefromcontractile,torepair
theynowpermanentlybecomerepairtypecells.
1
Ifthisprocessofrepairis
successful,theplaquewillbea
stableatheroscleroticplaqueand
willremainasymptomatic,
unlessitgrowsbigenoughto
occludeanartery.
Atsomepoint,Tlymphocyteswillalsoinvadethe
plaque.

Ifinflammationdominatesovertherepair
mechanismsofthesmoothmuscle,thentheplaque
maybecomeactiveorunstable,andthiscould
leadtoulcerationandthrombosis.
Manymoreproductsarereleasedbythe
macrophages,including,IL1,TNF,interferon
gamma,PDGFandmatrixmetalloproteinases.
Thesecancausethesmoothmusclecellsoverlying
theplaquetothin,andthustheprotectivefibrous
capcoveringtheplaquecanbecomeweak.
Themacrophagesthemselvescanalsodigest
collagenstrutsthatareholdingthecapinplace.
Thesechangesinthemselvesdontcompletely
destroythecap,butmakeitmorevulnerableto
externalshearingforces
Whenthecontentsoftheplaquebecomeexposedto
thelumen,thiscantriggerthrombusformation.This
maycausecompleteocclusionatthesiteofthe
plaque,butthethrombusmayalsobreakoff,and
causeablockagesomewhereelse.

Asthediseaseprogresses,thereare:
Moreplaques
Agreaternumberofmacrophagesandtlymphocytes
withintheplaques
Releaseofmorecytokinesandgrowthfactors
(includingIL1andIL6thatarechemotacticfor
macrophages
Elevatedlevelsofantibodiestopathogens,suchas
Chlamydiapneumoniae.Somepeopleareguethat
suchorganisms(alsoincludingcytomegalovirus,
herpesandhelicobacter)haveacausatoryrole(to
initiallystarttheinflammation)althoughthe
evidenceforthisislimited.
Incoronaryarterydiseaseelevatedlevelsof
inflammatorymarkers;suchasCRPthisisan
indicatoroffutureacuteevents.
Intransplantedheartspatientswithtransplanted
heartsmayhaveaparticularlyquicklyprogressing
formofthediseaseinthetransplantedheart.The
pathologyofthisdiseaseisalsoslightlydifferent
fromthatofnormalatheroma.Thisfurthersupports
thetheorythatthediseaseisaresultofanimmune
problem.Tominimizetheriskallhearttransplant
patientsaregivenlipidloweringdrugs.

Monoclonalcellssomepeoplehavelikenedthe
plaquestosmallbenigntumoursbecausethe
smoothmuscleproliferationthatispartofplaque
formationoccursfromtheproliferationofonecell;
thecellclonesitselfmanytimes.Inthisway,the
growthfactorscanbethoughtofasmutagens,
althougheffortstolocaliseandidentifyasingle
mutagenhavebeenunsuccessful.

DiseaseProgresssion

Advancedatherosclerosis

Individualplaquesevenwithinthesamepatientwill
progressatdifferentrates.Thisrateisstrongly
linkedtomechanicalstressthegreaterthestress,
thegreatertheproliferation.
Vulnerableplaquesarethoseinaplaceofhigh
mechanicalstress,withalipidrichcoreandathin
fibrouscap.

Stableplaqueshaveathickfibrouscap,possibly
withcalcification,andtheyhaveasmalllipidpool,
andmanycollagenouscrossstruts.

Itisthoughtthatlipidloweringtherapyhelpsto
stabilisevulnerableplaques.
Thrombusformationonplaques

Therearetwodifferentmechanisms.Eitherthe
fibrouscapoftheplaqueitselfgetsasuperficial
injury,andathrombusformsonit,or,inmore
advanced,unstableplaques,thefibrouscap
completelyruptures,andnotonlycansomeofthe
contentsescape,butbloodcanalsoentertheplaques,
formingathrombuswithintheremainingcapofthe
plaque.

Theplateletsthenreleaseserotoninandthromboxane
A2andthiscausesvasoconstrictioninthearea
resultinginreducedbloodflowtothemyocardium,
andischaemicinjury.

Abitaboutlipids
Lipoproteins
Thesearetheforminwhichmostlipidsare
transportedintheblood.Theycontainlarge
insolubleglyceridesaswellascholesterol.They
haveasuperficialcoatingofphospholipidsand
protein,whichmakethelipoproteinssoluble.The
proteinscoatingthesemoleculeswilloftenbindto
specificcellmembranereceptors,signallingthe
uptakeofthatparticularphospholipid.

Therearefourmaintypesoflipoprotein:
Chylomicronstheseconsistof95%triglyceride.
Thesecarryabsorbedlipidsfromtheguttotheliver.
VLDLsverylowdensitylipoproteinsthese
carrytriglyceridesmanufacturedbytheliver,aswell
assmallamountsofphospholipidandcholesterol.
Theprimaryfunctionoftheseistotransport
triglyceridestoperipheraltissues.Thesearethe
largestoftheDLs.
LDLslowdensitylipoproteinsthesecontain
veryfewtriglycerides,afewmorelipoproteins,and
lotsandlotsofcholesterol!Thesearethebad
cholesterol.Theirprimaryroleistodeliver
cholesteroltoperipheraltissue.
HDLshighdensitylipoproteinsthesearethe
smallestoftheDLs.Theyhaveroughlyequal
amountsoflipidandprotein.Thelipidsaremainly
phospholipidandcholesterol.Thesewilltransport
excesscholesterolbackfromperipheraltissuetothe
livertoexcretioninthebile!Theyaregood
cholesterol.

Lifecycle
TheliverwillsynthesiseVLDLs.Thesewillthenbe
releasedintothebloodtodelivertriglyceridestothe
peripheraltissues.LipoproteinLipasewillremove
lotsoftriglyceridesfromtheselipoproteins,creating
intermediatedensitylipoproteins.Thesewillthengo
backtotheliver,wheretheywillhavemoreoftheir
triglyceridesremoved,andlotsofcholesteroladded
tothem.TheywillthenbereleasedasLDLsto
delivercholesteroltoperipheraltissue.

LDLsareabsorbedbyreceptormediated
endocytosisintoperipheralcells.Theaminoacids
andcholesterolwillbereleasedintothecytoplasm.
Cholesterolnotusedbythecellwilldiffusebackout
ofit.Itwilldiffusebackintotheblood,whereitwill
betakenupbyHDLsandthentakenbacktothe
liver.Theywillhavetheircholesterolremovedfor
excretion,andtheHDLswillthencontinueinthe
bloodstreamtopickupmorecholesterol.
Prevention
Primarypreventionaimstopreventthediseaseinthe
firstplace,andinvolves:
Cessationofsmoking
ControlofBP
Weightreduction
Regularexercise
Dietarymodifications
1
Dietsthatarelowinsaturatedfat
areparticularlyassociatedwitha
reducedriskofdisease
2
Fattyacidsfoundinfishalso
havecardioprotectiveeffects
thusitisrecommendedyoueat
atleast2portionsofoilyfishper
week.

Secondarypreventionaimstoreducetheriskof
acuteeventsinthepresenceofatheroma.Itbasically
involvestheuseofdrugs,butyoushouldremember
thesedrugsareintendedforlongtermuseafteran
MIandarenotinvolvedintheacutetreatmentofa
recentMI.

Generallypatientsshouldbeofferedacombination
ofthefollowing4drugs:
ACEinhibitor
Aspirin
blocker
Statin

COBRAAmnemonicforSecondaryPreventionin
ACS
CClopidogrelantiplateletagent
OOmacarOmega3
BBisoprololblocker
RRamiprilACEi
AAspirin

AAtorvastatinverypotentstatin!
Delirium
Deliriumisdefinedasanacuteandfluctuating
disturbanceinlevelofconsciousness,attentionand
globalcognition.
Prompttreatmentisrequiredtoavoidpotentialbrain
damage.
Theunderlyingmechanismispoorlyunderstood,but
believedtoinvolveneurotransmitterabnormalities

andinflammation.

Epidemiology

Deliriumoccursmostcommonlyintheelderlyand
veryyoung.
Itispredictedthat10%ofpatientsover65show
signsofdeliriumonadmissiontohospital.
Affects15%ofinpatients.

SignsandSymptoms
Reducedlevelofconsciousness;
Psychiatricsymptoms:
1
Disorientation
(time/place/person);
2
Inattention;
3
Illusions/hallucinations;
4
Alteredpersonality;
5
Mooddisorders;
6
Speechdisorders(slurred
speech/aphasicerror/chaotic
pattern).
Lackinginsight.
Thesesymptomsfluctuateoverthecourseoftheday
andtendtobeworseatnight.Patientsmayshow
signsofhyperactivity(typicallyinwithdrawalstates)
orlethargy(commoninhepaticencephalopathy).
Causes
CNS
Stroke,abscess,tumour,subduralhaematoma
Drugs(orwithdrawal)
Anticholinergics,antiemetics,antipsychotics,
corticosteroids,digoxin,levodopa,TCAs,opioids,
alcohol
Endocrine
Hyperparathyroidism,hyper/hypothyroidism
Infection/injury
Encephalitis,meningitis,pneumonia,sepsis,UTI,
burns,hypothermia
Metabolic
Acidbasedisturbance,hepaticencephalopathy,
uraemia,hypo/hyperglycaemia,electrolyte
abnormalities,thiamine/vitaminB12deficiency
Other
Postoperativestates,othermentaldisorders,sleep
depravation
Diagnosis

Acollateralhistoryisneededtodetermineifthe
changesinmentalstatusarerecentandthepatients
normalleveloffunctioning.
Thiswouldbedifferentinapatientwithdementia,
wherethememoryproblemsaremorelikelytobe
chronicwithagradualonset.Patientswithdementia
arealsolesslikelytohaveinattentionorimpaired
levelofconsciousnessuntilthelaterstagesof
disease.

DeliriumVs.dementia

Delirium
Suddenonsetandfluctuatingcourseoverdays
weeks
Variationinlevelofconsciousness
Impairedattention
Psychomotorchanges
Dementia
Gradualonset,slowlyprogressiveovermonths
years
Consciousnessunimpaired
Attentionpreserved
Often Normal

Itisalsoimportanttotakeadrughistory(consider
anywithCNSeffectsornewadditionsasapotential
cause)andalcoholhistory.Aminimentalstate
examinationislikelytoshowdeficitsinattention
(e.g.immediaterepetitionof3objects).Diagnostic
toolssuchastheConfusionAssessmentMethod
(CAM)statesthatthefollowingfeaturesare
diagnostic:
Acutechangeincognitionwhichfluctuatesduring
theday;
Inattention;
Disturbanceofconsciousness;
Disorganisedthinking.
Thepatientshouldbeexaminedtolookforpotential
sitesofinfectionoranyfocalneurologicalsigns
(suggestingastructuralCNSdisorder.
Treatment
Treatingtheunderlyingcauseorremoving
aggravatingdrugsistheprincipletreatment.
Environmentalmanagement:nursepatientsinaquiet
andwelllitroom.
Minimisesensorydeficits(checkhearing
aids/glassesetc.)
Agitationcanbemanagedwithhaloperidol(0.5
1.0mgPO)orlorazepam(0.51.0mgPO),however,
theyshouldbeavoidedastheymayworsenor
prolongdelirium.
Dementia
Dementiaisaprogressiveglobaldeclinecognitive
function,withoutimpairmentofconsciousness.
Therearemanycausesofdementia,butthetwomost
commonare:
Alzheimersdisease(~4050%)
Diffusevasculardisease(akamultiinfarctdementia)
~25%
Inpracticeitisoftendifficulttodifferentiatethetype
ofdementiapresent

Epidemiology
Veryrare<55years510%prevalencein>65s20%
in>80years80%in>100years
Etiology

Alzheimersdisease
Geneticpredisposition
1
About15%ofcasesarefamilial.
Thesefallintototwocategories:
2
Anearlyonsetautosomal
dominantdisease
3
Alateronsettypeofdisease,
whoseinheritanceisvariable
4
Themostcommongene
mutationisapoE4although
mutationofthisgenedoesnot
necessarilymeanyouwill
developAlzheimers.
Insulinresistancemaybeapredisposingfactor
Female:Maleratio=2:1
Themajorityofcasesaresporadic
Noenvironmentalfactorshaveyetbeenproven
1
Cholesterol,atherosclerosisand
inflammationarethoughttobe
implicated
Symptoms
GeneralsymptomsofAlzheimersandVascular
dementia
Memorylossthisisusuallythefirstsymptomto
appear
1
Thedamagetobraintissueisnot
universal,andthussomeareasof
memory,notably
autobiographicalandpolitical
memoryisstoredinareasthat
arelessoftenaffected.
2
Shorttermmemoryismore
readilyaffected,andconfusion
mayoftenresult.Forexample,
patientsmaybuymanyidentical
itemsoffoodonseparate
occasions,andthenwonderwhy
theircupboardsarefullofthese
items.
Visuospatialproblemspatientsmaybeeasily
disorientatedbyunfamiliarsurroundings
Emotionaldisturbance
Lossofnormalsocialbehaviour
LanguageproblemsProblemsbothunderstanding
whatisbeingsaid,andnamingobjects
Concentrationissues
ShortattentionspanAlsounabletoplan,organise,
orsequenceactivities
BehaviouralchangesDelusions(persecutory),
agitiation,aggression,wandering
Variablemood
Poorsleep
Restlessness
Hallucinations
Apathy
Depression/euphoriaSeveredepressionisrare,
duetolossofinsight

Inlaterstagesofthedisease,theremayalsobe:
Selfneglect
Changeinpersonalitywhichgenerallyinvolves

lossofinhibition
Motorandsensoryabnormalities
Seizures

Inverylatestagediseasetheremaybe:
Thepatientmaybecomemute
Theymaytakelittleinterestinanything
Parkinsonianism
Wasting
Seizures
Incontinence
Thesecanbeparticularlydistressingforrelatives.

InAlzheimersdiseasetheprogressionofthe
symptomsisalwaysgradual,butindiffusevascular
disease,thesymptomsaremorelikelytooccur
acutely.Thereisoftenastepwiseprogression,as
moresmallinfarctscausedamage.

Incasesofvasculardementiayoumayalsofind
othervascularsings,forexample:
RaisedBP
Paststrokes
Suddenonset/stepwiseincreaseofsymptoms

Diagnosis
Themainsymptomisusuallyconfusion.Diagnosis
isusuallyclinical,andmadewiththehelpofthe
MMSE(MiniMentalStateExam).Sometimes,IQ
tests(WechslerAdultIntelligenceScale,mayalsobe
used).However,asconfusionisoftenapparent,you
mayhavetoperformmanyotherteststoruleout
otherdifferentials.Thelateroninlifethe
presentation,thelesslikelyitistobeinvestigated.
Alwaysassumeconfusionisduetoanacuteillness
untilprovenotherwise.Thismightmean,depending
onthehistory,thatyouaregoingtohavetodoalot
ofbloodtests:
Vitamindeficienciesfolate,B12,thiamine
thesecouldbeprimarydeficiencies,ormaybe
alcoholrelated.
TFTsthyroidproblems
FBCanaemia
U+Esrenalfailure/dehydration
LFTscarcinoma,cirrhosis,encephalopathy
Glucosediabetes
CRP/ESRacuteinfection
ImagingofthebrainCT/MRIthismaybeusedto
excludetreatablespaceoccupyinglesions,suchas:
1
Hydrocephalus
2
Tumour
3
Subduralhaematoma
4
HOWEVERthemostcommon
abnormalityseenonbrainscanis
generalatrophy.
History
Thisisveryimportant.Dementiaisslowly
progressive,andthesymptomsmayhavestarted
yearsago.Itishighlylikelyyouwillneedtospeak
torelativesaswellastothepatientthemselves
DifferentialsforConfusion

Alcoholabuse
Substancemisuse
Diabetes
Dementia
Delusion
Infection(UTIisparticularlycommon)
Dehydration
Constipation
Acuteconfusionalstate
Renalfailure
Tumours(meningioma)
SubduralHaematoma
Parkinsons
Syphilis
Pathogenesis
Alzheimersdse

Themeansurvivalis7years.Mostwillsurvive
between27.
Deathusuallyresultsfrombronchopneumonia
Thereisageneralatrophyofbraintissue,andthe
weightofthebrainisusuallyreduced.Thefrontal
andtemporallobesareparticularlyaffected.
Thereisoftencompensatorydilatationofthe
ventricles,resultinginhydrocephalus.
Thecerebellumandspinalcordarenormal
Thereisabuildupofamyloidplaquesinthebrain.
Thesearethebreakdownproductsofamyloid
factors.
Thereisalsoatrophyofcholinergicfibresthatrun
fromthehippocampustothecerebralcortex.
Initiallythereisareductiononcholinergic
transmission,andlaterareductioninthesynthesisof
acetylcholine,particularlyinthecerebralcortex
itself.
Thedamageisvariable,andcanoccuratdifferent
ratesindifferentpartsofthebrain.Mostlikelytobe
affectedaretheAmygdala,temporalcortex,anda
fewselectedbrainstemnuclei.
Thereisnochangeinthenumberofmuscarinic
receptors,butthenumberofnicotinicreceptorsis
reduced.
Inverylatestagediseasetherecanbevariable
depletionofotherneurotransmitters
Theremaybetheexcessdepositionofbetaamyloid
inthebrainleadingtotheformationofbeta
amyloidplaques.
VascularDementia
Thisistheresultofmanysmallinfarcts.
Cerebrovasculardiseasehastobeprettyadvanced
forvasculardementiatobecomeapparent,aslarge
partsofthecortexhavetohavebeenaffected.
Thediseasewillhaveastepwiseprogression,sofor
instance,therewillbenoapparentchangeinthe
condition,perhapsformanymonths,andthenthere
isasuddendropinfunction.Infarctsareparticularly
likelytoaffectfunctioniftheydamagethewhite
matter.

Aswellasdementia,eventuallytheremaybe:
Pseudobulbarpalsy
Shufflinggaitwithsmallstepsmarcheapetitspas

sometimescalledatheroscleroticParkinsons
disease.
ThereisoftenalsoahistoryifTIAs

Differentiatingtypesofdementia
Inthepast,aslongasB12andTSHlevelswere
normal,thiswasnotnecessary,however,thesedays,
therearespecifictreatmentsforAlzheimers.The
typesofdementiacanbedifferentiatedbya
combinationof;history,CT/MRIand
neuropsychologicaltesting.
Makingawill
Ifthediseaseisdiscoveredearlyenough,thenitis
possibletomakeawill,and/oranadvanceddirective
beforethepatientbecomestoillforoneoftheseto
beacceptedbylaw.Thepatientmustbeableto:
Understandandretaintheinformationinvolved
Believetheinformationistrue
Demonstratetheyareabletoweighuptheprosand
consofanargumentandcometoadecisionbased
onthese
Management
Inalltypesofthedisease,themanagementisonly
abletoreducetherateofprogressionofthedisease.
Thereisnocure.
Alzheimers
Anticholinesterasedrugse.g.donepezil,
galantamine,rivastigmine
Mechanismthesedrugsworkbyinhibiting
cholesterases,andthusincreasingcholinergic
transmissionwithinthebrain.
Unwantedeffectsanorexia,nausea,vomiting,
diarrhoea,abdopain,insomnia,confusion,agitation,
headache
1
Notethatsomeoftheseeffects
aresimilartotheclinical
symptomsofAlzheimers!
Clinicalusewilldelaythedeclineofcognitive
impairmentin40%ofpatientsprobablyonlyby
about36months.Probablymoreeffectiveinthose
withoutthegeneapoE4.
1
Importanttoassessefficacy,and
tostoptreatmentinthosewhodo
notrespond.
2
Rapiddeclineisseenwhenthe
drugisstoppedinpreviously
responsiveindividuals
3
Havefunctionalbenefitsthat
mayimproveQOL.

NMDAreceptorantagonistsmemantine
MechanismaninhibitorofglutamateNMDA
receptors.Itbindsselectively,dependingonthe
voltage,andthuspreventsexcitotoxicity,without
alteringgluatamtesroleinnormalmemoryand
learning.
ItcanbegivenWITHanticholinesterases
Unwantedeffects:
1
Diarrhoea,insomnia,dizziness,

Clinicaluse
1
2

headache,hallucinations
Again,notethatsomeofthese
aresimilartosymptomsof
dementia!
Usuallymorewelltoleratedthan
anticholinesterases,butprobably
notaseffective
Mayprovidesomebenefitin
cognitivefunction,andmayslow
cognitivedecline

Notwidelyused

###Drugtreatmentshouldonlybeinitiatedinthose
withaMMSEof>12!###
ThisismildtomoderatedementiaNICEguidelines
state:

Treatmenttobereviewedevery6months
DonttreatifMMSE<12,assideeffectsofdrug
likelytooutweighbenefits
Treatmentonlytobeadministeredandmonitoredby
specialistcentres
DontrelyonMMSEasyouronlytoolforaiding
prescribing,e.g.getcollateralhistories,assess
functionandbehaviour
Drugtherapyiscontroversial

Drugsareexpensive
Sometrialshaveshownnobenefitofthedrugsover
placebos
Inmanycasesitisthoughtthattheyatleastallowa
fewmoremonthsinahomecareenvironment
VascularDementia
Prevention
Reductionofvascularriskfactors:
Aspirinorwarfarintherapyaspirinoftenquoted
anecdotally,butthereisactuallynowevidencethat
thesortoflowdosetherapythatmanyindividuals
takeprovidesanybenefitagainstvasculardementia.
Someatriskpatientsmaybeputonwarfarin
therapy.
ControllingBPusenormalsystem(ACD(+B))
forinitiatingblooppressuremaintenancetherapy
Anticholinesterasesandmemantinemayhave
somebenefitinvasculardementia.

Theburdenofcare
Thecourseofthediseaseisoftendistressingforboth
familiesandpatient.Supportivecareisnecessaryto
ensurethepatientstaysinafamiliarhome

environmentaslongaspossible.Oftentheburdenof
carefallstorelatives.
Somerecentevidencesuggeststhatengagingin
cognitivelytaxingactivitieslateoninlifecanprotect
againstdementia!
VitaminEhasshowninsomeinstancestoprotect
againstdementia
Othertypesofdementia
Lewybodydementia(~1525%ofallcasesof
dementia)
ThisischaracterisedbythepresenceofLewybodies
inthebrainstemandneocortex.Itcanbe
differentiatedfromothertypesofdementiaby:
Symptomsfluctuate
Permanentmemorydysfunctionisnotapparentin
theearlystages
AssociatedwithParkinsonianism
Associatedwithdepressionandsleepdisturbance
Causesvisualhallucinationsoftenfrighteningand
persecutory
TheremaybetransientLOC
Thedrugrivastigminemayhelptoimprove
symptoms

Frontotemporaldementia
Inthisconditionthereisatrophyofthefronto
temporalregion,withoutthehistologyseenin
Alzheimers.itmaybedifficulttodifferentiatefrom
Alzheimers,butbehavioural/personalitychangeare
morelikelytooccurearlyon,andthingslike
memoryandspatialawarenessmaybepreservedfor
longer.Thereisoftenmassivedisinhibition.

Rarecauses
Whipplesdisease
Parkinsonsdisease
Alcohol/drugabuse
Huntingtonsdisease
CJD
HIV
Picksdisease
DifferentialsforDementia
Pseudodementiaseeninmooddisorders(e.g.
depression).Symptomsmimicdepressione.g.a
declineincognitivefunction,butwillresolvewhen
themooddisorderistreated.Thereisalsooftena
historyofdepressionorothermentalillness
Delerium
Mild/moderatelearningdifficulties