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Importància,clínica,dels,infarts,lacunars,i,la,seva,

repercussió,en,la,cognició,

IDC$Salut$Hospital$Sagrat$Cor$de$Barcelona6$Consorci$Sanitari$Parc$Taulí$de$

Sabadell.$$

Universitat$Autònoma$de$Barcelona,$Facultat$de$Medicina.$$

Departament$de$Psiquiatria$i$Medicina$Legal.$

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Doctorat$de$Psiquiatria$(itinerari$Neurociència$cognitiva)$

AUTORA:$Lorena$Blanco$Rojas$

DIRECTOR$DE$TESI:$Dr.$Adrià$Arboix$

TUTOR:$Dr.$Diego$Palao$

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Aquest'treball'ha'estat'realitzat'amb'molt'a'cura,'perseverança'i'especialment'amb'

il·lusió.'Moltes' persones'm’han' acompanyat' en' aquest' viatge' i' gràcies' a' elles' he'

arribat' fins' al' final' del'meu' somni.'Un' camí' a' vegades' gratificant' a' vegades'dur,'

però'sempre'fructífer.''

Li'dedico'aquest' llibre'a' la'meva'mare,'perquè'm’has'ensenyat' el' significat'de' la'

paraula' AMOR,' per' ensenyarHme' a' lluitar' per' els' meus' somnis' i' per' tot' el' teu'

recolzament'incondicional.''

Al' meu' pare,' per' l’alegria' que' desprèn' cada' dia' de' la' seva' vida,' per' tots' els'

somriures'que'm’has'robat.'Per'ser'únic'com'ets.''

Gràcies'al'Doctor'Adrià'Arboix'perquè'ha'estat'com'un'pare'en'el'món'de'la'ciència.'

Tot'un'exemple'a'seguir'de'professionalitat,'elegància'i'constància'en'el'seu'treball'

diari.'Sense'vostè'la'publicació'd’aquest'treball'no'hagués'estat'possible.''

A' tots' i' cadascun'dels'professionals'que'han' contribuït' a' l’aprenentatge'del'meu'

coneixement' científic' i' que'm’han' ensenyat' dia' a' dia' a' ser'millor' professional' i'

especialment,'millor'persona.''

Als'meus'amics'i'familiars'que'transformeu'les'vostres'alegries'en'meves'i'que'amb'

el' vostre' entusiasme' i' estima' heu' omplert' cadascuna' de' les' pàgines' d’aquest'

treball'

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I' especialment' al'meu' company,' amic,' parella' i' estimat' Julián,' que' cada' dia' que'

passo'al'teu'costat'és'especial,' i'et'dono'les'gràcies'per'la'teva'manera'd’estimarH

me'i'recolzarHme'en'tots'els'meus'projectes.''

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‘EL'HOMBRE'NUNCA'SABE'DE'LO'QUE'ES'CAPAZ''HASTA'QUE'LO'INTENTA’''

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INDEX$GENERAL$

!!1.,Introducció$ 1$

A. Història!

B. Concepte!de!l'infart!lacunar!

C. Fisiopatologia!de!petit!vas!

D. Factors!de!risc!

E. Manifestacions!clíniques!

F. Topografia!lacunar!

G. Epidemiologia!

H. Alteracions!neuropsicològiques!dels!infarts!lacunars!

I. Neuroimatge!dels!infarts!lacunars!

J. Antecedents!d'estudis!clínics!segons!el!gènere!

K. Estratègies!pel!tractament!secundari!de!l'infart!lacunar!

L. Línies!d'investigació!futures! ! !

2.,Hipòtesis,i,Objectius$ 33$

3.,Mètodes$ 37$

4.$Publicacions$ 43$

Primera$publicació:$ 46$

Advancements!in!understanding!the!mechanisms!of!symptomatic!lacunar!ischemic!

stroke:!translation!of!knowledge!to!prevention!strategies.!!Expert!Rev.!Neurother.!

14(3),!261–276!(2014).!Adrià+Arboix,+Lorena+Blanco<Rojas,+Josep+Lluis+Martí<Vilalta.!$

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Segona$publicació:! 65$$

Clinical! characteristics! of! acute! lacunar! stroke! in! women:! emphasis! on! gender!

differences.!Acta!Neurol!Belg.!2014!Jun;114(2):107H12.!Doi:!10.1007/s13760H013H

0257H8.!Epub!2013!Nov!6.!Adrià+Arboix,+Lorena+Blanco<Rojas,+Montserrat+Oliveres,+

Luis+García<Eroles,+Emili+Comes,+Juan+Massons.$ $

Tercera$publicació:! 73$

Cognitive!profile!in!patients!with!a!firstHever!lacunar!infart!with!and!without!silent!

lacunes:! a! comparative! study.! BlancoHRojas! et! al.! BMC! Neurology! 2013,! 13:203.!

Lorena+Blanco<Rojas,+Adrià+Arboix,+David+Cánovas,+Marta+Grau<Olivares,+Joan+Carles+

Oliva+Morera+and+Olga+Parra.$ $

Quarta$publicació:$ 83!!

Cognitive!impairment!in!ischaemic!lacunar!stroke.!European!Neurological!Review,!

2013;8!(2):!144H8.!Adrià+Arboix+and+Lorena+Blanco<Rojas.$ $

5.$Discussió$ 89$

6.$Conclusions$ 113$

7.$Bibliografia$ 117$

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Abreviatures:$

AIT' ' Accident'isquèmic'transitori'

DCL' ' Deteriorament'cognitiu'lleu'

DCS' ' Deteriorament'cognitiu'subjectiu'

DVS' ' Demència'vascular'subcortical'

DWI' ' DiffusionHweighted'imaging''

HSB'' ' Hiperintensitat'de'substància'blanca'

IL'' ' Infart'lacunar'

IMC' ' Índex'de'massa'corporal'

mg' ' Mil·ligrams'

mmHg'' Mil·límetres'de'Mercuri'

MPV' ' Malaltia'de'petit'vas'

RM'' ' Ressonància'magnètica'

SPS3' ' Secondary'Prevention'of'Small'Subcortical'Stroke'

TC' ' Tomografia'Computeritzada'

ROI' ' Regions'of'Interest'

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1.#Introducció!

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A. Història*

El!terme!‘lacunar’,!que!vol!dir!cavitat,!forat!o!lesió!de!mesura!petita,!va!ser!utilitzat!

per!primer!cop!com!a!criteri!neuropatològic!pel!metge!francès!Déchambre!a!1838!

(1812E1886),! considerantEse! un! sinònim! de! ‘cavitat! cerebral’.! Déchambre! va!

descriure!les!llacunes!cerebrals!com!a!cavitats!petites!que!s’observaven!en!mostres!

del! teixit! nerviós! del! cervell! com! a! resultat! de! la! reabsorció! del! teixit! necròtic!

desprès!d’un!infart!cerebral!de!petit!vas.!!!

Des!de!les!primeres!descripcions!del!terme!fins!a!l’últim!segle,!han!aparegut!moltes!

contradiccions!sobre!el!terme!lacunar!ja!que!va!ser!emprat!per!a!descriure!lesions!

cavitatòries!de!l’état*criblé!i!de!la!substància!!grisa!(DurantEFardel,!1842)!descrites!

com! a! múltiples! i! petites! lesions! trobades! a! la! substància! blanca! d’ambdós!

hemisferis! secundaris! en! la! dilatació! perivascular! dels! espais! de! VirchowERobin,!

localitzat!entre!la!piamare!i!les!artèries!perforants!cerebrals.!El!terme!lacunar!era!

emprat! indistintament! per! a! descriure! una! lesió! residual! d’infarts! petits,! lesió!

d’hemorràgies! antigues! i! petites! o! porosi! a! causa! d’autòlisis! bacteriana! post!

mortem.!!

A! 1901,! i! a! partir! d’un! estudi! de! 50! casos! d’infart! capsular,! Pierre! Marie! va!

reprendre!el!significat!original!del!terme!llacuna,!com!a!lesió!secundària!a!un!infart!

cerebral!petit!i!de!topografia!profunda!degut!a!un!procés!arterioscleròtic!.!!

Al!1902,!Ferrand!va!estudiar!88!necròpsies!i!va!arribar!a!les!mateixes!conclusions!

que!Pierre!Marie.!Des!de!Foix,!Thurel,!Trelles,!Garcin!i!Lapresle!van!reportar!casos!

únics!clinicopatològics.!

Durant!les!primeres!dècades!del!segle!XX,!les!llacunes!cerebrals!són!considerades!

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com!un!concepte!patològic! i!va!generar!molta!confusió!sobre! l’etiologia! lacunar! ,!

assenyalant! que! els! infarts! cerebrals,! hemorràgies! petites! o! inflamació! arterial,!

anomenades!‘!vaginalitis!destructive’,!podien!constituir!la!causa!de!les!llacunes!(1)!

(2).! Els! patòlegs! alemanys! Cécile! i! Oskar! Voght! van! demostrar! que! les! llacunes!

eren!causades!per!infarts!isquèmics.!!

Al!final!del!1950,!Fisher!reprèn!els!estudis!dels!infarts!lacunars!des!del!criteri!clínic!

i! patològic! i! descriu! les! principals! síndromes! lacunars:! hemiplegia! motora! pura!

(1965)!(3);!síndrome!sensitiva!pura!(1965)!(4);!parèsia!crural!i!atàxia!homolateral!

(1965)!(5)!que!actualment!es!coneix!amb!el!nom!d’atàxia!hemiparèsia!(1978)!(6);!i!

disàrtria! màEfeixuga! (1967)! (7),! les! quals! són! considerades! com! a! expressions!

clíniques! dels! infarts! isquèmics! cerebrals.! En! aquest! estudi! patològic,! l’autor! va!

analitzar!114!cervells! i!va!descriure! les! llacunes!com!a!petites!cavitats!resultants!

de! l’oclusió! de! vasos! sanguinis! petits! d’entre! 2! i! 17! mil·límetres! de! diàmetre,!

localitzats! concretament! als! ganglis! basals! i! a! la! càpsula! interna.! Arran! d’aquest!

treball,! Fisher! va! concloure! que! la! ‘hipòtesi! lacunar’! establia! la! relació! entre! els!

símptomes! focals! amb! presència! d’una! síndrome! lacunar,! una! localització!

topogràfica!específica,!amb!un!enfocament!etiològic!i!terapèutic!propi.!!

Uns! anys!més! tard,!Mohr! va! descriure! la! síndrome! sensitiva!motora! (1977)(8)! i!

Fisher!(1982)!(9)!va!expandir!el!nombre!de!síndromes!lacunars!per!tal!d’incloure!

les!lesions!isquèmiques!de!mida!petita!i!amb!un!perfil!clínic!específic,!diferent!de!

les! síndromes! lacunars! clàssiques! descrites,! i! van! constituir! les! anomenades!

síndromes!lacunars!atípiques.!Posteriorment,!la!hipòtesi!lacunar!va!

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ser! qüestionada!per!diversos! autors,! pels! quals! la! síndrome! lacunar!podia! ser! el!

resultat! també! d’un! infart! isquèmic! extens,! de! petites! hemorràgies! cerebrals! i!

d’altres!etiologies!diferents!de!l’infart!lacunar.!

Tot!i!això,!moltes!!sèries!clíniques!prospectives!van!demostrar!posteriorment!que!

les!síndromes!lacunars!eren!causades!per!infarts!cerebrals!de!tipus!lacunar!en!més!

del! 80%!de! casos! i! per! aquest!motiu,! es! va! confirmar! la! validesa!de! la! hipòtesis!

lacunar!(10E12)!

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B. Concepte*

Les! llacunes!o! l’infart! cerebral!de! tipus! lacunar!és!un! infart! isquèmic!petit! (<!20!

mm! de! diàmetre)! localitzat! en! el! territori! de! distribució! de! les! arterioles!

penetrants!o!profundes.!Aquestes!arterioles!mesuren!de!100!a!400!μm!de!diàmetre!

i!proporcionen!la!vascularització!sanguínia!dels!territoris!més!propers!i!profunds!

de! l’artèria! cerebral! mitja,! de! l’artèria! cerebral! anterior,! posterior! o! basilar.! Els!

pacients! amb! un! IL! presenten! habitualment! una! de! les! cinc! síndromes! lacunars!

clàssiques! com! són! l’hemiparèsia! motora! pura,! la! síndrome! sensitiva! pura,! la!

síndrome! sensitiuEmotora,! la! disàrtria! màEfeixuga! i! l’hemiparèsia! atàxica.!

Ocasionalment! s’identifica! també! la!disàrtria! amb!parèsia! facial! central,! disàrtria!

aïllada,!hemiatàxia!aïllada!o!la!síndrome!hemicorea!hemibalisme!i!representen!les!

síndromes!lacunars!atípiques!més!habituals.!

Els!infarts!lacunar!són!més!freqüents!en!els!pacients!hipertensos!i/o!diabètics.!!

El!concepte!de!síndrome!lacunar!va!ser!introduït!a!la!pràctica!clínica!per!a!referirE

se!a!aquells!quadres!clínics!que!són!causats!per!un!infart!cerebral!de!tipus!lacunar,!!

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i! encara! que! en! un! 10E15%! dels! casos! poder! ser! atribuïbles! a! altres! trastorns!

vasculars! cerebrals! (principalment! hemorràgies! intracerebrals! petites! o! infarts!

subcorticals! grans)! o! per! trastorns! no! vasculars! (per! exemple:! processos!

expansius,!hematoma!subdural!o!malaltia!desmielinitzant).!!

En! la! pràctica! clínica,! aproximadament! un!de! cada! cinc! pacients! amb!un! episodi!

d’isquèmia! cerebral! va! ser! un! IL! (13).! En! el! Registre! de! Barcelona! de! Malalties!

Vasculars!Cerebrals,!la!freqüència!de!l’infart!lacunar!va!ser!d’un!11%,!es!a!dir,!399!

en!un!total!de!3577!pacients!amb!infart!agut.!En!el!NINDS!Stroke!Data!Bankun!un!

total!de!337!de!1273!pacients!amb!un!infart!cerebral!van!presentar!una!síndrome!

lacunar!clàssica!(27%)!(14).!

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C. Fisiopatologia*de*la*malaltia*de*petit*vas!

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S’identifiquen!diverses! causes!de! l’origen!de! la!malaltia!de!petit! vas! com!ara,! les!

arteriopaties!trombòtiques,!l’oclusió!embòlica!i!altres!causes.!!

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Arteriopaties!trombòtiques!

Les!llacunes!són!causades!per!diferent!tipus!d’arteriopaties.!El!microateroma!està!

relacionat!amb!el! segment!proximal!de! l’artèria!penetrant!de!gran!calibre! (entre!

200!i!400!μm!de!diàmetre)!i!configura!el!mecanisme!més!comú!d’estenosi!arterial!

subjacent!als!infarts!simptomàtics!cerebrals!(15).!!

Ocasionalment,! el! microateroma! s’observa! a! prop! de! les! plaques! d’ateroma!

assentades!en!la!paret!de!l’artèria!gran!(placa!mural)!la!qual!bloqueja!les!branques!

penetrants!causant!els!infarts!lacunar!de!gran!mida!.!!

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Per! altra! banda,! la! lipohialinosi!està! considerada! formalment! com! la! causa!més!

freqüent!dels!IL,!afectant!les!artèries!penetrants!petites!(<!200!μm!de!diàmetre)!i!

explicaria! les! llacunes! més! petites,! especialment! aquelles! que! són! clínicament!

asimptomàtiques.!

La! lipohialinosi! es! dóna! com! a! conseqüència! de! la! hipertensió! crònica,! i! és!

considerada!com!un!pas!intermedi!entre!el!microateroma!i!la!necrosi!fibrinoide.!!

La! necrosis! fibrinoide! es! troba! a! les! arterioles! i! els! capil·lars! cerebrals! que! han!

patit! un! augment! sobtat! de! pressió! arterial,! com! l’encefalopatia! hipertensiva! o!

eclàmpsia.! Aquest! mecanisme! és! produït! per! un! desordre! en! l’autoregulació!

cerebrovascular!i!produeix!nivells!de!pressió!arterial!elevats!i!fa!que!les!parets!no!

es!contreguin!i!com!a!conseqüència!dóna!lloc!a!la!necrosis!vascular!(16).!

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Oclusió!embòlica!

L’oclusió! embòlica! de! les! artèries! penetrants! (o! de! les! pròpies! arterioles!

perforants)! pot! ser! deguda! a! dues! causes:! l’embolisme! d’origen! cardíac! i!

l’embolisme!d’origen!arterial.!La!primera!causa!es!dona!com!a!conseqüència!d’un!

èmbol! cardíac,! particularment,! secundari! a! fibril·lació! atrial,! malaltia! valvular!

cardíaca! reumàtica! o! una! miocardiopatia.! Per! altra! banda! l’embolisme! arterial!

també! es! pot! relacionar! amb! l’ateromatosi! de! l’arc! aòrtic! o! de! l’artèria! carotídia!

com! a! causa! d’un!microèmbol! dels! fragments! d’ateroma! o! cristalls! de! colesterol!

que!poden!ser!la!causa!dels!IL!(17).!

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!Altres!causes!

L’estenosi!de!l’artèria!penetrant!dóna!com!a!resultat!un!estat!d’hipoperfusió!distal!

i! causa! IL.!Aquest! tipus!d’IL! relacionats! amb! les!alteracions*hemodinàmiques! són!

caracteritzats! prèviament! com! a! atacs! isquèmics! transitoris! (AIT),! els! qual! es!

caracteritzen! per! una! clínica! fluctuant,! progressiva! i! recurrents! en! les! següents!

setmanes!a!l’aparició!del!primer!episodi!(18).!!

Les!llacunes!que!han!estat!relacionades!amb!la!trombosi!causada!per!aneurismes!

de! CharcotEBouchard! són! resultants! de! la! dissecció! progressiva! de! les! parets!

arterials!a!la!hipertensió!crònica!(15).!

Els!casos!de!policitèmia*vera*o*trombocitèmia!essencial!poden!causar!isquèmia!en!

la!distribució!del!territori!de!les!arterioles!cerebrals! i!poden!ser!causants!dels!IL.!

Les! infeccions! en! forma! d’una! vasculitis! infecciosa! crònica,! com! en! la! sífilis!

meningovascular! o! la! neurocisticercosi! també! s’han! descrit! com! a! causants! d’IL!

(19).!

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Una!nova!hipòtesis!lacunar!

Basada!en!l’observació!clínica!de!la!progressió!de!la!malaltia!vascular!a!mig!i!llarg!

termini,!Wardlaw*et*al.*van!considerar!una!nova!hipòtesi!per!explicar!la!progressió!

de!la!microangiopatia!cerebral!tot!considerant!els!IL!com!a!una!manifestació!focal!

d’una!malaltia!vascular!progressiva! i!difusa!de! les!arterioles!petites,! les!quals!son!

les! causants! de! l’alteració! cognitiva! i! demència! quan! la! lesió! és! suficientment!

extensa!(20).!Les!alteracions!a!l’endoteli!provocades!per!la!hipertensió!i!la!diabetis!

produirien! una! sobtada! alteració! de! la! permeabilitat! de! la! barrera!

hematoencefàlica!amb!l’extravasació!de!components!sanguinis!que!són!tòxics!per!al!

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teixit! cerebral! (plasmina! i! d’altres! proteases)! que! afecten! la! paret! arteriolar! i!

subseqüentment!al! teixit!perivascular,!produint!dany!glial! i! neuronal.!Per! tant,! el!

fluït! intersticial!podria!causar! la! interrupció!de! la! transmissió!del!senyal!axonal,! i!

l’amplitud! de! la! paret! del! vas! podria! determinar! el! detriment! del! lumen! i! la!

reducció!del!flux!cerebral.!Aquest!procés!gradual!i!asimptomàtic!podria!explicar!la!

formació!dels!IL!silents,!leucoaraiosi,!declivi!cognitiu!i!demència.!!

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D. Factors*de*risc*

Són!diversos!els!factors!de!risc!associats!als!infarts!lacunars.!!

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Edat!

La!mitja!d’edat!d’aparició!oscil·la!entre!els!55!i!75!anys.!Els!estudis!clínics!que!han!

dividit!l’edat!en!els!següents!subgrups!d’edats(<!65!anys;!65E74!anys;!75E84!anys!i!

>85!anys)!mostren!que!els! IL!van!ser!més! freqüents!al!grup!de!pacients!per!sota!

dels!65!anys!(29,6%)!i!en!el!grup!de!65E74!anys!(31,7%)!(19).!L’aparició!d’aquesta!

patologia!de!petit!vas!en!el!grup!d’adults!joves!per!sota!dels!45!anys!és!infreqüent,!

aproximadament!el!8%!en!una!sèrie!clínica!de!227!pacients!(21).!!

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Sexe!

Diversos!estudis!han!mostrat!que! la! incidència!en! infarts! lacunars!és!superior!en!

homes!que!en!dones,!independentment!de!l’edat! !del!pacient! !(19)!(21).!Arboix*et*

al.!!han!posat!de!manifest!diferències!clíniques!entre!ambdós!sexes!(22).!

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!Hipertensió!arterial!

La!hipertensió!arterial!és!simultàniament!un!factor!de!risc!(!per!l’arteriosclerosi)!i!

causa!(mitjançant!la!lipohialinosi)!de!l’infart!lacunar.!Està!present!en!un!97%!dels!

casos!i!es!va!considerar!una!etiologia!específica!als!estudis!de!Fisher.!És!un!factor!

de!risc!independent!per!a!l’infart!isquèmic,!però!és!el!major!factor!de!risc!per!!l’IL!

en!particular!en!comparació!amb!altres!subtipus!d’infarts!(>70%)!(11,!21).!A!més,!

la!presència!de!múltiples!infarts!lacunar!està!associada!de!forma!!significativa!amb!

la!hipertensió!arterial!i!aquesta!està!relacionada!amb!la!leucoaraiosi!i!els!IL!silents!

clínicament!silents,!amb! la!seva!recurrència! i!amb!un!risc!elevat!de!presència!de!

deteriorament!cognitiu!en!pacients!amb!infarts!lacunars(23,!24).!!

!

Diabetis!mellitus!

La!diabetis!constitueix!un!factor!de!risc!i!probablement!un!factor!etiològic!dels!IL,!

de!forma!similar!a!la!hipertensió!arterial.!La!seva!incidència!es!menor:!11%!en!les!

sèries! de! Fisher,! 16%! en! les! sèries! de!Norvingand! Staff! i! 29%! en! el! Registre! de!

Barcelona!de!Malalties!Vasculars!Cerebrals.!La!prevalença!de!la!diabetis!mellitus!és!

més!alta!en!els!IL!que!en!la!resta!de!subtipus!d’infarts,!i!es!confirma!com!a!factor!de!

risc!independent!per!als!infarts!lacunars,!particularment!en!els!casos!de!múltiples!

infarts! lacunars! (25).! La! presència! de! diabetis! mellitus! està! associada! amb! una!

pitjor!recuperació!funcional!en!pacients!amb!infart!lacunar(24).!

!

!

!

! 11!

!Malaltia!cardíaca!

La!malaltia!cardíaca!isquèmica!és!un!factor!de!risc!cerebrovascular!i!un!indicador!

d’aterosclerosis!general,!amb!un!índex!del!26%!en!la!nostra!sèrie!(21)!i!entre!el!!

17%! (26)! i! el! 39%! en! altres! sèries! publicades! a! la! literatura! (27).! L’elevada!

freqüència!de!presentació!de!fibril·lació!atrial,!la!baixa!freqüència!de!la!hipertensió!

arterial! ! i! la! presència! de!diabetis!mellitus! actues! com!a!mecanismes!patogènics!

cardioembòlics! i!es!donen!amb!major!freqüència!en!els!pacients!que!es!situen!en!

un!segment!d’edat!molt!avançada!(85!anys!o!més).!!

!

Aterosclerosi!carotídia!!L’aterosclerosi! carotídia! que! es! manifesta! com! una! forma! de! estenosi! carotídia,!

amb!una!reducció!del!lumen!(>50%)!!i!que!s’ha!evidenciat!en!un!8E13%!dels!infarts!

lacunars.! L’estenosi! carotídia! és! un! indicador! d’aterosclerosi! general,! i! pot!

intervenir!com!a!causa!de! l’infart!per!el!mecanisme!emboligen!artèriaEartèria.!En!

un! estudi! clínic! el! 8%! dels! pacients! amb! un! IL! van! tenir! una! claudicació!

intermitent.! En! aquest! pacients,! l’estenosi! arterial! carotídia! gran! del! 50%! es! va!

trobar!en!el!15,4%!dels!casos!comparats!amb!el!6,5%!de!resta!de!pacients!i!va!ser!

un! factor!predictor! independent!de! l’IL!associat!a! la!claudicació! intermitent!(28).!

En! altres! estudis,! la! presència! de! diabetis! i! hiperlipèmia! van! ser! associades! de!

forma! independent! amb! les! llacunes! en! pacients! amb! estenosi! arterial! carotídia!

(29).!

!

!

! 12!

Atacs!isquèmics!transitoris!(AIT)!

En!els!estudis!clínics,!estan!descrits!un!20%!de!AIT!previs!als!infarts!lacunars!(30).!

No!s’ha!correlacionat!amb!un!subtipus!concret!de!llacuna!ni!amb!la!severitat!de!la!

clínica.! Comparant! els! AIT! de! les! grans! artèries,! els! AIT! ! previs! als! IL! tenen! un!

major!nombre!d’episodis,!el!dèficit!neurològic!de!major!durada,!un!menor! temps!

de! latència! entre! el! primer! i! l’últim! AIT! i! l’infart! definitiu.! L’inici! progressiu! i!

fluctuant!és!més!comú!als!infarts!lacunars!amb!AIT!que!sense!presència!d’AIT.!S’ha!

trobat! una! correlació! positiva! entre! nombre! de! AIT! previs! i! el! volum! de! l’infart!

lacunar!(29).!

!

Tabaquisme!

El!tabaquisme!és!considerat!com!a!factor!de!risc!dels!IL,!amb!una!incidència!entre!

el! 28%! (26)! i! 68%! (27).! En! dos! estudis! de! casos! control! el! tabaquisme!

incrementava!el!risc!de!patir!un!IL!en!2,3!(31)!i!6,6!vegades!respectivament!(32).!

!

Altres!factors!de!risc!

La! hipercolesterolèmia,! el! consum! d’alcohol,! un! nivell! d’hematòcrit! alt! i! l’ús! de!

contraceptius!orals,!no!són!considerats!com!a!factors!de!risc!de!l’IL.!En!el!cas!d’un!

estudi!clínic,!els!nivell!d’homocisteïna!van!ser!associats!amb!l’edat!i!amb!l’estil!de!

vida!i!contribueixen!al!risc!de!patir!IL!silents.!La!majoria!de!lesions!eren!inferiors!a!

10!mil·límetres!de!diàmetre!i!van!ser!localitzades!a!la!substància!blanca!subcortical!

o! en!els! ganglis!basals! (33).!En! canvi!un!altre! estudi! van!mostrar!que!els!nivells!

d’homocisteïna!total!apareixen!associats!amb!l’infart!lacunar!(34).!

!

! 13!

Infart!lacunar!d’etiologia!inusual!!

Menys!d’un!5%!dels!casos!amb!IL!són!causats!per!etiologia!inusual,!principalment!

per! trastorns! hematològics,! infeccions! o! arteritis! inflamatòria.! Les! alteracions!

hematològiques!poden!ser!la!policitèmia!vera,!trombocitemia!essencial!i!síndrome!

primari!antifosfolipid!anticossos.!

L’embolisme! produït! per! una! placa! carotídia! arterioscleròtica! o! associat! a! una!

estenosi! severa! de! les! arterioles! perforants! i! l’angiopatia! amiloide! cerebral! són!

altres!causes!poc!comunes!d’etiologia!de!l’IL!(30).!

L’arteritis!infecciosa!a!causa!de!!neurosífilis,!neurocisticercosis,!neuroborreliosis!i!!

el! SIDA!han!estat!associats!amb! IL.!Els!pacients!amb!un!primer! infart! lacunar,! la!

infecció! d’Helicobacter! pylori! detectat! amb! anticossos! IgG! està! associat! amb! un!

risc!d’oclusions!d’arteries!petites.!

!

E. Manifestacions*clíniques!

Les! diferents! formes! en! que! es! poden! presentar! els! IL! són! les! següents:! infart!

lacunar! asimptomàtic,! accident! isquèmic! transitori,! síndrome! lacunar! clàssic! i!

síndrome!lacunar!atípic.!

!

Infarts!lacunars!asimptomàtics!

Els!IL!asimptomàtics!són!més!freqüent!en!pacients!amb!hipertensió!arterial! i!són!!

freqüents!els!infarts!múltiples!i!causats!per!mecanismes!de!lipohialinosi.!Els!infarts!

silents!es!troben!en!un!52%!dels!casos!en!sèries!clinicopatològiques!(35),!i!en!un!

77%!en!les!sèries!patològiques!de!Fisher!(36).!Els!infarts!silents!acompanyen!als!IL!

clàssics!en!un!42%!dels!casos,! i!són!fàcilment!evidenciats!mitjançant!ressonància!

magnètica! (RM)! cerebral! ! (37).! Degut! a! la! mesura! petita! i! a! la! topografia,! els!

! 14!

símptomes! clínics! focals! neurològics! només! es! produeixen! quan! els! IL! afecten!

àrees!motores!o!sensitives!(30).!!

!

Accident!isquèmic!transitori!(AIT)!

Els! AIT! lacunars! són! aquells! episodis! neurològics! transitoris! i! la! disfunció! és!

causada! per! una! isquèmia! focal! de! petit! vas! cerebral! sense! la! presència! d’infart!!

agut!amb!una!duració!habitualment!de!minuts! i!generalment! inferior!a!una!hora.!

Les!troballes!de!la!restricció!de!la!difusió!a!partir!de!la!RM!cerebral!ocasionalment!

es! poden! correlacionar! amb! la! disfunció! transitòria! lacunar.! Nombrosos! estudis!

han!mostrat!que!els!AIT!tant!de!petit!vas!com!de!gran!vas!arterial!presenten!un!risc!

alt!a!curt!termini!de!provocar!infarts!cerebrals!definitius,! i!particularment,!el!risc!

s’incrementa!en!un!27%!passat!els!90!dies!desprès!de!l’AIT!(38).!!

!

Les!síndromes!lacunars!clàssics!

!

Les!síndromes!lacunars!clàssiques!són!aquells!accidents!vasculars!no!transitoris!i!

presenten!dèficits!neurològics!específics!en!forma!de!hemiparèsia!motora!pura,!la!

síndrome! sensitiva!pura,! la! síndrome! sensitivoEmotora,! l’hemiparèsia! atàxica! i! la!

síndrome!de!disàrtria!mà!feixuga.!Segons!el!ritme!circadià,!la!disfunció!neurològica!

focal!es!produeix!en!un!32,5%!durant!el!somni!i!en!un!67,5%!durant!el!ritme!diürn!

(39).!!

Les! manifestacions! neurològiques,! neuropsicològiques! i! clíniques! observades! en!

aquests! pacients! es! detallen! a! continuació,! destacant! però! l’absència! de! dèficits!

visuals!i!oculomotors;!el!bon!nivell!de!consciència;!l’absència!d’atacs!epilèptics!i/o!

símptomes! suggestius! d’implicació! dels! tronc! encefàlic;! la! no! presència!

! 15!

d’alteracions! de! funcions! cognitives! superiors! com! afàsia,! agnòsia,! apràxia! i!

negligència;!l’absència!d’afectacions!dismnèsiques;!o!deteriorament!de!les!funcions!

cognitives! superiors;! i! l’absència! de! vòmits! i! símptomes! vegetatius! (9).! En! el!

moment!agut!de!la!malaltia!poden!aparèixer!mals!de!cap!en!un!9E23%!dels!casos!!

especialment!en!les!lesions!lacunars!de!tronc!encefàlic!i!substància!grisa!cerebral!

(40).!Alguns! estudis!han!mostrat!una! recuperació!neurològica!més! lenta!quan!el!

mal!de!!cap!persisteix!en!els!infarts!de!tronc!encefàlic!i!de!substància!grisa!(41).!!

Les! síndromes! lacunars! clàssiques! en! ordre! descendent! de! freqüència! serien!!

l’hemiparèsia! motora! pura,! la! síndrome! sensitiva! pura,! la! síndrome! sensitiva!

motora,! l’hemiparèsia! atàxica! i! la! disàrtria!màE! feixuga! (9)! (30).! Això! coincideix!

amb!els!resultats!d’un!estudi!multicèntric!espanyol!retrospectiu!portat!a! terme!a!

l’any!1989,!on!van!participar!15!serveis!de!Neurologia!i!on!es!van!reclutar!un!total!

de!1194!pacients!amb!IL!(42).!!!!

!

Hemiparèsia!motora!pura!

També!conegut!com!a!infart!motor!pur,!és!la!forma!clínica!més!comuna!entre!els!IL!

(al!voltant!de!la!meitat!o!dos!terços!del!total!de!IL).!Segons!els!diferents!registres!!

la!hemiparèsia!motora!pura!(HMP)!es!presenta!en!un!12.7!%!del!pacients!amb!un!

primer! infarts! i! un! 50%!de! totes! les! síndromes! lacunars! (43).! Les! localitzacions!

cerebrals! més! freqüents! són! el! braç! posterior! de! la! càpsula,! corona! radiata! i!

protuberància!(43,!44).!Alguns!infarts!en!el!mesencèfal!(45)!o!medul·lars!(46)!han!

estat!reportats!ocasionalment.!!

La! HMP! va! ser! la! primera! síndrome! clínica! reconeguda.! Les! característiques!

clíniques!inclouen!hemiplegia!que!afecta!a!la!cara,!el!braç!i!les!extremitats!inferiors!

(facioEbraquioEcrural)! o! hemiparèsia! incomplerta! amb! una! distribució!

! 16!

braquiofacial! o! braquiocrural! en! absència! de! dèficit! sensitiu,! dèficit! visual! i!

alteració!de!la!consciència!o!un!trastorn!de!las!funcions!cognitives!superiors!(30).!

El! dèficit! braquiofacial! o! braquiocrural! ! han! estat! acceptat! com! una! síndrome!

lacunar!parcial,!sense!altra!dèficit!associat,!i!són!d’origen!cortical!(30).!En!una!sèrie!

de!222!pacients!amb!HMP!es!van!trobar!IL!en!un!85%!de!la!mostra,!mentre!que!el!

10,4%! era! causat! per! un! infart! no! lacunar! i! la! resta! per! la! síndrome! lacunar!

hemorràgica!(43).!!

!

La!síndrome!sensitiva!pura!

La! síndrome! sensitiva! pura! (SSP)! també! coneguda! com! a! infart! sensitiu! pur! i! la!

seva! clínica! es! presenta! com! a! dèficit! sensitiu! (hipoestèsia)! i/o! alteracions!

sensitives! ! irritatives! (parestèsies)! tant! en! la! sensibilitat! superficial! ! com! en! la!

profunda! o! en! ambdues.! Les! síndromes! hemisensitives! completes!

(faciobraquiocrurals)!són!les!més!freqüents!.!En!canvi,!les!síndromes!de!distribució!

queiroEoral!!o!queiroEoralEpedal!són!molt!poc!freqüents.!La!topografia!lacunar!més!

habitual!és!el!nucli!ventroposterolateral!del!tàlem!(4,!47).!Però!altres!localitzacions!

amb!compromís!de!les!vies!sensitives!són!les!projeccions!talamocorticals!i!el!bulb!

raquidi.! Segons! un! registre! d’infarts! d’uns! 2500! pacients! seleccionats! durant! 12!

anys!van!trobar!que!99!d’aquest!pacients!presentaven!la!síndrome!sensitiva!pura.!

Aquesta!síndrome!es!va!comptabilitzar!en!un!5.4!%!dels!infarts!isquèmics!aguts!i!

en!un!17,4%!de!les!síndromes!lacunars!(47).!!!

!

! 17!

Síndrome!sensitiumotor!

Aquesta!síndrome!es!pot!presentar!com!a!completa!(faciobraquiocrural)!o!com!a!

incomplerta!(faciobraquial!o!braquiocrural)!i!s’associa!un!dèficit!piramidal!amb!un!

trastorn! sensitiu! concomitant! ! ipsilateral! (8,! 30).! Aquesta! síndrome! es! deguda! a!

infarts! lacunars! en! el! 69,5%.! Però! l’altra! 30,5%! es! degut! a! altres! tipus! d’infarts!

cerebral!(48).!

!

Atàxia!hemiparèsia!

Aquesta! síndrome! clínica! es! manifesta! de! forma! secundària! a! una! lesió!

corticopontocerebel.losa,!dentatorubrotalamocortical!o!de!les!vies!somestèsiques!

propioceptives!de!la!part!posterior!de!la!càpsula!interna!o!de!la!protuberància!(49E

51).! S’han! fet! referència! a! altres! localitzacions! topogràfiques! com! el! tàlem! i! la!

corona! radiata.! Aquesta! síndrome! inclou! presència! simultània! de! síndrome!

piramidal! (de! predomini! crural)! associada! a! una! síndrome! atàxica! homolateral.!

També! es! pot! observar! la! paràlisis! crural! aïllada! associada! a! una! hemiparèsia!

atàxica! ipsilateral.! S’han! descrit! casos! en! els! quals! els! símptomes!motors! poden!

anar!acompanyats!!per!un!dèficit!sensitiu!transitori!conegut!també!amb!el!nom!de!!

hemiparèsia* atàxica* amb* hipoestèsia* (52).! A! les! sèries! conclouen! que! el! 39%!

d’aquest! pacients! es! recuperen! de! forma! ràpida! degut! a! l’absència! de! dèficit!

neurològic!focal!greu!!i!presenten!una!escassa!o!nul·la!mortalitat!hospitalària!(51).!!

!

!

!

!

!

!

!

! 18!

Disàrtria>!mà!feixuga.!!

Es!considerada!una!de! les!síndromes! lacunars!clàssiques!més! infreqüents!encara!

que! té! un! bon! pronòstic! a! llarg! termini.! Les! manifestacions! clíniques! inclouen:!

moderada!o!severa!disàrtria!amb!debilitat!facial!central;!hiperreflèxia!lateral!amb!

signe!de!Babinski!positiu;!debilitat!a!les!mans!amb!una!clara!dificultat!a!les!tasques!

que!requereixen!habilitats!manuals!que!estan!associades!a!dèficits!motors!(7,!30,!

53).!En!el!registre!hospitalari! !de!Malalties!Vasculars!Cerebrals!de! l’Hospital!dels!

Sagrat!Cor!de!Barcelona!amb!un!mostra!amb!un!total!de!2500!pacients!es!va!trobar!

que!la!freqüència!d’aquesta!síndrome!va!ser!del!6,1%!degut!a!infart!lacunar!(53).!

Respecte! a! la! topografia! es! troben!normalment! a! lesions!originàries! a! la! càpsula!

interna!i!a!la!protuberància,!encara!que!es!troba!algun!a!la!corona!radiata!i!a!infarts!

al!peduncle!cerebel·lós.!!La!absència!de!dèficit!focal!intens!fa!que!el!46%!d’aquests!

pacients!es!recuperin!completament!a!l’alta!hospitalària!(53).!

!

La!síndrome!lacunar!atípica.!!

Miller! Fisher! va! descriure! 22! síndromes! clíniques! lacunars! no! descrites! en! les!

síndromes! clàssiques! (9).! L’Autor! va! identificar! entre! d’altres! les! següents!

síndromes:! alteracions! ! extrapiramidals! (hemicoreaE! hemibal·lisme! o! distonia);!

infarts! bilaterals! paramedials! talàmics;! hemiparèsia! motora! pura! amb! afàsia!

subcortical! i! formes! parcials! de! síndromes! lacunars! clàssiques! com! la! disàrtria!

aïllada! o! la! disàrtria! amb! parèsia! facial! central! aïllada.! Els! infarts! talàmics!

bilaterals! es! caracteritzen! per! diferents! nivell! d’alteració! de! la! consciència!

(somnolència! i! obnubilació),! alteracions! de! la! conducta! apatia! i! indiferència!

afectiva,! alteracions! oculomotores! i! deteriorament! de! les! funcions! cognitives!

! 19!

superiors.!La!síndrome! lacunar!atípica!es!causada!per! infarts!en!àrees!capsulars,!

pontines!i!al!tàlem.!!

Cal! afegir! que! la! prevalença! de! la! síndrome! lacunar! atípica! es! d’un! 6,8%! segons!

una! sèrie! clínica! de!Arboix* et* al.! (54).! Els! factors! de! risc! vascular! cerebral! i! les!

dades!demogràfiques!concomitants!són!les!mateixes!que!en!el!grup!de!síndromes!

lacunars!clàssiques.!

!

Síndrome!pseudobulbar!

Descrit! per! Thurel! com! a! una! síndrome! lacunar! amb! presència! de! disàrtria,!

disfàgia!i!alteracions!mímiques!(riure!o!un!plor!espasmòdic)!(4)!i!ocasionada!per!la!

presència!de!IL!de!repetició.!També!s’associa!amb!un!peculiar!trastorn!de!la!marxa!

(petits! passos),! apràxia! de! la!marxa! i! urgència! involuntària! urinària.!Hi! han! tres!

tipologies! d’infarts! pseudobulbar:! la! forma! corticosubcortical! de! FoixEChavanyE

Marie! o! síndrome! bipercular;! la! forma! pontocerebelosa;! i! la! forma! central! i!

semioval,! que! és! la! més! freqüent! deguda! a! infarts! lacunars! subcorticals!

disseminats!i!identificats!com!l’estat!lacunar!de!Pierre!Marie!(30).!

!

Síndrome!de!Binswanger!

La!síndrome!de!Binswanger!està!associada!a!l’alteració!significativa!i!important!de!

la! substància! blanca! perivascular! i! també! coneguda! amb! el! nom! de! leucoaraiosi!

(55).! Les! lesions! de! substància! blanca! s’observen! a! partir! de! la! Tomografia!

Computeritzada! (TC)! o! en! la! RM! cerebral! ! com! a! imatges! puntiformes!

hiperintenses! i! es! poden! quantificar! mitjançant! escales! observacionals! com! són!

l’escala! de! Scheltens! o! Fazekas.! Està! relacionada! amb! diferents! alteracions!

cognitives! i! demència,! i! es! produeixen! com! a! conseqüència! de! les! alteracions!

! 20!

hemodinàmiques!secundàries!a!la!aterosclerosi!de!les!artèries!penetrants!(56).!La!

síndrome! de! Binswanger! és! una! malaltia! progressiva! que! danya! la! substància!

blanca!de!tots!dos!hemisferis!i!els!factors!de!risc!són!la!hipertensió!arterial!severa,!

alteracions!cardiovasculars,!diabetis!i!quadres!d’hipotensió!recurrents.!Existeixen!

controvèrsies! sobre! la! patofisiologia! de! la! malaltia! associada! a! la! demència!

vascular! subcortical:! per! una! banda! la! oclusió! del! lumen! arteriolar! degut! a!

l’arteriosclerosi!dóna! lloc!a! la! formació!de! llacunes.! I!per!altra!banda,! la!estenosi!

crítica!i!la!hipoperfusió!de!les!arterioles!medul·lars!causada!per!infarts!incomplerts!

disseminats!de!la!substància!blanca!profunda!(55).!!

La!malaltia!de!Binswanger!s’identifica!amb!infarts!a!estructures!dels!ganglis!basals!

i! al! tàlem.!Normalment!hi!ha!presència!de! la! focalitat!neurològic! i! una!demència!

progressiva!lenta!(57,!58).!!

!

Infarts!en!el!centre!semioval!

Els! infarts! en! el! centre! semioval! són! poc! comuns! però! probablement! estan! ben!

reconeguts!a!la!RM!cerebral!en!les!seqüències!de!difusió!(DWI)!i!es!relacionen!amb!

l’oclu! les! branques! perforants! medul·lars! (59).! Aquest! tipus! d’infarts! són!

heterogenis!de!forma!patològica!i!patogenètica,!i!per!aquest!motiu!s’han!dividit!en!

dos!grups:!els!petits!(diàmetre!màxim!son!<1.5!mil·límetres;!i!per!altra!banda,!els!

grans! (! diàmetre! màxim! son! >1.5! mil·límetres)! (60).! La! presentació! clínica!

d’aquest! tipus!d’infarts!és! similar!a! les!oclusions!de! les!artèries! cerebrals!mitges!

profundes!associada!a!síndromes!lacunars!clàssics!com!són!la!hemiparèsia!motora!

pura,!la!síndrome!sensitiva!motora!i!predominantment!atàxia!hemiparèsica.!!

! 21!

!

F. Topografia*cerebral*lacunar*

En!la!actualitat!la!topografia!de!les!llacunes!han!estat!categoritzades!com!territoris!

de!la!circulació!anterior!que!irriguen!les!àrees!dels!ganglis!basals,!capsula!interna!i!

corona! radiata.! Per! altra! banda,! es! descriu! aquelles! àrees! que! corresponen! a! la!

circulació!posterior!(protuberància!i!el!cerebel)!i!el!tàlem!(61).!!

!

!

G. Epidemiologia*

* L’ictus! lacunar! representa! una! quarta! part! del! total! d’infarts! de! tipus!

isquèmics.! En! algunes! races! la! prevalença! és!major! com!per! exemple,! els! IL! són!

més! freqüents! en! la! raça! negra! (caribenys)! en! la! que! suposa! un!40%!dels! casos!

respecte! a! la! dels! blancs! no! hispànics! que! mostren! una! prevalença! del! 7%.! Els!

subjectes!afroamericans! i!els!caribenys!blancs!mostren!una!prevalença!d’un!25%!

(62)!.!El!nombre!de!casos!en!la!raça!asiàtica!es!inclús!superior!i!estarien!al!voltant!

d’un!42%!(63).!!

La! prevalença! dels! infarts! silents! s’estima! entre! un! 8%! i! un! 28%!de! la! població!

general!en!edats!compreses!entre!els!50!i!94!anys!(64).!Per!els!pacients!més!joves!

(30!i!49!anys)!solament!hi!han!dades!del!Offspring!Framingham!Cohort!Study!que!

indica!que!la!prevalença!és!superior!al!6%!d’ambdós!sexes!(65).!!

La!reaparició!de!noves!lesions!cerebrals!silents!després!d’haver!patit!un!primer!IL!

se! situa!entre!un!2%! i!un!3%!anual! allò!que! suposa!una! incidència! cinc!vegades!

superior!a!la!de!presentar!un!ictus!a!la!població!general!(64).!!L’edat!i!la!presència!

d’un! IL! previ! són! els! factors! de! risc! relacionats! amb! l’aparició! de! nous! infarts!

silents.!!

! 22!

Segons!les!dades!obtingudes!per!dues!cohorts!a!Estats!Units!(ARIC*i*Cardiovascular*

Health* Study)! la! incidència! anual! d’infarts! silents! per! 100.000! persones! a! l’any!

entre!els!30!i!39!anys!seria!de!1.600!persones!i!s’incrementaria!als!16.400!entre!els!

70! i!79!anys.!Aquestes!dades! informen!que!més!d’onze!milions!de!persones!dels!

Estats!Units!que!van!presentar!ictus!aproximadament!en!770.000!persones!va!ser!

simptomàtic!mentre!que!les!restant!van!ser!infarts!silents!(66).!!

! El!pronòstic!respecte!a!les!alteracions!cognitives!després!d’un!IL!és!positiu!

quan!es! tracta!d’un!primer! IL! i! en!absència!d’infarts! silents!previs! i! leucoaraiosi.!

Aquests!dos!últims!factors!determinen!un!pitjor!pronòstic!respecte!a!les!funcions!

cognitives! ja! que! presenten! demència! un! 5%! dels! pacients! a! l’any! següent! a!

l’esdeveniment,!un!11%!als!tres!anys!i!un!23%!als!quatre!anys!següents.!Els!factors!

de!risc!associats!són!la!presència!d’atròfia!cerebral!i!l’ictus!recurrent!(67).!!

! L’estudi! de! Rotterdam! va! mostrar! que! la! presència! d’infarts! silents!

clínicament!multiplica!per!dos! el! risc!de!desenvolupar!una!demència,! incloent! la!

Malaltia! d’Alzheimer! (68).! Altra! estudi! com! el! Cardiovascular* Health* Study* va!

descriure* que! un! 44%! dels! casos! en! els! que! es! va! diagnosticar! una! demència!

incident!poden!classificarEse!com!a!possible!o!probable!demència!vascular!segons!

els!criteris!del!ADDTC!(modified*States*of*California*Alzheimer’s*Disease*Diagnostic*

and*Treatment*Centers)*(69).!!

! Com! ja! s’ha!mencionat,! els! IL! silents! es! consideren! un! substrat! patològic!

important!per!a!la!demència!vascular!però!que!també!estan!relacionats!al!risc!de!

patir!la!Malaltia!d’Alzheimer.!!

!

! 23!

!

H. Alteracions*neuropsicològiques*dels*infarts*lacunars.*

!

L’associació! entre! alteracions! cognitives! en! múltiples! dominis! i! les! malalties! de!

petit! vas! (MPV)! han! estat! ben! documentades! en! els! últims! anys,! encara! que!

existeixin! controvèrsies.! La! MPV! és! considerada! com! una! causa! major! de!

deteriorament!cognitiu!vascular! i! la!causa!més!comuna!de!demència!vascular.!Hi!

han!factors!que!contribueixen!al!deteriorament!cognitiu!en!el!MPV!com!ara!els!IL!

silents,! la! leucoaraiosi,! les!microhemorràgies! i! l’atròfia!cerebral.!Aquests!pacients!

presenten!diferents!perfils!cognitius!on!hi!són!presents!les!alteracions!de!funcions!

executives,! velocitat! de! processament! i! alteracions! atencionals! però! la!memòria!

episòdica! resta! conservada(70,! 71).! Els! mecanismes! responsables! del!

deteriorament!cognitiu!vascular!en!la!MPV!es!relaciona!amb!la!desconnexió!de!les!

xarxes! cortico! subcorticals! i! cortico! corticals! secundàries! a! la! patologia! de!

substància!blanca!difusa,!múltiples!IL!i!microhemorràgies!(72)!

! Són! escassos! el! nombre! de! treballs! que! fan! referència! a! les! alteracions!

neuropsicològiques!a!la!fase!aguda!de!la!malaltia,!especialment!en!aquells!pacients!

que!han!patit! infarts!múltiples.!Des!de! la!nostra! aportació! al! coneixement!de! les!

MPV,! el! nostre! grup! de! recerca! va! publicar! un! estudi! on! es! van! fer! evidents! les!

alteracions!de! les! funcions!executives!però!solament!en!aquells!pacients!que!van!

patir!un!primer!IL!únic(73)!i!especialment,!en!aquells!que!presentaven!la!síndrome!

hemiparèsia!motora!pura!i!la!síndrome!lacunar!atípica.!Els!pacients!van!presentar!

un!deteriorament!cognitiu!lleu!de!tipus!vascular!en!el!57%!de!la!mostra!associada!

a!la!MPV.!També!s’han!trobat!estudis!de!cas!únic!i!topografia!cerebral!estratègica!

especialment!en!àrees!dorsomedials!i!anterior!del!tàlem!que!descriuen!disfuncions!

! 24!

de!la!fluència!verbal,!dismnèsia!i!abúlia!o!heminegligència!espacial,!afàsia!atípica!i!

alteracions! dels! processament! cognitiu! (74).! Per! tant,! trobem! diferents! estudis!

amb!una!diversitat!de!perfils!neuropsicològics!segons!la!localització!topogràfica,!la!

grandària! i! l’afectació! de! IL.! ! Però! la! majoria! de! les! dades! sobre! deteriorament!

cognitiu!associat!a!les!MPV!han!estat!proporcionat!per!l’estudi!LADIS.!(75).!És!un!

estudi! Europeu! longitudinal! i! multicèntric! que! han! seleccionat! pacients! des! de!

diferents!marcs!clínics:!unitats!de!infarts,!clíniques!de!malalties!cerebrovasculars,!

clíniques!de!memòria!i!demència,!seccions!de!geriatria!i!neurologia!i!d’estudis!de!

poblacions!de!la!tercera!edat!.!!Desprès!d’un!període!de!seguiment!de!tres!anys!van!

mostrar! que! el! 37%! dels! pacients! presentaven! DCV! de! subtipus! vascular,! la!

majoria! d’ells! deteriorament! cognitiu! sense! demència.! La! severitat! basal! dels!

esdeveniments! vasculars,! la! progressió! de! la! malaltia! de! substància! blanca,! els!

episodis! de! nous! infarts! cerebrals,! el! creixent! nombre! de! llacunes! i! la! atrofia!

medial! temporal,! a! vegades! coexistents! amb! les! MPV,! es! consideren! predictors!

independents!del!deteriorament!cognitiu!(76)!.!!Altra!aportació!al!coneixement!de!

les! alteracions! neuropsicològiques! en! els! IL! únics! la! trobem! a! l’estudi! de! A.M*

Paulovic*et*al.!on!es!va!identificar!alteracions!cognitives!vasculars!en!el!63,9%!de!la!

mostra:! el! 22,1%! complien! criteris! de! demència! vascular! i! el! 44,8%! alteracions!

cognitives!sense!criteri!de!demència!(72).!!

!!

Per!altra!banda,!els!IL!silents!es!relacionen!amb!un!augment!del!risc!de!infarts,!de!

deteriorament! cognitiu! i! de! demència.! Diversos! estudis! han! mostrat! un! pitjor!

rendiment!de!la!habilitat!cognitiva!global!i!de!dominis!cognitius!específics!com!a!la!

memòria! i! la! velocitat!psicomotriu.!En! els! estudis!de!Blum*et*al.! va! reportar!que!

l’hipocamp! era! més! petit! en! els! pacients! amb! IL! silents! i! que! el! grau! d’atròfia!

! 25!

d’aquesta! àrea! es! relacionava! amb! les! alteracions! neuropsicològiques! descrites!

(77).! ! I! en! concordança,! a! l’estudi! de! Thong* JYJ* et* al.* van! mostrar! les! següents!

contribucions:! que! la! atròfia! cerebral! i! els! IL! silents! contribueixen! de! manera!

diferent!al!declivi!de!l’atenció,!del!llenguatge!i!la!memòria;!solament!els!IL!silents!

s’associen! al! deteriorament! de! les! funcions! executives! i! velocitat! visomotora! ;! i!

s’observa! una!disminució! del! còrtex! de! les! àrees! occipitals! i! temporals,! així! com!

l’augment!dels!ventricles!laterals!i!es!relaciona!amb!alteracions!visuoconstructives!

(78).!En!l’estudi!de!Dolcos*et*al.!van!trobar!que!el!grau!d’atròfia!era!més!severa!en!

el!hemisferi!dret!que!en!l’esquerre!en!els!pacients!amb!IL!silents.!Aquests!resultats!

suggereixen! que! l’hemisferi! dret! és!més! sensible! al! dany! produït! per! l’edat! que!

l’esquerre.!Segons!els!autors! la!patologia!vascular,! incloent!els! IL!silents,!podrien!

tenir! un! major! impacte! sobre! l’hemisferi! dret! però! el! desenvolupament! aquest!

conceptes!formen!part!de!línies!d’investigacions!futures!(79).!

!

! Pel!que! fa!a! la!prevalença!dels! IL!asimptomàtics!en!pacients!majors!de!65!

anys!s’observa!entre!20E28%!de!casos!trobats!a!la!RM!cerebral!(23).!Altres!estudis!

han! mostrat! que! entre! un! 10! i! 50%! de! pacients! amb! patologia! lacunar! silent!

presenten!un!nou! infart! silent! als! 3! anys! posteriors! confirmat! per!RM! cerebral! .!

Però! els! pacients! amb! IL! presenten! una! progressió! de! la!malaltia! de! substància!

blanca! en! un! 40%! (80).! Per! aquest! motiu! és! important! controlar! el! risc! de!

recurrència!vascular! i! les!alteracions!cognitives!associades!en!els!pacients!d’edat!

avançada!que!pateixen!una!malaltia!de!petit!vas!silent.!Però!els!aspectes!cognitius!

s’han!posat!de!manifest!gràcies!a!les!troballes!per!el!grup!que!encapçalen!l’estudi!

LADIS! (Leukoaraiosis! and! Disability).! En! un! estudi! longitudinal! de! Jokinen* et* al.!

han!presentat!resultats!en!un!interval!de!3!anys!en!una!mostra!de!639!pacients! i!

! 26!

van!concloure!que!el!nombre!de!noves!llacunes!es!relaciona!directament!amb!una!

disminució!sobtada!en!el!rendiment!de! les! funcions!executives,!de! la!velocitat!de!

processament! i! control!motor!però!no!de! les! capacitats! cognitives!generals! (81).!

Per!tant,!els!autors!confirmen! !que!els!IL!associats!amb!la! leucoaraiosi!presenten!

alteracions! neuropsicològiques! a! llarg! termini! relacionades! amb! la! velocitat! de!

processament!i!alteracions!executives.!Les!llacunes!per!si!mateixes!exerceixen!un!

efecte! nociu! a! la! cognició.! L’explicació! de! la! disfunció! cognitiva! associada! als! IL!

resulta!del!dany!selectiu!dels!circuits! frontoEsubcorticals! implicats!en! la!velocitat!

de!processament! i! funcions!executives! i!que!estan!directament!relacionades!amb!

els!circuits!dorsolaterals!prefrontals!(82,!83).!!

A! l’actualitat!hi!han!estudis!que!han!suggerit!el! terme!deteriorament!cognitiu!

subjectiu! (DCS)! com! a! precursor! del! deteriorament! cognitiu! i! de! la! demència.!

Encara!que!els!mecanismes!psicopatològics!estan!encara!per!a!determinar,!el!DCS!

s’associa! amb! HSB! o! la! degeneració! del! lòbul! temporal,! particularment! de!

l’hipocamp.!Els!autors!van!determinar!el!terme!DCS!a!partir!del!resultat!límits!a!les!

proves!neuropsicològiques! i!especialment! la! resposta!a! la!pregunta!de! ‘Ha! tingut!

problemes!amb!la!seva!memòria!o!altres!capacitats!mentals?’.!Narashimhalu*et*al.!

van!trobar!que!els!infarts!dels!ganglis!basals!s’associaven!al!DCS!i!que!presentaven!

un!volum!inferior!de!l’hipocamp!respecte!a!la!seva!àrea!homòloga(84).!!Els!ganglis!

basals!es!considera!una!estructura!implicada!en!els!processos!d’aprenentatge!i!per!

tant,! els! pacients! que! presentaven!DCS! van!mostrar!més! dificultat! per! aprendre!

que!per!a!retenir!o!transferir!la!informació!apressa.!!

!

!

!

! 27!

I. Neuroimatge*dels*infarts*lacunars.**!

Estudis! actuals! pretenen! explicar! la! relació! entre! les! estructures! cerebrals! i! el!

deteriorament! cognitiu! associat! als! IL! mitjançant! les! tècniques! de! neuroimatge!

funcional.!Aquests!valors!són!definits!com!a!marcadors!de!la!RM!del!deteriorament!

cognitiu!com!la!presència!de!HSB!i!d’IL!en!les!seqüències!de!T2!(cavitats!entre!3!i!

15!mm).!La!RM!és!!imprescindible!per!al!diagnòstic!de!la!MPV!i!s’empra!com!a!eina!

per!a!investigar!els!mecanismes!implicats!en!les!alteracions!cognitives!associades!a!

les!MPV!.!!

L’autor!P.Benjamin*et*al.!!va!mostrar!!la!relació!entre!el!nombre!i!el!volum!total!de!

les!llacunes!(74).!També!van!estudiar!la!importància!de!la!localització!topogràfica!

lacunar,! especialment! la! importància! del! tàlem! com! a! una! estructura! complexa!

amb!múltiples!subcomponents!i!propietats!connectives.!!Els!autors!van!investigar!

la! distribució! espacial! de! les! llacunes! per! a! definir! l’impacte! cognitiu! d’aquests!

infarts! estratègics! a! partir! de! l’atles! del! tàlem!basat! en! les! connexions!d’aquesta!

àrea!subcortical!amb!el!còrtex!cerebral.!Van!identificar!les!regions!d’interès!!(ROI)!

del! tàlem! i! van! emprar! la! Voxel* Based* Morfometry! (MBV)! per! a! investigar! la!

existència! d’associacions! significatives! entre! les! ROI! i! altres! àrees! del! cervell.!!

Consideren!al!tàlem!com!a!una!estructura!associada!de!forma!independent!amb!els!

dèficits!de!la!velocitat!de!processament!com!a!conseqüència!de!la!disrupció!!de!les!

connexions!entre!el!sistema!orbitofrontal!i!l’escorça!prefrontal.!!

Altres! tècniques!emprades!pel! l’estudi!de! les! connexions!estructural!de! les!àrees!

afectades!pels!IL!és!el!Difussion*Tensor*Imaging!(DTI)!i!suggereix! !si!el!dany!difús!

ultraestructural!de!la!substància!blanca!és!important!en!el!deteriorament!cognitiu!i!

el!grau!d’implicació!dels! IL,!de! la!substància!blanca! i!de! la!atròfia!cerebral!en! les!

! 28!

alteracions! neuropsicològiques! associades! a! les! MPV.! Les! funcions! cognitives!

depenen! de! funcionament! eficient! de! les! distribucions! de! les! xarxes! cerebrals!

connectades! a! partir! dels! tractes! de! substància! blanca.! Les! MPV! poden!

interrompre!aquestes!connexions!produint!un!mal!funcionament!de!les!mateixes!i!

afecten!a!la!cognició!per!via!de!la!‘síndrome’!de!desconnexió.!La!tècnica!de!la!DTI!

també!permet!valorar!més!enllà!del!dany!focal!produït!per! la!pròpia!lesió!de!l’IL.!

Diversos! autors! han! suggerit! que! els! IL! presenten! un! efecte! extensiu! a! la!

microestructura!de! la! substància!blanca!atribuïble! a!una!degeneració! secundària!

com! a! conseqüència! de! una! resposta! inflamatòria! o! afectació! del! tracte! de!

substància!blanca.!Les!alteracions!microestructurals!de!la!substància!blanca!poden!

ser!estudiades!in!vivo!a!partir!de!la!DTI!però!en!canvi,!no!apareixen!amb!l’anàlisi!

basat!en!ROI!(Region!Of!Interest)!!o!a!partir!del!Tract[Averaged*Approach*(85)*.!Els!

resultats! van! mostrar! anormalitats! estructurals! en! àrees! remotes! a! la! zona!

infartada! i! no! van! ser! visibles! amb! la! RM! cerebral.! Segons! els! autors! els!

mecanismes!responsables!de! la!degradació!de! la!estructura!de!substància!blanca!

està!relacionada!directament!amb!la!lesió!lacunar!(86).!

Per!altra!banda,!l’estudi!de!J.Lawrence!van!aplicar!la!anàlisis!gràfica!del!Diffussion*

Tensor* Tractografy! (DTT)! per! l’obtenció! del! mapa! de! les! connexions! cerebrals,!

enteses!com!a!una!col·lecció!de!nodes!(regions!cerebrals)!que!es!comuniquen!amb!

tractes!de!substància!blanca!a!partir!del!dany!de!la!substància!blanca!detectable!en!

la!DTI.!Els!resultats!avalen!que!MPV!mostren!xarxes!neuronals!connectades!menys!

denses,! connexions! de! menor! pes! i! menys! eficaces! en! la! eficiència! connectiva!

global! i! local.! ! Aquestes! alteracions! demostren! problemes! en! el! rendiment! de! la!

velocitat!de!processament!i!en!les!funcions!frontals!i!una!eficiència!global!reduïda!!

! 29!

!

de! les! connexions! estructurals! associada! al! rendiment! de! la! tasca.! Per! tant,! van!

mostrar! que! la! connectivitat! ! de! les! xarxes! de! la! substància! blanca! estaven!

alterades! en! els! pacients! amb! MPV! simptomàtica! i! el! grau! de! disrupció! està!

relacionat!amb!l’alteració!cognitiva!(87).!

Altra! tècnica! és! la! Large* Deformation* Diffeomorphic* Metric* Mapping! (LDDMM)!

emprada!en!l’estudi!de!Thong*JYJ*et*al.!entesa!com!una!tècnica!avançada!de!mapeig!

cerebral!per!a!examinar!el!gruix!cortical!i!la!forma!dels!ventricles!laterals!i!de!les!

àrees!subcorticals!a!partir!de!la!imatge!corregida!de!les!seqüències!en!T1!de!la!RM!

cerebral! (78).!Amb!aquest!article,! l’autor!volia!mostrar!que!els! IL!silents!estaven!

relacionats! amb! la! grandària! de! l’atrofia! cerebral! i! les! anormalitats! de! les! àrees!

subcorticals!no!solament!s’evidencien!a!l’hipocamp!sinó!també!als!ganglis!basals!i!

al!tàlem.!!

!

J. Antecedents*d’estudis*clínics*segons*el*gènere.*

*

L’autor!Arboix*et*al.!en!el!seu!treball!sobre!la!patologia!cerebrovascular!aguda!

en! dones! publicada! a! l’any! 2001! (22)! i! a! partir! del! ! registre! hospitalari! de!

L’Hospital!Sagrat!Cor!de!Barcelona!en!una!mostra!de!2000!pacients!amb!un!infart!

isquèmic! i!hemorràgic,!es!van!establir!els! factor!de!risc! i! les!variables!clíniques! i!

demogràfiques! de! les! dones! amb! aquesta! MPV! (48%! de! la! mostra).! L’autor! va!

concloure!que!les!dones!amb!un!infart!difereixen!dels!homes!en!diversos!aspectes:!

en!la!distribució!dels!factors!de!risc!(obesitat,!patologia!cardiovascular,!fibril·lació!

atrial,!hipertensió,!debilitat!a!les!extremitats!i!l’edat)!,!en!la!severitat!de!l’infart!i/o!

les! diferències! en! la! anatomia! funcional! o! la! plasticitat! del! cervell! entre! ambdós!

! 30!

sexes.! Per! aquest!motiu! s’ha! de! reconsiderar! un!maneig! terapèutic! òptim! en! les!

dones!amb!infart.!!

!

K. Estratègies*pel*tractament*secundari*dels*IL.*

*

Segons!les!publicacions!derivades!de!l’estudi!SPS3!(Secondary!Prevention!of!Small!

Subcortical! Stroke)! amb! una!mostra! de! 3020! pacients! amb! un! primer! IL! on! els!

pacients! van! ser! randomitzats! en! dos! grups! on! rebien! 75! mg! de! clopidogrel! o!

placebo!diari! (branca!antiplaquetària).!Tots!dos!grups!van!rebre!una!dosis!diària!

d’aspirina! 325! mg.! Per! altra! banda! es! van! dividir! als! pacients! en! dos! grups! de!

tensió! arterial:! intensiu! (<130! mmHg)! i! usual! (130–149! mmHg)! (branca!

hipertensió!arterial).!Els!resultats!d’aquest!estudi!va!determinar!que!el!clopidogrel!

amb!l’aspirina!no!redueix!de!forma!significativa!el!risc!de!un!infart!de!recurrència!i!

si!augmenta!el!risc!de!sagnat! i!de!mort.!Tot! i!que!els!resultats!de! l’estudi!van!ser!

negatius,! la! teràpia! dual! antiplaquetària! es! va! recomanar! per! a! aquells! infarts!

d’origen!aterotrombòtic!(24).!!

!

L. Línies*d’investigació*futures*

*

A!continuació!es!descriuen! les! línies!d’investigació!que!proporcionaran!un!major!

coneixement!de!la!patologia!vascular!de!petit!vas.!

1. L’estudi!dels!IL!en!relació!a!les!diferències!de!gènere!és!deficitari!ja!que!no!

hi! han! treballs! que! valorin! específicament! el! sexe! femení! en! els! IL.! La!

principal!justificació!clínica!d’aquest!estudis!seria!identificar!les!diferències!

! 31!

en! la! patologia! de! l’infart! cerebral,! en! la! anatomia! funcional! i/o! en! la!

plasticitat!dels!cervells!tant!en!homes!com!en!dones.!

2. Realitzar!estudis!que!determinen!la!importància!del!deteriorament!cognitiu!

lleu! en! els! malalts! amb! un! primer! IL! a! llarg! termini! i! amb! mostres! més!

grans.!!

3. Identificació!dels!factors!genètics!de!la!MPV.!!

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! 33!

!

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!

!

!

2.!Hipòtesis!i!Objectius!!

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!

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!

! 35!

A. Hipòtesis!

!

I. HIPOTESI! PRIMERA.! Els! IL! presenten! unes! característiques! clíniques! i!

demogràfiques! diferenciades! i! pròpies! de! la! resta! d’ictus! i! de! la! resta!

d’infarts! cerebrals.! Així! mateix! els! IL! en! el! sexe! femení! poden! presentar!

unes! característiques! clíniques! diferenciades! en! comparació! amb! els!

pacients!amb!IL!de!sexe!masculí.!!

II. HIPOTESI! SEGONA.! En! els! pacients! amb! un! primer! IL! i! la! presència!

concomitant!d’isquèmia!cerebral!de!petit!vas!silent!clínicament!es!relaciona!

amb!la!presència!de!deteriorament!cognitiu!o!d’alteracions!neurocognitives.!

El!pes!dels! IL! ! silents!clínicament! i!de! la! leucoaraiosi!és!significatiu!en! les!

alteracions! neuropsicològiques! que! potencialment! presenten! els! pacients!

amb!patologia!de!petit!vas.!!

!

B. Objectius!

!

I. Revisió!de!la!bibliografia!científica!respecte!els!aspectes!clínics,!demogràfics!!

i!de!tractament!secundari!dels!IL.!!

II. Analitzar! les! diferències! significatives! clíniques! i! dels! factors! de! risc! en!

homes!i!dones!que!han!patit!un!IL.!!

III. Analitzar!la!influència!dels!infarts!silents!i!la!presència!de!leucaraiosi!en!la!

fase! aguda! de! la! malaltia! com! a! factor! predictor! de! les! alteracions!

neuropsicològiques!en!els!pacients!que!han!patit!un!primer!IL.!

IV. Realitzar! una! revisió! bibliogràfica! sobre! el! deteriorament! cognitiu! i! les!

alteracions!neuropsicològiques!associades!als!IL.!!

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! 37!

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!

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3.!Mètodes!

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!

!

! 39!

!

! Aquesta!tesi!doctoral!s’ha!realitzar!a!partir!de!compendi!de!publicacions!i!es!

composa!de!quatre!articles!publicats!a!revistes! internacionals!de! l’especialitat!de!

Neurologia.!!

! Per!respondre!al!primer!objectiu,!s’ha!realitzats!una!revisió!exhaustiva!de!la!

literatura!dels!aspectes!clínics,!demogràfics,!de!factors!de!risc,!pronòstic,!evolutius!

i! tractaments! que! fa! referència! al! tema! de! la!malaltia! de! petit! vas! cerebral! i! als!

infarts!cerebrals!de!tipus!lacunar.!Per!a!la!recerca!bibliogràfica!es!van!incloure!els!

termes! ‘treatment’,! ‘! etiology’,! ‘prognosis’! ‘cognitive! impairment’! ‘lacunar! infarct’!

‘lacunar!stroke’!‘!i!‘risk!factors’!Aquest!article!ha!estat!publicat!a!la!revista!Expert!

Review! in! Neurotherapeuthics! a! l’any! 2014! amb! el! títol! ‘.! Advancements* in*

understanding*the*mechanisms*of*symptomatic*lacunar*ischemic*stroke:*translation*

of* knowledge* to*prevention* strategies! ‘.! Expert! Rev.! Neurother.! Early! online! 1E16!

(2014).!!

!

! Per!respondre!al!segon!objectiu,!s’analitza!una!mostra!310!dones!!(8.1%)!i!!

423!en!homes!(11.1%)!d’un!total!de!3,808!pacients!amb!infart!inclosos!a!la!base!de!

dades! que! confirma! el! registre! hospitalari! a!Barcelona! (Catalunya)! de! L’Hospital!

Universitari! Capio! Sagrat! Cor! de! Barcelona! durant! un! període! de! 19! anys.! En!

aquest! treball! es! comparen! les! dades! clíniques! i! els! factors! de! risc! de! les! dones!

respecte!als!homes.!Aquest!article!ha!estat!publicat!a!la!revista!Acta!Neurològica!

Belgica! a! l’any! 2014! que! porta! el! títol! ‘! Clinical* characteristics* of* acute* lacunar*

stroke* in* women:* emphasis* on* gender* differences’.! Acta! Neurol! Belg.! 2014!

Jun;114(2):107E12.!doi:!10.1007/s13760E013E0257E8.!Epub!2013!Nov!6.!

! 40!

! !!

! Per!respondre!al!tercer!objectiu!es!va!analitzar!una!mostra!consecutiva!de!

72!pacients!amb!un!primer!episodi!d’IL!visualitzats!a!partir!!de!la!RM!cerebral!que!

van! ser! admesos! al! Departament! de! Neurologia! de! l’Hospital! Sagrat! Cor! de!

Barcelona! entre! Gener! del! 2006! i! Desembre! del! 2011.! Tots! els! pacients! van! ser!

valorats!mitjançant! una! bateria! extensa! de! proves! neuropsicològiques! pròpia! de!

l’hospital.!Aquesta!incloïa!test!de!memòria!California!Verbal!Learning!Test!(CVLT)!

(CVLT),! fluències! verbals! fonètiques! i! semàntiques! i! memòria! de! treball! amb! la!

subprova!de!Dígits!del!WAISEIII.!L’anàlisi!estadístic!es!va!realitzar!amb!el!paquet!

informàtic! SPSS! 18.0.! L’anàlisi! descriptiu! es! va! fer! amb! freqüències! absolutes! i!

relatives,!mitjana!i!desviació!típica!(o!mediana!i!rang!interquartílic).!Les!variables!

continues! van! ser! analitzades! amb! t! de! Student! o! la! Chi! quadrat! (χ2)! o! la! proba!

exacta!de!Fisher!(quan!va!ser!apropiat)!per!a! les!variables!categòriques! .!El!grau!

d’associació!individual!de!les!variables!va!ser!estimat!a!partir!de!la!Odds!ratio!amb!

un! interval!de!confiança!del!95%.!L’anàlisi!de! regressió! linear!multivariant!es!va!

emprar! per! valorar! l’efecte! d’una! variable! sobre! altra! ajustant! les! dades! per! les!

covariants! de! confusió.! Per! altra! banda,! per! l’anàlisi! univariant,! la! freqüència! de!

cada!variable!en!el!grup!concret!van!ser!comparats!amb!altres!grups!!amb!l’anàlisi!

de! la! variància! (ANOVA).! Aquest! article! va! estar! publicat! a! la! revista! BMC!

Neurology! !a! l’any!2013!amb!el! títol!de! ‘!Cognitive*profile*in*patients*with*a*first[

ever* lacunar* infarct*with* and*without* silent* lacunes:* a* comparative* study! ‘! .! BMC!

Neurology!2013,!13;203.!

!

Per! respondre! al! quart! i! últim! objectiu,! es! realitza! una! revisió! bibliogràfica! dels!

aspectes! neuropsicològics! dels! IL! i! el! deteriorament! cognitiu! associat! a! aquesta!

! 41!

malaltia! de! petit! vas! cerebral.! En! la! recerca! bibliogràfica! es! van! incloure! les!

següents! paraules! clau;! ‘lacunar! infarct’! ‘brain! atropy’! ‘prognosis’! ‘cognitive!

impairment’! ‘neuropsychology’! i! ‘cerebral! smallEvessel! disease’! en! sessions!

successives.!Després!de!la!lectura!crítica!dels!principals!treballs,!es!va!realitzar!una!

exposició!narrativa!de!les!dades!més!rellevants.!Aquest!article!va!estar!publicat!a!la!

revista! European! Neurological! Review! a! l’Abril! del! 2013! que! porta! el! títol!

‘Cognitive*impairment*in*ischaemic*lacunar*stroke!’.!European!Neurological!Review,!

2013;8!(2):!144E8.!!

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4.!Publicacions!

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! 45!

! En!aquesta!secció!es!presentaran!els!articles!científics!publicats!que!formen!

part!del!cos!de!la!tesi.!!

En! primer! lloc,! es! donarà! pas! a! la! primera! publicació! de! ‘Advancements* in*

understanding*the*mechanisms*of*symptomatic*lacunar*ischemic*stroke:*translation*

of* knowledge* to* prevention* strategies’! .! En! aquesta! publicació! es! realitza! una!

actualització! de! l’antiagregació! plaquetària! i! del! tractament! per! a! la! prevenció!

secundària!dels!IL.!!

En!segon!lloc,!presentarem!l’article!titulat!*‘Clinical*characteristics*of*acute*lacunar*

stroke*in*women:*emphasis*on*gender*differences’,*on!posem!de!manifest!l’èmfasi!del!

gènere!i!les!seves!diferències!respecte!a!les!conseqüències!clíniques!dels!IL!

Em! tercer! lloc! es! presentarà! la! tercera! publicació! de! la! tesi! que! porta! el! títol!

‘Cognitive*profile*in*patients*with*a*first[ever*lacunar*infart*with*and*without*silent*

lacunes:*a*comparative*study’*on!es!mostren!els!resultats!de!la!comparació!entre!els!

perfils!cognitius!dels!pacients!que!presenten!un!únic!IL!versus!múltiples!IL.!!

I! la!quarta! i!última!publicació!on!presentem!una!recopilació!sobre! les!alteracions!

cognitives! en! els! IL! fins! al! dia! d’avui! ! i! porta! el! títol! de! ‘Cognitive* Impairment* in*

Ischaemic*Lacunar*Stroke’..! !

A! continuació! donarem!pas! a! un! resum! acurat! de! cadascuna! de! les! publicacions!

que! conformen! la! tesi! per! tal! de! poder! facilitar! al! lector! la! comprensió! del!

contingut!de!cadascun!d’elles.!!

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! 46!

Article!1:!Avenços!en!la!compressió!dels!mecanismes!implicats!en!els!infarts!

lacunars:!explicació!del!coneixement!des!de!les!estratègies!preventives.!!

!

Antecedents!

Els! IL! isquèmics! or! infarts! subcorticals! petits! comptabilitzen! una! quarta! part! de!

tots!els!infarts!cerebrals.!Aquest!tipus!d’infart!isquèmic!són!deguts!a!l’oclusió!d’una!

artèria!penetrant!única!dels!microateromes!o!lipohialinomes!o!de!l’alteració!de!la!

branca! ateromatosa! intracraneal.! En! un! 5E10%! dels! casos! l’etiologia! és!

principalment! no! aterotrombòtica! en! relació! amb! l’èmbol! d’origen! cardíac,!

alteracions!hemodinàmiques,!trastorns!hematològics!i!altres!disfuncions!inusuals.!!

Els! infarts! lacunars! recurrents! s’associen! a! unes! característiques! clíniques! més!

severes! i! ha! estat! reconegut! com! un! factor! rellevant! involucrat! en! el!

desenvolupament! de! l’estat! lacunar! i! la! demència! vascular! subcortical.! Per! a! la!

determinació! d’estratègies! òptimes! per! la! prevenció! secundària! dels! infarts,! ! cal!

precisar!la!distinció!subjacent!de!les!diferents!patologies!que!envolten!a!l’IL.!En!el!

primer! assaig! clínic! multicèntric! Secondary* Prevention* of* Small* Subcortical*

Stroke(SPS3)! enfocat! a! la! prevenció! de! l’infart! en! pacient! amb! IL! recents,! el!

tractament! amb! clopidogrel! i! aspirina! no! redueix! significativament! el! risc! d’un!

infart! recurrent,!però! incrementa!de! forma!significativa!el! risc!d’hemorràgia! i!de!

mort.! L’Aspirina! està! acceptada! com! a! teràpia! antiplaquetària! estàndard! en!

pacients!amb!IL.!Tot!i!això,!si!l’IL!és!fonamentalment!no!aterotrombòtic,!llavors!la!

prevenció! secundària! apunta! a! no! ser! gaire! efectiva! en! la! prevenció! de! la!

progressió! de! l’ateroma.! ! Un! descens! de! la! pressió! arterial,! els! agents! que!

disminueixen! els! lípids,! els! enzims! inhibidores! de! la! angiotensina,! i! els!

antiinflamatoris!no!esteroïdals!poden!actuar!a!la!circulació!reduint!l’infart!a!través!

! 47!

de!mecanismes!més!simples!com!la!prevenció!en!la! formació!d’ateromes,! i!com!a!

conseqüència! podran! ser! efectius! en! el! cas! dels! infarts! lacunars.! La! eficàcia! dels!

medicaments! que!milloren! la! funció! endotelial! en! els! pacients! amb! IL! ha! de! ser!

estudiada!en!!futur!assajos!clínics.!!

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Advancements inunderstanding themechanisms of symptomaticlacunar ischemic stroke:translation of knowledge toprevention strategiesExpert Rev. Neurother. 14(3), 261–276 (2014)

Adria Arboix*1,Lorena Blanco-Rojas1

and Josep LluısMartı-Vilalta2

1Department of Neurology,Cerebrovascular Division, HospitalUniversitari del Sagrat Cor, Universitatde Barcelona, C/Viladomat 288,E-08029 Barcelona, Catalonia, Spain2Department of Neurology, AcuteStroke Unit, Hospital de la Santa Creu iSant Pau, Universitat Autonoma deBarcelona, C/Antoni M. Claret 167,E-08025 Barcelona, Catalonia, Spain*Author for correspondence:Tel.: +34 934 948 940Fax: +34 934 948 906aarboix@hscor.com

Symptomatic lacunar ischemic stroke (25% of all brain infarctions) results from occlusion of asingle penetrating artery by microatheromas or lipohyalinosis and rarely from an intracranialatheromatous branch disease. Recurrent lacunar stroke may be associated with more severeclinical features and has been involved in producing lacunar state and vascular subcorticaldementia. In the first multicenter randomized clinical trial (SPS3) focused on stroke preventionamong patients with recent lacunar stroke, the addition of clopidogrel to aspirin not only did notreduced significantly the risk of recurrent stroke, but also increased significantly the likelihood ofhemorrhage and fatal outcome. If lacunar stroke is primarily non-atherothromboembolic,secondary prevention aimed at preventing atheroma progression may not be very effective. Theefficacy of drugs that improve endothelial function in lacunar stroke patients remains to bestudied in the future.

KEYWORDS: cognitive impairment • etiology • lacunar infarct • lacunar stroke • prognosis • risk factors • treatment

Cerebral small vessel disease (SVD) or microan-giopathies have a crucial role in the field ofstroke, cognitive decline and age-related disabil-ity, and is characterized by alterations in thecerebral microcirculation [1–3]. Cerebral microcir-culation is formed by the small terminal arteries,arterioles, capillaries, venules with their arteriove-nous anastomoses and terminal cerebral veins.The small blood vessels are found both in theinner or subcortical cerebral tissue and in thesurface of the brain, including superficial ormedullary vessels and deep branches of the pen-etrating arteries (lenticulostriate, thalamogenicu-lated, thalamoperforating, brainstem paramedianpontine branches) [1]. Hypertension and suddenchanges in cerebral perfusion may cause damageto arteries of the microvasculature especiallypenetrating arteries because they are terminalbranches without anastomoses. Hypertensioncauses atherosclerosis, microatheromatosis and

lipohyalinosis, which give rise to wall thickeningof the penetrating artery with a decrease in thelumen, fibrous proliferation of the intima, dis-ruption of the elastica interna, hyalinosis in thetunica media and adventitial fibrosis, with thin-ning of the arterial wall. Lipohyalinosis has beenthought to be an intermediate stage between thefibrinoid necrosis of severe hypertension and themicroatheroma associated with more long-standing hypertension. It appears histopathologi-cally as a brightly eosinophilic, finely granularor homogeneus deposits involving the connec-tive tissue of blood vessels [1]. The cerebralmicrocirculation provides blood supply to corti-cal (distal zones of frontier territories predomi-nantly in the centrum semiovale) and subcortical(central or deep encephalic areas, such as caudatenucleus, internal capsule, globus pallidus, puta-men, midline of the brainstem and cerebellum)areas [4,5].

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Symptomatic SVDs are mainly of atherosclerosis-degenerativetype, such as microatheromatosis or intracranial atheromatousbranch disease. Other types include lipohyalinosis, hereditary(cerebral autosomal dominant arteriopathy with subcorticalinfarcts and leukoencephalopathy), mitochondrial (mitochondrialencephalopathy, lactic acidosis and stroke-like episodes), deposi-tion of substances in the vessel wall (amyloid in sporadic andhereditary cerebral amyloid angiopathy or ceramide in Fabry’sdisease) or inflammatory, immunologic or toxemic cause. Altera-tions of microcirculation may be also caused by disorders thatproduce an increase in blood viscosity, blood flow resistanceand aggregation of blood cell elements giving rise to cerebralischemia, such as polycythemia vera, hemoglobinopathies or pro-teinopathies [2,6]. Other SVDs are venous collagenosis, post-radiation angiopathy and non-amyloid microvessel degenerationin Alzheimer’s disease [1,2,6].

Lacunar infarct is the most common clinical entity resultingfrom angiopathies that affect microcirculation. White matterchanges (leukoencephalopathy or leukoaraiosis) are frequentfindings in patients with lacunes. The association of lacunarinfarcts and white matter changes supports the concept thatSVD as the underlying mechanism in both conditions [1,7,8].Clinically silent microhemorrhages (microbleeds) seen T2*-weighted gradient recalled echo MRI sequences may be consid-ered another neuroradiological manifestation of SVD [9,10].Cerebral microangiopathy accounts for an important numberof cases of ischemic stroke and may also cause cognitiveimpairment and dementia. Between 20 and 30% of all strokesare due to cerebral SVD [2,11]. Signs of SVD in conventionalMRI include recent subcortical infarcts, white matter changes,lacunes, prominent perivascular spaces, cerebral microbleedsand atrophy [12]. However, isolated analysis of neuroimagingdata without the clinical context and diagnostic methods maybe confusing, for example, an old large striatocapsular infarct

due to middle cerebral artery embolus or atheroma with achronic lacunar infarct due to intrinsic cerebral microvasculardisease. Given the frequent co-existence of different forms ofSVD (i.e., white matter changes, lacunar infarcts and micro-bleeds), all relevant lesion types should be considered [3].

The present review is focused on physiopathological aspectsof symptomatic ischemic lacunar stroke and the relevance ofadequate management of lacunar stroke patients to achieve anoptimal secondary prevention.

ConceptLacunar infarctionLacunes are small infarctions of ischemic type, generally of<20 mm, found in the blood supply territory of a penetratingarteriole (FIGURE 1) [5]. Patients with lacunar stroke usually presentwith one of the five typical lacunar syndromes [13,14], whichinclude pure motor hemiparesis [15], pure sensory syndrome [16],sensorimotor syndrome [17], dysarthria-clumsy hand [18] andataxic hemiparesis [19]. In some cases, patients may present anatypical lacunar syndrome [20]. Lacunar strokes are frequent inhypertensive and/or diabetic patients [21,22].

The lacunar syndrome concept refers to a series of clinicalfeatures mostly caused by a cerebral infarction of the lacunartype, although in 10–15% of cases may be attributable to othercerebral vascular disorders (mainly small intracerebral hemor-rhages or large subcortical infarcts) [23–26] or even to non-vascular disorders (e.g., expansive processes, subdural hematomaor demyelinating disease) [27].

In routine practice, lacunar stroke is diagnosed in one out offour or five patients with ischemic infarction [3]. In the Sagrat-Cor Stroke Registry in Barcelona, the incidence of lacunarinfarction among acute stroke patients was 11% [11], with anincidence of 27% in the Stroke Data Bank Project [28].

White matter changes or leukoaraiosisWhite matter changes (leukoaraiosis, white matter leukoence-phalopathy) can be detected by computed tomography andMRI (hyperintensities) in older asymptomatic individuals withvascular risk factors, in acute stroke patients and in those withcognitive decline [29]. White matter changes are caused byischemia associated with SVD [30] through a hemodynamicmechanism secondary to atherosclerotic thickening of penetrat-ing arteries providing blood supply to the white matter. Whitematter changes are also seen in hypertensive patients withsevere and persistent high blood pressure (BP), diabetes, cardio-vascular diseases and recurrent hypotension [31]. It has beenshown that white matter changes are more extensive in patientswith lacunar infarct than in those with non-lacunar ischemicstroke [32,33].

Cerebral microbleedsCerebral microhemorrhages or microbleeds appearing as hypo-intense and small dot-like lesions correspond to hemosiderindeposits in perivascular spaces of the cerebral microvasculature.These lesions are usually silent and frequently observed in the

Figure 1. Lacunar infarct in the posterior arm of the inter-nal capsule in the distribution territory of lenticulostriatearterioles visualized by MRI (diffusion sequences) in apatient with a first-ever stroke clinically manifested aspure motor hemiparesis.

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context of white matter changes, lacunar stroke and in hyper-tensive subjects [34–39]. T2*-weighted gradient recalled echoMRI is a highly sensitive technique to assess the presence ofmicrobleeds, which are found in 68% of cases in the basal gan-glia and less frequently in the frontal, parieto-occipital andtemporal regions [36,37]. It has been suggested an increased cere-bral microvasculature permeability with endothelial damage asa common physiopathological mechanism involving micro-bleeds and lacunar infarction [35,40].

Physiopathology of SVDThrombotic arteriopathiesSeveral distinct but related arteriopathies cause lacunes. Microa-theroma usually involving the proximal segment of the penetrat-ing arteries of larger caliber (between 200 and 400 mm indiameter) is a frequent pathophysiological mechanism inpatients with symptomatic lacunar stroke [1,4]. Occasionally, amural atheromatous plaque in the parent arterial vessel blockspenetrating branches causing a lacunar infarction of a largersize. In these cases, the histological characteristics of the microa-theroma are identical to those affecting the larger arteries. Thispicture has been also named ‘branch atheromatous disease’ [41].

Lipohyalinosis an intrinsic cerebral microvascular diseaseinvolving penetrating arteries of <200 mm in diameter is fre-quently observed in small asymptomatic lacunar infarctions [14].The cause of lipohyalinosis is not known. However, lipohyali-nosis is related to chronic high BP (FIGURE 2) and is considered asan intermediate pathological lesion between microatheromaand fibrinoid necrosis [4,5,14].

Fibrinoid necrosis usually occurs in cases of highly elevatedBP as in cases of hypertensive encephalopathy or eclampsia [5].Disordered cerebrovascular autoregulation at high BP levelsseems to be the mechanism involved, and in these circumstances,the arteries are unable to constrict resulting in vascular necrosis.

Embolic occlusionOcclusion by emboli of the penetrating arterial vessels due toan emboligenous cardiac source, in particular, atrial fibrillation,valve heart disease and non-bacterial thrombotic endocarditishave been documented in necropsy studies as a very rare causeof lacunar infarction. Embolism of arterial origin includingatheromatosis of the aortic arch [42] or the carotid artery maygive rise to microemboli of atheroma fragments or cholesterolemboli, which may cause lacunar infarction [43].

Other causesHemodynamic alterations include stenosis of a penetratingartery, which may cause a status of distal low perfusion. Lacu-nar infarcts related to hemodynamic alterations are character-ized by previous transient ischemic attacks (TIAs), fluctuatingor progressive onset, with recurrences of the initial clinical pic-ture in the subsequent weeks [44–46].

Development of lacunes has been also related to thrombosis ofCharcot-Bouchard aneurysms, stagnation of formed elements incase of polycythemia vera [47] or essential thrombocythemia [48] as

well as infection-related alterations of the cerebral small vessels incases of meningovascular syphilis or neurocysticercosis [49,50].

Other mechanisms such endothelial dysfunction and subtilblood–brain barrier damage with altered permeability, localsubclinical inflammation and oligodendrocyte apoptosis couldbe involved in ischemic SVD and contribute to the final patho-logical picture of diffuse white matter changes [51,52]. In thestudies of Wardlaw et al. [52] and Taheri et al. [53], blood–brainbarrier permeability was abnormal in patients with the smallvessel form of vascular cognitive impairment and showed thatthe areas of increased permeability were within the whitematter hyperintensities.

The first two mechanisms (lipohyalinosis and microathero-matosis) are proven pathologically. Other mechanisms havebeen proposed to account for lacunar infarcts, but none arepathologically proven. One alternate explanation is that failureof the arteriolar and capillary endothelium and the blood–brainbarrier leads to SVD, lacunar stroke and white matter changes.This failure allows extravasation of blood components into thevessel wall, which results in perivascular edema and damage tothe vessel wall, perivascular neurons and glia [52,53]. In a recentneuropathological study, circulating markers of endothelial acti-vation (intercellular adhesion molecule-1, thrombomodulin)and inflammation (IL-6) were analyzed and only thrombomo-dulin was augmented in aged SVD cases compared with agedcontrols (p = 0.012) and in vessels with higher sclerotic index(an indicator of SVD severity; p < 0.01). These data confirmevidence of endothelial involvement in SVD [54].

Pathologic findingsBecause of the favorable prognosis of lacunar stroke patients,with a very low in-hospital mortality rate, pathologic series oflacunar infarcts are scarce and about 11 autopsy studies of lacu-nar infarction have been reported [1,55–65]. Lacunes seen inautopsy studies range between 0.2 and 15 mm3 in size (FIGURE 3)

and are variable in number. More than five lacunes were found

Figure 2. Hyalinization and fibrinoid changes as well asocclusion of the lumen in a terminal segment oflenticulostriate artery.Reproduced with permission from [164].

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in two autopsy series [57,61] and less than two in one [63]. In adecreasing order, lacunes predominate in the lenticulate nucleus,the thalamus, frontal white matter, pons, basal ganglia, internalcapsule and caudate nucleus. Microscopic findings include: cys-tic or residual lacunes, recent lacunes and lacunes due to dilata-tion of the perivascular space [66–69]. Lammie et al. [70] describedtype 1b or ‘incomplete lacunar infarction’, with selective neuro-nal necrosis and relative preservation of glial elements around apenetrating vessel. Poirier and Derouesne [71–73] classifiedlacunes into: type I, originated from an old lacunar infarct, typeII due to an old hemorrhage and type III due to dilatation ofthe perivascular space.

Clinical impact of lacunar strokeLacunar strokes are clinically relevant for many reasons,including the symptomatic clinical forms, the high frequencyof presentation (one-fourth of all cerebral ischemic strokes),the characteristics profile of cardiovascular risk factors (with ahigh prevalence of hypertension and diabetes), typical semiol-ogy of classical lacunar syndromes and more rarely of atypicallacunar syndromes, and the risk of cognitive decline, despitethe relative favorable functional prognosis at hospital dis-charge (lesser medical complications, low in-hospital mortal-ity and good functional recovery) as compared with othersubtypes of cerebral ischemia [1,74–77]. Also, recurrent lacunarinfarctions may occur as a failure of secondary preventionstrategies and are associated with a high risk of subcorticalvascular dementia [78].

Symptomatic lacunar strokeFrom a clinical perspective in daily practice, symptomatic lacu-nar strokes are important for the following three reasons: thepresence of mild cognitive impairment in some patients withfirst-ever lacunar stroke, the worse functional prognosis ofpatients with a lacunar stroke of progressive clinical course, andthe role of neuroimaging findings as a predictors of the poten-tial risk of cognitive decline.

Mild cognitive impairment in first-ever lacunar infarctsLacunar strokes are less severe than other types of stroke in termsof the clinical picture during the acute phase and short-termprognosis. Lacunar stroke may be associated with high disabilityin case of gaps in strategic areas such as pons. It has been tradi-tionally considered that lacunar infarcts due to their small sizeand subcortical topography do not cause neuropsychologicalalterations. However, alterations of executive functions, with ful-fillment of vascular-type mild cognitive impairment have beenreported in more than 50% of patients with lacunar stroke [79–81].In the Secondary Prevention of Small Subcortical Strokes (SPS3)clinical trial, mild cognitive impairment was identified in half ofthe participants and was an important clinical sequelae of lacunarischemic stroke more prevalent than physical disability [82]. In arecent systematic review of cognitive impairment in lacunarischemic stroke, impaired cognition appears less selective thanpreviously thought, involving episodic memory and all majorcognitive domains [83]. In a review of 24 relevant studies, whichincluded 2860 patients with lacunar stroke, 24% had mild cog-nitive impairment or dementia post-stroke [84]. According tothese observations, the long-term outcome of lacunar ischemicstroke patients cannot be thought of as benign in terms of func-tional impairment [85,86].

Lacunar strokes with progressive clinical courseA worsening of neurological impairment especially motor func-tion during the first hours or days after the onset of stroke isobserved in 20–30% of patients with a lacunar stroke. Neurolog-ical deterioration is often associated with an important degree offunctional disability and is a clinical manifestation of poor prog-nosis [87,88]. Progressive lacunar stroke were more closely associ-ated with lacunar infarcts having the characteristics of branchatheromatous disease during hospitalization, Also branch athero-matous disease predicts recurrent strokes after discharge [87,89].

A plausible explanation supported by early description ofFisher [14] may be local thrombosis with propagation of thethrombus to proximal or distal areas of a penetrating artery.Hemodynamic alterations have been also involved in the patho-genesis of atheromatous branch disease. High-resolution MRIstudies are useful to assess morphological characteristics of intra-cranial vessels and the presence of atheromatous plaques [87].

The role of excitotoxicity and inflammation in progressivelacunar stroke are another factors [90]. However, molecularmechanisms underlying the pathophysiology of infarction havebeen reported during the acute stroke phase irrespective ofstroke subtype and progression of the ischemic lesion. In lacu-nar stroke patients, the following variables have been identifiedto be associated with progression: diabetes, degree of motorinvolvement on admission, pontine site of lesion, high systolicBP (SBP), presence of stenosis of the parent artery, hypertrigly-ceridemia, age over 74 years, female gender, lacunar infarctioninvolving the posterior aspect of corona radiata and precedinglacunar TIAs [91].

In one study, a polymorphism of the IL-6 gene associatedwithin increased inflammation was an independent risk factor

Figure 3. Macroscopic specimen showing lacunar infarctsat the level of the basal ganglia.

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for progressing in lacunar stroke [92]. Also, an associationbetween leukocyte count and outcomes after stroke has alsobeen found in lacunar stroke, as well as other stroke subtypes.These data support the hypothesis that inflammatory mecha-nisms may contribute to the risk of lacunar disease and its pro-gression [87,93,94]. Cardioembolic stroke showed significantlyhigher levels of inflammatory biomarker blood levels such asTNF-a, IL-6, IL-1b, whereas the lacunar subtype showed sig-nificantly lower median plasma levels of TNF-a, IL-6 andIL-1b [95,96]. The minor grade of immunoinflammatory activa-tion of patients with lacunar stroke could be related to theminor extension of the infarct size, owing to the typical micro-vascular disease that could also explain the reported better out-come of this ischemic stroke subtype [97].

Prognostic value of neuroimaging dataLacunar stroke is an relevant predictor of post-stroke cognitiveimpairment and dementia of vascular type during follow-up[84,98,85,86,99,100]. Some neuroimaging factors are significantly relatedto cognitive decline after lacunar stroke. These include the pres-ence of multiple silent lacunes (infarcts not related to clinicallyobvious stroke and found incidentally on neuroimaging) [101–103],white matter changes, microbleeds and brain atrophy [101,104].White matter changes have been related to cognitive, mood, gaitand urinary problems in cross-sectional studies, and with cogni-tive decline and dementia in longitudinal studies [30,105]. Baselinevolume of white matter changes was the strongest predictor offuture cognitive decline in cerebral SVD based on the hypothesisthat white matter changes might reduce brain plasticity and cog-nitive reserve [104]. On the other hand, microbleeds might be anadditional risk factor risk for dementia [39,40]. Brain atrophy canbe the end stage of multiple pathological processes and is a well-recognized feature of many neurological diseases, includingAlzheimer’s disease and multiple sclerosis. Atrophy is also a fea-ture of cerebral SVDs [106–108]. In a clinical study in which voxel-based morphometry was used for assessing grey matter atrophy inpatients with a first-ever lacunar infarction that fulfilled criteriafor mild cognitive impairment of the vascular type, [109], greymatter shrinkages were observed different regions (temporal, pari-etal, frontal, hippocampus, cerebellum). These findings are consis-tent with functional neuroimaging data and provide evidence thatbeyond the area of infarction, remote effects of subcortical dam-age may occur [110,111].

Recurrent lacunar strokeAlthough infrequently fatal, lacunar stroke is associated with ahigh risk of recurrence and cognitive impairment [112,113]. Therate of recurrence among lacunar stroke patients is about 4–11%per year [86,114], slightly higher than percentages observed in otherstroke subtypes. Recurrent lacunar ischemic stroke is a major fac-tor involved in producing vascular subcortical dementia. Approxi-mately 55–70% of recurrences in lacunar stroke patients are alsolacunes, supporting a distinctive pathomechanism [86]. In theSPS3 clinical trial, 224 patients suffered recurrent ischemicstrokes [113]. Etiological subtypes of recurrent ischemic strokes

were as follows: lacunar ischemic strokes in 133 (59.5%) ofpatients, large artery atherosclerosis in 26 (11.5%) (intracranial17, extracranial 9), cardioembolism in 19 (8.5%), other etiologiesin 9 (4%) and unknown strokes in 37 (16.5%). In another clini-cal study, cognitive impairment (Mini Mental State Examinationscore <24) was detected in 16% of patients with first lacunarstroke recurrence and in 40% of those with multiple recur-rences of lacunar stroke [114]. Therefore, prevention of lacu-nar stroke recurrence in patients with first-ever lacunarinfarction is a crucial strategy in the fight against vasculardementia. Recurrent lacunar ischemic stroke, silent progres-sion of SVD and perivascular leukoaraiosis in cases of clini-cally symptomatic multiple lacunar infarctions are associatedwith an increased risk of cognitive impairment [83].

Treatment & secondary lacunar stroke preventionTo determine optimal strategies for secondary stroke preventionin patients with lacunar infarction it is necessary to considerthe following actions: [11]: adequate treatment of the acutephase of the disease, to establish a correct etiological and phys-iopathological diagnosis (excluding unusual causes of lacunarstroke) and if possible, to make a precise differentiation ofunderlying pathologies of lacunar infarction (individualizingbranch atheromatous disease from intrinsic microatheromatosisor arteriolar lipohyalinosis), and control and treatment of cere-brovascular risk factors. Accordingly, in optimal preventionstrategies the relevance of physiopathological mechanisms oflacunar infarction should be the gold standard and a priority inthe quality of the patient’s care.

Treatment of the acute phaseTreatment with intravenous recombinant tissue plasminogenactivator within the 4.5-h window after the onset of symptomsis recommended. Usual doses are 0.9 mg/kg (maximum of90 mg), starting with a bolus of 10% of the dose followed bya 60-min infusion. The response to thrombolytic therapy inthe acute stroke phase is similar in patients with ischemic cere-bral infarction independently of the subtype of infarction[115,116]. However, recombinant tissue plasminogen activatortreatment seems less beneficial for lacunar stroke patients with-out arterial occlusion than other clinical subgroups [117]. Onthe other hand, data of the third International Stroke Trial [118]

provides evidence that thrombolysis with intravenous alteplasefor acute ischemic stroke does not affect survival, but does leadto statistically significant, clinically relevant improvements infunctional outcome and health-related quality of life that aresustained for at least 18 months. In this randomized trial, therewere 137 (12%) and 133 (11%) patients with lacunar infarc-tion assigned to the alteplase and control groups, respectively.Nonetheless, until better data are available, we recommend thatpatients with lacunar syndromes be selected for thrombolysisaccording to current guidelines in the same way as patientswith other subtypes of ischemic stroke.

According to the specific pathophysiological mechanisms(platelet aggregation, thrombosis or embolism), antiplatelet

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agents, anticoagulants or drugs to reduce blood viscosity maybe indicated.

In progressive lacunar stroke secondary to intracranial branchatheromatous disease, two studies have shown preliminaryresults of the usefulness of intravenous tirofiban [119,120] andone study about intravenous eptifibatide [121]. Eptifitabide is anantiplatelet drug of the glycoprotein IIb/IIIa inhibitor class.Glycoprotein IIb/IIIa inhibitors may be in combination withneuroprotectant agents or anti-inflammatory drugs, appear apromising therapeutic strategy to be assessed in future random-ized trials of progressive lacunar infarction. Although resultswith the use of tirofiban and eptifitabide are promising, studiesare observational and the study population rather small.

Treatment of hyperglycemia [122] and control of body tempera-ture >37.5ºC are general therapeutic measures in the acute phaseof stroke. Routine BP lowering therapy is not recommended fol-lowing acute stroke. Cautious BP lowering is recommended inpatients with extremely high BP levels (>220/120 mmHg) onrepeated measurements, or with severe cardiac failure, aortic dis-section or hypertensive encephalopathy. It is recommended thatabrupt lowering of BP should be avoided and low BP secondaryto hypovolemia or associated with neurological deterioration inacute stroke should be treated with volume expanders.

Secondary prevention in lacunar strokePrevention of recurrent lacunar infarction is mandatory to preventcognitive decline and dementia of the vascular type in lacunarstroke patients. To date, ischemic stroke caused by small-vesseldisease has rarely considered a specific aim of clinical trials.Patients with ischemic stroke should be treated with a combina-tion of aspirin and dipyridamole, or clopidogrel alone. Also,aspirin monotherapy or triflusal monotherapy can be adminis-tered [123]. However, clinical trials of secondary prevention inpatients with cerebral ischemia provide indirect data based on aposteriori analysis of results obtained in the subgroup of patientswith lacunar stroke. However, there was no evidence that onedrug or combination was better than another [124].

In the French study Accidents Ischemiques Cerebraux Lies al’Atherosclerose [125], reduction of recurrence was comparedbetween treatment with aspirin monotherapy or aspirin combinedwith dipyridamole versus placebo. In the subset of 96 patientswith lacunar infarction, a reduction of 69% (p < 0.03) inpatients treated with aspirin with and without dipyridamole wasobserved. In the Canadian-American Ticlopidine Study [126]

(ticlopidine vs placebo), a 50% reduction of the relative risk ofrecurrent stroke and stroke-related mortality per year was docu-mented in the subgroup of 275 patients with lacunar infarction.Also, in the Chinese Acute Stroke Trial [127], a reduction of therelative risk of recurrence or 30-day mortality (aspirin vs placebo)of 10% in the subset of patients with lacunar infarcts (n = 6120)was reported. It should be noted that short-term prognosis wasonly assessed in the Chinese Acute Stroke Trial study, and theproblem for lacunar stroke is to prevent long-term recurrence.

In the Cilostazol Stroke Prevention Study [128] (cilostazol100 mg/day vs placebo), active treatment resulted in a reduction

of the relative risk of lacunar stroke recurrence of 43.4% in thesubset of 810 patients with lacunar stroke. Cilostazol is a differ-ent type of antiplatelet agent that inhibits type 3 phosphodiester-ase and decreases thromboxane formation by enhancement of theplatelet/cAMP level. The increase in cAMP level leads to an inhi-bition of platelet aggregation, has a vasodilatadory action, pro-tects endothelial cells inhibiting vascular smooth muscle cellproliferation and acts favorably on lipid metabolism. Moreover,cilostazol reduces coronary restenosis in patients with stentimplantation and intracranial arterial stenosis in acute strokepatients [129]. In another study [130], the combined treatment ofcilostazol and the neuroprotectant edavarone in larger lacunar-type infarct resulted safe and effective in improving functionaloutcome.

In the Warfarin–Aspirin Recurrent Stroke Study [131], a totalof 1237 patients with lacunar infarction were enrolled, and therate of recurrence or death was 8% in those treated with aspirinas compared with 9% in the warfarin-treated group (p = 0.31).Therefore, anticoagulation was not useful for the secondaryprevention of cerebral ischemia in lacunar infarcts. In the Afri-can American Aspirin Stroke Prevention Study [132], a signifi-cant reduction of the relative risk of stroke recurrence andstroke-related mortality in ticlopidine-treated patients versusthose treated with aspirin in the subgroup of patients withlacunar infarction (n = 1221) was not found.

In the management of atherothrombosis with clopidogrel inhigh-risk patients with TIA or stroke [133] (clopidogrel 75 mg vsclopidogrel 75 mg plus aspirin), combined treatment was associ-ated with a non-significant reduction of the primary end point(cerebral infarct, myocardial infarction, death of vascular cause orrehospitalization due to ischemic events), and a significantincrease of intracranial and extracranial hemorrhages. However,results in patients with lacunar infarction were not analyzed. Thelack of response of the double antiplatelet aggregation therapywas attributed to the high number of patients with lacunarinfarcts included in the study (n = 3148); it was argued that iflacunar stroke is primarily non-atherothromboembolic, then sec-ondary prevention aimed to preventing atheroma progressionmay not be very effective. In the management of atherothrombo-sis with clopidogrel in high-risk patients with TIA or strokestudy [133], the diagnosis of lacunar stroke was based on clinicalfeatures and computed tomography scanning and given that mag-netic resonance with diffusion imaging was not used, some of thelacunar strokes may actually have been cortical strokes. This maybe viewed as potential limitation of the study.

The Stroke Prevention by Aggressive Reduction of CholesterolLevels [134] showed that patients with SVD and increased low-density lipoprotein cholesterol have a similar risk of stroke recur-rence as do patients with large vessel strokes and that treatmentwith atorvastatin 80 mg daily is equally effective in reducing thisrisk, implying that patients with SVD also benefit from statintherapy. Since then statin therapy is recommended in subjectswith non-cardioembolic stroke [123,135]. Statins and other drugstargeting inflammation may play an important role for inhibitinginflammation and stabilizing atherosclerotic plaques.

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The SPS3 Phase III study [113] is the first double-blind, multi-center trial of secondary stroke prevention focusing specifically onpatients with recent symptomatic, confirmed MRI lacunarinfarcts. The aims of the trial were to define the optimal inter-ventions (antiplatelet therapy of either enteric-coated aspirin325 mg/day or aspirin plus clopidogrel 75 mg/day), and two tar-get levels of SBP control, either intensive (<130 mmHg) or usual(130–149 mmHg) to prevent stroke recurrence and cognitivedecline. The secondary prevention of lacunar stroke as detectedby the use of MRI has not previously been the focus of a ran-domized trial. In this cohort of patients (n = 3020; mean age of63 years; 63% men) with recent lacunar infarcts identified onMRI, after a mean follow-up of 3.4 years the addition of clopi-dogrel to aspirin did not significantly reduce the risk of recurrentstroke (2.5% per year for dual antiplatelet therapy and 2.7% peryear for aspirin monotherapy) but increased the risk of majorbleeding (2.1% per year for dual antiplatelet therapy and 1.1%per year for aspirin alone) (hazard ratio [HR]: 1.97; p < 0.001)and death. Despite the overall negative study results, it should benoted that dual antiplatelet therapy was associated with a trendtoward a reduction in recurrent strokes attributed to atherosclero-sis (17 patients in arm of aspirin alone vs 9 patients in the armof aspirin plus clopidogrel; p = 0.11), but not in recurrent lacu-nar strokes (67 patients in arm of aspirin alone vs 66 patients inthe arm of aspirin plus clopidogrel; p = 0.89), a finding that sup-ports the hypothesis that the role of antiplatelet agents is differentin different types of ischemic cerebrovascular disease. This mayalso be related to the logical speculation that thrombosis mayhave a minimal role in precipitating occlusions of small, penetrat-ing cerebral arteries. On the other hand, an increase of eitherextracranial bleeding (the majority of cases gastrointestinal) (HR:2.15; p < 0.001) and intracranial bleeding (HR: 1.52; p = 0.21)was observed, although the latter increase was not statistically sig-nificant. In conclusion, the SPS3 trial documents the lack of ben-efit of dual antiplatelet therapy in a specific, well-defined subtypeof ischemic stroke that results primarily from cerebral small-arterydisease. Aspirin is accepted as standard antiplatelet therapy inpatients with symptomatic lacunar infarcts. SPS3 also demon-strates quite clearly that lacunar stroke cannot possibly be anintracranial atheromatous disease, otherwise dual antiplateletdrugs would have been helpful not harmful.

Secondary prevention in lacunar stroke patients of rarecausesWhen the cause of lacunar infarction is an emboligenous heartdisease, these patients should be given oral anticoagulants (warfa-rin, international normalized ratio 2.0–3.0) [136,137], despite thefact that the efficacy of anticoagulation in preventing lacunarinfarction has not been proven [131]. Cardioembolism is anuncommon cause of lacunar infarction [138]. In a clinical study ofpatients with lacunar stroke, emboligenous heart disease as aunique etiology occurred in 4% of patients [25]. In the subgroupof lacunar infarcts in very old patients (‡ 85 years of age), thehigher occurrence of atrial fibrillation and the lower prevalence ofhypertension and diabetes suggest that the cardioembolic source

may be more frequent among the oldest old lacunar strokepatients [139]. Small deep infarcts in atrial fibrillation might beoriginated from SVD rather than cardioembolism [140].

In a recent meta-analysis, non-vitamin-K-antagonists (apixa-ban, dabigatran and rivaroxaban) seem to have a higher efficacyand safety to prevent stroke or systemic embolism than warfa-rin in patients with atrial fibrillation and previous ischemicstroke or TIA [137].

Of note, in the stroke prevention in reversible ischemia trial,leukoaraiosis together with an age older than 65 years were theonly independent predictors of major bleeding during anticoa-gulation started after cerebral ischemia [141]. Leukoaraiosis wasan independent risk factor for warfarin-related intracranialhemorrhage in another clinical study. However, despite theseevidences, SVD (white matter changes and/or microbleeds) can-not be taken as a contraindication to anticoagulation treatment.Future studies may provide answer to the question whetherlower doses of anticoagulant drugs should be used in patientswith clinical manifestations of SVD.

In the rare cases in which lacunar infarction developed inpatients with neurosyphilis, neurocysticercosis or connective tis-sue disease, treatment with penicillin, praziquantel or predni-sone, respectively, should be indicated [49,50]. Also, cytoreductiontherapy may be useful when the lacunar stroke is caused byessential thrombocythemia or polycythemia vera; in cases withhematocrit level >45%, phlebotomy may be indicated [47,48].

In patients with cerebral autosomal dominant arteriopathywith subcortical infarcts and leukoencephalopathy, antiplateletaggregation therapy is effective [142]; also, it seems that resvera-trol (a polyphenol SIRT1 activator) may be a potential usefuldrug in this entity. In Fabry’s disease, enzyme replacementtherapy (a-galactosidase) may be a potential therapeutic alter-native that has not been demonstrated to be useful as secondarystroke prevention. Other unusual causes of ischemic lacunarinfarct include carotid plaque atheromatous embolism or inassociation with severe stenosis of a penetrating arteriole andamyloid angiopathy [3,143].

In relation to carotid stenosis in patients with lacunar stroke,in a series of 135 patients with single lacunar infarction, ipsilat-eral carotid stenosis ‡50% was documented in 22% of casesand stenosis ‡70% in 14% [144]. The role of carotid stenosis inthe presence of lacunar infarction has been recently evaluatedin the patients enrolled in North American SymptomaticCarotid Endarterectomy Trial, in which 12.2% of the patientswith 70–99% stenosis had a hemispheric stroke classified asprobable lacunar stroke (lacunar syndrome and an appropriatelacunar lesion). Carotid endarterectomy reduced the risk ofstroke by 35% in this type of cerebral ischemia [145].

Treatment of risk factors for cerebrovascular diseaseSecondary stroke prevention measures also include a correctdiagnosis and adequate management of risk factors for cerebraldisease, particularly hypertension and diabetes.

Hypertension is the most important risk factor for the occur-rence of a lacunar infarction as well as the most important

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modifiable risk factor for the development of SVD [124]. Thereis a large body of evidence for treating hypertension in strokeprevention. Optimal treatment of hypertension has a directimpact in reducing the incidence of first-ever stroke and strokerecurrence [146,147]. Adequate BP control may reduce whitematter hyperintensity (WMH) progression and cognitiveimpairment of vascular type [148]. In relation to BP targets inpatients with recent lacunar stroke, recent data of theSPS3 trial have recommended a SBP <130 mmHg [149]. In theperindopril protection against recurrent stroke study MRI sub-study [150], active BP-lowering regimen stopped or delayed theprogression WMHs in patients with cerebrovascular disease. Ina recent population-based longitudinal MRI study in the Neth-erlands [151], means of BP were calculated over a 5-year periodbefore longitudinal MRI scanning, and white matter changesprogression was subsequently measured on 2 scans 3.5 yearsapart. After adjustment for baseline white matter lesion(WML) volume, only SBP remained significantly associatedwith WMLs progression. This study established that high BPprecedes WMLs and implies that hypertension treatment couldreduce WML progression in the general population. However,evidence of BP lowering as a proven and effective treatment foreither WMH or lacunar stroke remains inconclusive.

Diabetic patients are also at risk of cerebral ischemic diseaseincluding lacunes [1,3]. In addition to adequate management ofaltered glucose levels during the acute phase of stroke, bloodglucose levels should be regularly monitored during the post-stroke follow-up period. Standard lifestyle measures should berecommended together with individualized antidiabetic treat-ment, including pioglitazone in type 2 diabetic patients wheninsulin is not required [123,135].

In a recent preliminary study, combined therapy with probu-col and cilostazol on endothelial function in silent lacunar cere-bral infarcts and mild hypercholesterolemia resulted in subacuteimprovement in flow-mediated vasodilatation/endothelial func-tion [152]. The authors conclude that this combination therapyhas the potential to reduce the risk of cardiovascular events viaimprovements in endothelial function and lipid profiles [152].

General measuresGeneral recommendations for stroke patients (such as earlyrehabilitation, anticoagulation to prevent thromboembolism,adequate treatment of concomitant diseases, regular physicalactivity, healthy diet, restrain from cigarette smoking and heavyalcohol consumption, weight loss in overweight patients,etc.) [153,154] also applies to patients with lacunar stroke.

A summary of secondary prevention strategies in lacunarischemic stroke related to the more frequent potential underly-ing mechanism is shown in TABLE 1.

New platelet anti-aggregantsThere are several emerging antiplatelet drugs that have morepotent and predictable antiplatelet effect compared with currentavailable agents. Prasugrel, ticagrelor and cangrelor are new-generation P2Y12 receptor antagonists [156]. Their efficacy is

relatively free of hepatic activation, resistant to esterases andless dependent on CYP2C19 oxidation. Accordingly, they exerta more potent and predictable antiplatelet effect. Their efficacyand safety in stroke remains to be studied in the future. How-ever, it would be wise to be cautious in view of the adverseeffect of dual antiplatelet drugs in SPS3 [113], the absence ofatheroma in lacunar stroke and the association of lacunar strokewith microbleeds and bleeding risk.

Future research in stroke will also focus in identifying factorsassociated with therapeutic resistance to aspirin and conven-tional platelet anti-aggregant therapy [157] and genes involved inplatelet response to antiplatelet treatment [158,159]. Currentlyongoing genome-wide association studies of stroke may revealadditional prevalent and clinically significant genetic abnormali-ties in the near future.

Neuroprotection includes a set of therapeutic strategies directedto block the biochemical processes of the ischemic cascade leadingto neuronal necrosis or apoptosis in the ischemic penumbra area.However, up to the present time no pharmacological measureshas shown a conclusive evidence of a beneficial effect in humans,despite promising results in experimental models of cerebral ische-mia. In a recent study, citicoline was not effective in the acutephase of ischemic stroke in the International Citicoline Trial onacute Stroke, in which 5% of patients had lacunar stroke [160].

Magnesium may have an effect on the white matter in subcor-tical models of ischemia [161,162] through endothelial vasodilatoryactions or because of mild BP-lowering effects, rather thanthrough neuroprotection. In the intravenous magnesium efficacyin stroke study [162], treatment with intravenous magnesium sul-fate in ischemic stroke within 12 h of onset did not show a sig-nificant reduction in mortality or disability at 90 days, but insubgroup analyses a beneficial effect on lacunar infarcts was dem-onstrated with a reduction in the disability rate at 3 months [163].More evidence from randomized controlled trials is neededregarding the potential beneficial effects of magnesium.

These results should be confirmed in future clinical trials butopen the possibility that patients with lacunar infarct constitutean adequate target group for neuroprotectant drugs with bio-logical activity in the cerebral white matter substance.

Expert commentaryLacunar ischemic stroke accounts for one-fourth of cerebralinfarctions. Paradoxically, despite the high frequency of lacunarinfarction, clinical trials aimed at assessing treatment strategies forsecondary prevention of this stroke subtype, except for the dataprovided by the SPS3 study [80]. Also, some trials of secondarystroke prevention had negative results, which was consistent witha recruitment of a high number of patients with lacunar infarct.It should be noted that lacunar ischemic strokes usually resultfrom occlusion of a single penetrating artery by lipohyalinosis ormicroatheroma. Data of the SPS3 trial are against intracranialatheromatous branch disease as the etiopathogenetic mechanismof lacunar stroke. In only 5–10% of cases, the etiology of lacunarstroke is due to an emboligenous cardiopathy, hemodynamicalterations, hematologic diseases or other unusual causes. The

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Table 1. Prevention strategies in lacunar ischemic stroke related to more frequent potential underlyingmechanism†.

Underlyingmechanism/cause

First choice Second choice Third choice Future research

Microatheromatosis Aspirin Aspirin plus dipyridamole New-generationP2Y12 receptorantagonists (prasugrel,ticagrelor andcangrelor)

Identifying genesinvolved in plateletresponse to antiplatelettreatment

Statins Clopidogrel

Treatment of risk factors(mainly hypertension anddiabetes)

Cilostazol

Avoid cigarette smokingand heavy use of alcohol

Intracranialatheromatous branchdisease

Aspirin Aspirin with dipiridamol New-generationP2Y12 receptorantagonists (prasugrel,ticagrelor andcangrelor)

Identifying genesinvolved in plateletresponse to antiplatelettreatment

Statins Clopidogrel

Treatment of risk factors(mainly hypertension anddiabetes)

Cilostazol

Avoid cigarette smokingand heavy use of alcohol

Glycoprotein IIb/IIIa inprogressing stroke(tirofiban or eptifibatide)

Glycoprotein IIb/IIIainhibitors combined withanti-inflamatory orneuroprotectant agentsin progresing lacunarinfarct

Lipohyalinosis Statins Antiplatelet agents Cilostazol Identifying genesinvolved in response totreatment

Treatment of risk factors(mainly hipertension anddiabetes)

Cilostazol

Avoid cigarette smokingand heavy use of alcohol

Emboligenouscardiopathy

Warfarin

Dabigatran

Apixaban

Rivaroxaban

Drugs targeting inflammation may play an important role for inhibiting inflammation and stabilizing atherosclerotic plaques.†In all patients, regular physical activity and diet low in salt and saturated fat, high in fruit and vegetables and rich in fiber is recommended. Subjects with an elevatedbody mass index are recommended to adopt a weight-reducing diet. Sleep-related breathing disorder such as obstructive sleep apnea is recommended to be treatedwith continuous positive airway pressure breathing. Moreover, an adequate control and treatment of concomitant disorders is mandatory.‡Others monogenic conditions that predispose to mainly ischemic and less commonly hemorrhagic stroke of small vessel origin include cerebral autosomal recessive arte-riopathy with subcortical infarcts and leukoencephalopathy, retinal vasculopathy with cerebral leukodystrophy, hereditary endotheliopathy with retinopathy, nephropathyand stroke, collagen type IV, a1-related disorders, Pontine autosomal dominant microangiopathy and leukoencephalopathy, demencia hereditaria multi-infarto and amy-loid cerebral angiopathy associated with mutation of the APP gene. Other monogenic diseases that may present with microangiopathy are pseudoxanthoma elasticum,neuroacanthocytosis and sickle-cell anemia.CADASIL: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

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objective of secondary prevention is to avoid recurrent lacunarischemic stroke, which may be associated with a more severe clin-ical picture and is one of the major factors involved in producinglacunar state and vascular subcortical dementia. At the presenttime, the addition of clopidogrel to aspirin does not reduce sig-nificantly the risk of lacunar stroke recurrence but increases signif-icantly the risk of bleeding and death. Aspirin is accepted asstandard antiplatelet therapy in patients with lacunar ischemicstroke, and information on treatment with clopidogrel alone insecondary prevention of lacunar stroke is still lacking. However,it seems clear that to establish optimal strategies for secondarystroke prevention, the precise differentiation of underlying pathol-ogies of lacunar infarction is an important issue. If lacunar strokeis primarily of non-atherothromboembolic etiology, then second-ary prevention strategies aimed at preventing atheroma progres-sion may not be very effective. Drugs that improve endothelialfunction, BP lowering, lipid-lowering agents, angiotensin-converting enzyme inhibitors and non-steroidal anti-inflammatoryagents may act on the circulation to reduce stroke through mech-anisms other than simply by preventing atheroma, and thereforemay be effective in preventing lacunar infarction. The role of pra-sugrel, ticagrelor and cangrelor, a new-generation P2Y12 receptorantagonists, in stroke prevention remains to be studied in thefuture. Mechanisms of resistance to platelet anti-aggregant therapyshould also be taken into account.

Five-year viewSome aspects are not definitively established in the field of pre-vention strategies in lacunar infarction. Aspects that merit fur-ther investigation include the following:

• The potential pathophysiological mechanisms underlyinglacunar ischemic stroke are still unclear. The results ofMATCH and SPS3 studies point that thrombosis plays aminor role in small vessel disease.

• High-field MRI is a useful technique for the assessment ofbranch atheromatous disease in the parent artery in patientswith lacunar infarction. This is important because lacunarstroke secondary to branch atheromatous disease is character-ized by a worse prognosis and a higher likelihood of lacunarinfarction recurrence. In these cases, platelet anti-aggregationtreatment may be particularly useful; also, double anti-aggregation therapy may be a more effective strategy for sec-ondary prevention in this particular subgroup of patients.Future studies with a prospective, consecutive design will beable to separate branch atheromatous disease from intrinsicdisease of penetrating arteries (by microatheromatosis orlipohyalinosis).

• Citostazol is a promising different type of antiplatelet agent,the efficacy of which should be assesses in a randomized clin-ical trial of lacunar stroke patients.

Table 1. Prevention strategies in lacunar ischemic stroke related to more frequent potential underlyingmechanism† (cont.).

Underlyingmechanism/cause

First choice Second choice Third choice Future research

Mieloproliferativediseases

Cytoreductor therapy

Phlebotomy (inpolycythemia rubra vera)

Antiplatelet agents

Infectious disease Antibiotics (e.g.,praziquantel inneurocisticercosis;penicillin in neurosyphilis)

Fabry’s disease Enzyme replacementtherapy (a-galactosidase)

Inflammatory arteritis Prednisone

CADASIL‡ Antiplatelet agents Resveratrol (apolyphenolicSIRT1 activator)

Donepezil

Drugs targeting inflammation may play an important role for inhibiting inflammation and stabilizing atherosclerotic plaques.†In all patients, regular physical activity and diet low in salt and saturated fat, high in fruit and vegetables and rich in fiber is recommended. Subjects with an elevatedbody mass index are recommended to adopt a weight-reducing diet. Sleep-related breathing disorder such as obstructive sleep apnea is recommended to be treatedwith continuous positive airway pressure breathing. Moreover, an adequate control and treatment of concomitant disorders is mandatory.‡Others monogenic conditions that predispose to mainly ischemic and less commonly hemorrhagic stroke of small vessel origin include cerebral autosomal recessive arte-riopathy with subcortical infarcts and leukoencephalopathy, retinal vasculopathy with cerebral leukodystrophy, hereditary endotheliopathy with retinopathy, nephropathyand stroke, collagen type IV, a1-related disorders, Pontine autosomal dominant microangiopathy and leukoencephalopathy, demencia hereditaria multi-infarto and amy-loid cerebral angiopathy associated with mutation of the APP gene. Other monogenic diseases that may present with microangiopathy are pseudoxanthoma elasticum,neuroacanthocytosis and sickle-cell anemia.CADASIL: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

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• Glycoprotein IIb/IIIa inhibitors (tirofiban or eptifibatide), possi-bly combined with anti-inflammatory or neuroprotectant agentsis a promising strategy that merits to be studied in randomizedcontrolled trials in progressing lacunar ischemic stroke.

• The efficacy, tolerability and safety of antiplatelet treatmentwith prasugrel, ticagrelor and cangrelor, a new-generationP2Y12 receptor antagonists is still unknown.

• Non-vitamin-K-antagonists (apixaban, dabigatran and rivarox-aban) seem to be more efficacious and safer to prevent strokeor systemic embolism compared with warfarin in patients withatrial fibrillation and previous stroke or TIA. In patients withlacunar stroke of cardioembolic source, the efficacy of theseagents in secondary stroke prevention should be evaluated.

• The inclusion of cognition as an outcome in future prospec-tive observational studies and clinical trials is urgentlyrequired. Lacunar ischemic strokes offer a target for beneficialintervention to preserve cognition in older people.

• There is an urgent need for large genetic association studiesdesigned to assess the presence of genetic risk factors underlyingischemic stroke subtypes. No genes have yet been found for lacu-nar stroke and scarce for white matter changes. These discoveriesmay permit the identification of new therapeutic targets aimedat stroke prevention and neuroprotection from ischemic injury.

• Elevated levels of anti-inflammatory markers after a firstsmall subcortical stroke seem to increase the risk of recurrentischemic stroke and other vascular events. The importance of

inflammation in cerebral ischemic of the lacunar subtype isstill poorly studied.

• The role of antiplatelet therapy (combined vs single) inreducing inflammatory markers among stroke patients or therole of relative efficacy of antiplatelet therapy among thosewith, and without elevated levels of inflammation should bethe objective of further studies.

• The study and efficacy of treatment of lacunar stroke in veryold patients (>85 years of age) in another clinically relevantquestion that merits the design of studies focused on this seg-ment of the population.

Acknowledgements

The authors thank M Grau-Olivares, J Massons, M Oliveres, E Comes,MJ Vidal, N Amoros, A Cartanya, M Lowak, M Pizarro, R Rouco andS Estevez for their help in the care of patients with lacunar infarcts of theSagrat Cor Hospital of Barcelona Stroke Registry. We also thank MPulido, for editing the manuscript.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement withany organization or entity with a financial interest in or financial conflictwith the subject matter or materials discussed in the manuscript. Thisincludes employment, consultancies, honoraria, stock ownership or options,expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Lacunar stroke accounts for one-fourth of all cerebral infarctions.

• Lacunar stroke are not a benign vascular condition; by contrast, they present a high risk of recurrence and vascular dementia in the

mid- and long-term.

• Recurrent lacunar stroke may be associated with a more severe clinical picture and is one of the major factors involved in producing

lacunar state and vascular subcortical dementia.

• Recurrent strokes are more likely to be lacunar if the index event was lacunar.

• Progressive lacunar stroke may suggest the presence of branch atheromatous disease. In these cases, stroke recurrence after the acute

phase may be possible.

• High-resolution MRI can be used to study the morphology of intracranial artery vessels and can on the elucidation of stroke mechanisms.

• To determine optimal strategies for secondary prevention, precise differentiation of the underlying pathologies of lacunar infarction is an

important issue.

• Hypertension is the most important modifiable risk factor in lacunar stroke.

• If lacunar stroke is primarily non-atherothromboembolic, then secondary prevention aimed at preventing atheroma progression may not

be very effective.

• Drugs that improve endothelial function, blood pressure lowering, lipid-lowering agents, angiotensin-converting enzyme inhibitors and

non-steroidal anti-inflammatory agents may act on the circulation to reduce stroke through mechanisms other than simply by preventing

atheroma, and therefore may be effective in preventing lacunar stroke.

• Aspirin is accepted as standard antiplatelet therapy in patients with lacunar stroke.

• Among patients with recent lacunar stroke, the addition of clopidogrel to aspirin does not seem to reduce significantly the risk of

recurrent stroke but increases significantly the risk of bleeding and death.

• The value of prasugrel, ticagrelor and cangrelor, a new-generation P2Y12 receptor antagonists, in stroke prevention remains to be established.

• Non-vitamin-K-antagonists (apixaban, dabigatran and rivaroxaban) seem to be an attractive option for stroke prevention for patients

with lacunar stroke of cardioembolic origin.

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• Adequate review of diagnosis andtreatment of patients with cerebralautosomal dominant arteriopathywith subcortical infarcts andleukoencephalopathy.

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!

! 65!

!

Article!2:!Característiques!clíniques!en!l’infart!lacunar!agut!en!dones:!èmfasi!

en!les!diferències!de!gènere.!!

!

Antecedents!

A!la!literatura!hi!han!pocs!estudis!que!analitzen!les!característiques!dels!subtipus!

d’infarts!isquèmics!en!dones.!!

Mètode!

Es!van!avaluar!les!diferències!clíniques!en!el!pacients!amb!infart!lacunar!basades!

en!un!recull!de!dades!que!conformen!el!registre!prospectiu!d’infarts!a!Barcelona,!

(Catalunya).!!

Resultats!

Els!infarts!isquèmics!lacunars!van!ser!diagnosticats!en!310!dones!!(8.1%)!i!423!en!

homes!(11.1%)!d’un!total!de!3,808!pacients!amb!infart!inclosos!a!la!base!de!dades!

que!confirma!el!registre!hospitalari!a!Barcelona!(Catalunya)!!durant!un!període!de!

19!anys.!Els! factors! independents!per!als! IL!en!dones!van!ser!tractats!a!partir!de!

l’anàlisi! multivariant.! Les! dones! conformen! el! 42%! de! tots! els! IL! (n=733)! del!

registre!i!el!11.4%!de!tots!els!pacient!amb!infarts!isquèmic!(n=2704).!Els!pacients!

d’edat!avançada!(85!anys!o!més!grans)!es!van!trobar!en!un!20.3%!de!dones!versus!

el!11.1%!dels!homes!(P*<!0.0001).!Segons!l’anàlisi!de!regressió!logística,!l’obesitat!

(Odds!Ratio![OR]!=!4.24),!l’estància!prolongada!a!l’hospital!(>!12!dies)!(OR!=!1.59),!

la! hipertensió! arterial! (OR! =! 1.50),! i! l’edat! (OR! =! 1.06)! van! ser! variables!

significativament! independents!associades!a! IL!en!dones!mentre!que! la!patologia!

vascular!perifèrica! (OR!=!0.51),! la!malaltia!pulmonar!crònica!obstructiva! (COPD)!

! 66!

(OR!=!0.46),! la!disfunció!renal!(OR!=!0.13),! i!ser! fumador!(OR!=!0.04)!van!ser! les!

variables!independents!dels!infarts!en!homes.!!

Conclusió!

El! gènere! determina! de! forma! clara! les! diferencies! existents! segons! l’edat! i! la!

comorbiditats! en! pacients! amb! IL! isquèmic.! Les! dones! amb! IL! són! notablement!

més!grans!i!presenten!obesitat!i!hipertensió!arterial!més!freqüents!que!els!homes.!

La!severitats!dels!IL!són!iguals!tant!en!homes!com!en!dones.!!

!

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!

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!

!

!

ORIGINAL ARTICLE

Clinical characteristics of acute lacunar stroke in women:emphasis on gender differences

Adria Arboix • Lorena Blanco-Rojas •

Montserrat Oliveres • Luis Garcıa-Eroles •

Emili Comes • Juan Massons

Received: 8 June 2013 / Accepted: 26 October 2013! Belgian Neurological Society 2013

Abstract There are few studies analyzing features ofischemic stroke subtypes in women. We assessed gender

differences in lacunar stroke subtype based on data col-

lected from a prospective stroke registry in Barcelona,Spain. Lacunar ischemic stroke was diagnosed in 310

(8.1 %) women and 423 (11.1 %) men of a total of 3,808

consecutive stroke patients included in a prospective hos-pital-based stroke registry, in Barcelona, Catalonia (Spain),

over a period of 19 years. Independent factors for lacunar

stroke in women were assessed by multivariate analysis.Women accounted for 42 % of all lacunar stroke patients

(n = 733) in the registry and 11.4 % of all patients with

ischemic stroke (n = 2,704). Very old age (85 years orolder) was found in 20.3 % in women versus 11.1 % in

men (P \ 0.0001). In the logistic regression analysis,

obesity [odds ratio (OR) = 4.24], prolonged hospital stay([12 days) (OR = 1.59), arterial hypertension

(OR = 1.50), and age (OR = 1.06) were significant vari-

ables independently associated with lacunar stoke inwomen, whereas peripheral vascular disease (OR = 0.51),

chronic obstructive pulmonary disease (OR = 0.46), renaldysfunction (OR = 0.13), and heavy smoking

(OR = 0.04) were independent variables for lacunar stroke

in men. Women with lacunar stroke were remarkably olderand presented with obesity and hypertension more fre-

quently than did men. Lacunar stroke severity was similar

in men and women. These findings in lacunar strokepatients could be explained by differences in gender for

ischemic stroke in general.

Keywords Lacunar stroke ! Ischemic stroke ! Acute

cerebrovascular event ! Women ! Men ! Gender

differences ! Prospective study ! Stroke registry

Introduction

The ischemic stroke subtype of lacunar infarcts comprisesabout 25 % of all brain infarctions and is a common cause

of dementia of vascular origin [1]. Knowledge of differ-

ences in clinical features and outcome of stroke victimsbetween men and women is a matter of increasing interest,

particularly, because women typically live longer than

men, stroke is much more common among older peoplethan among younger, and the recognition of higher mor-

tality, higher disability, and higher incidence of dementiain women who survive a stroke as compared with men [2–

7]. Although a number of studies have assessed the influ-

ence of gender in acute stroke patients [8, 9], the analysisof clinical features in the subset of female patients with

lacunar stroke has been poorly characterized. To our

knowledge, this is the first study that provides data on sex-based differences in patients with lacunar infarction. To

this purpose, we conducted a study to determine whether in

a cohort of 3,808 consecutive patients collected in a pro-spective stroke registry over a 19-year period, lacunar

stroke in women and men was different regarding vascular

risk factors, clinical characteristics, and early outcome.

A. Arboix (&) ! L. Blanco-Rojas ! M. Oliveres ! E. Comes !J. MassonsCerebrovascular Division, Department of Neurology, HospitalUniversitari del Sagrat Cor, University of Barcelona, Viladomat288, 08029 Barcelona, Catalonia, Spaine-mail: aarboix@hscor.com

L. Garcıa-ErolesClinical Information Systems, Hospital de la Santa Creu i SantPau, Universitat Autonoma de Barcelona, Barcelona, Catalonia,Spain

123

Acta Neurol Belg

DOI 10.1007/s13760-013-0257-8

Patients and methods

Patients

This study included 3,808 patients with first-ever acutestroke admitted consecutively to the Department of Neu-

rology of Sagrat-Cor Hospital of Barcelona (Spain)

between January 1986 and December 2004. Data of thesepatients were collected prospectively in a stroke registry

[10]. Criteria of the Cerebrovascular Study Group of the

Spanish Society of Neurology [11], which is similar to theNational Institute of Neurological Disorders and Stroke

Classification [12] were used for the classification of stroke

subtypes. For the purpose of the present study, female(n = 310) and male (n = 423) patients with first-ever

lacunar infarction were selected. Prior to conducting the

study, approval was obtained from the ethical committee ofclinical research of the hospital.

Lacunar infarctions were defined according clinical and

neuroimaging criteria as follows: (a) sudden or gradualonset of a focal neurological deficit lasting [24 h of the

type described in the common lacunar syndromes (pure

motor hemiparesis, pure sensory stroke, sensorimotorstroke, ataxic hemiparesis, dysarthria-clumsy hand and

atypical lacunar syndromes); (b) brain computed tomog-

raphy (CT) scans or magnetic resonance imaging (MRI)studies were either normal or demonstrated only small,

localized brain lesions with diameter smaller than 20 mmthat seemed appropriate for the neurological deficits, and

(c) absence of cortical ischemia, cervical carotid stenosis

([50 % diameter) or major source for cardioembolicstroke. These criteria have been used by our group in

previous studies of lacunar stroke [13–15]. In cases in

which the initial CT scan was unrevealing, a second CTscan was performed before the patient’s discharge from the

hospital in order to exclude non-lacunar ischemic lesions

that could have passed unnoticed on the first CT scan.All patients were admitted to the hospital within 48 h of

the onset of symptoms. A brain CT and/or MRI was per-

formed within the first week of hospital admission. Foreach patient, demographic data, cardiovascular risk factors,

clinical features, neuroimaging findings, and early outcome

were recorded. Details of these variables were reported inprevious studies [10, 13]. Causes of death were analyzed

according to criteria of Silver et al. [16].

Statistical analysis

In the univariate analysis, the frequency of each variable inthe groups of women and men with lacunar infarction was

compared with the analysis of variance (ANOVA) and the

Chi square (v2) test with Yates or Bonferroni’s correctionwhen necessary. Statistical significance was set at

Table 1 Results of univariate analysis

Women Men P value

Total patients 310 (42.3) 423 (57.7)

Age, years, mean (SD) 77.34 (8,46) 71.79 (10.68) 0.0000

Age strata, years 0.0000

\65 28 (9) 95 (22.5)

65–74 75 (24.2) 148 (35.0)

75–84 144 (46.5) 133 (31.4)

C85 63 (20.3) 47 (11.1)

Risk factors

Hypertension 235 (75.8) 290 (68.6) 0.032

Diabetes 87 (28.1) 131 (31.0) 0.395

Ischemic heart disease 40 (12.9) 64 (15.1) 0.393

Atrial fibrillation 38 (12.3) 43 (10.2) 0.372

Heart failure 13 (4.2) 11 (2.6) 0.231

Valvular heart disease 12 (3.9) 9 (2.1) 0.162

Cerebral infarct 42 (13.5) 75 (17.7) 0.127

Intracerebral hemorrhage 3 (1.0) 6 (1.4) 0.835

Headache 11 (3.5) 0 0.000

History of transientischemic attack

32 (10.3) 48 (11.3) 0.660

Chronic obstructivepulmonary disease(COPD)

15 (4.8) 46 (10.9) 0.003

Obesity (BMI C30 kg/m2) 31 (10.0) 16 (3.8) 0.001

Chronic renal disease 3 (1.0) 18 (4.3) 0.008

Heavy smoking ([20cigarettes/day)

2 (0.6) 84 (19.9) 0.000

Hyperlipidemia 69 (22.3) 97 (22.9) 0.830

Peripheral vasculardisease

16 (5.2) 41 (9.7) 0.024

Alcohol abuse([80 g/day)

0 21 (5.0) 0.000

Chronic liver disease 4 (1.3) 11 (2.6) 0.216

Lacunar syndromes 0.356

Pure motor hemiparesis 156 (50.3) 196 (46.3)

Pure sensory stroke 51 (15.5) 76 (18)

Sensorimotor stroke 41 (13.2) 42 (9.9)

Ataxic-hemiparesis 8 (2.6) 16 (3.8)

Dysarthria-clumsy hand 20 (6.5) 39 (9.2)

Atypical lacunarsyndromes

34 (11) 54 (12.8)

Complications during hospitalization

Neurologic complications 11 (3.5) 11 (2.6) 0.457

Respiratory complications 9 (2.9) 8 (1.9) 0.369

Urinary complications 9 (2.9) 11 (2.6) 0.804

Cardiac complications 6 (1.9) 2 (0.5) 0.128

Infectious complications 12 (3.9) 16 (3.8) 0.951

Symptom-free at discharge 68 (21.9) 98 (23.2) 0.694

In-hospital death 3 (1) 1 (0.2) 0.412

Transfer to convalescent/rehabilitation units

24 (7.7) 16 (3.8) 0.020

Acta Neurol Belg

123

P \ 0.05. Variables independently associated with lacunar

stroke in women were analyzed in a logistic regressionmodel based on demographic, vascular risk factors, clinical

data, and outcome. In this model, a forward stepwise

selection procedure for variables with a P value of \0.10after univariate testing was followed. Female gender,

coded as absent = 0 and present = 1 was the dependent

variable. Age was used as a continuous variable with aconstant odds ratio for each year. The level of significance

to remain in the model was 0.15. The tolerance level wasestablished as 0.0001. The maximum likelihood approach

was used to estimate weights of the logistic parameters.

The odds ratio (OR) and 95 % confidence intervals (CI)were calculated from the beta coefficients and standard

errors. The hypothesis that the logistic model adequately fit

the data was tested by means of the goodness-of-fit v2 test.The SPSS-PC? and BMDP computer programs were used

for statistical analysis.

Results

The group of 310 women with first-ever lacunar infarction

accounted for 11.4 % of all ischemic strokes in the stroke

registry. The mean (SD) age was 77.3 (8.5) years. Twentypercent of women were older than 84 years. As shown in

Table 1, statistically significant differences between

women and men with lacunar infarction included older agein women, a higher percentage of women with hyperten-

sion, headache, and obesity [body mass index (BMI)

C30 kg/m2], and a higher percentage of men with COPD,renal dysfunction, heavy smoking ([cigarettes/day),

peripheral vascular disease, and alcohol abuse ([80 g/day).

The percentage of male and female patients undergoingbrain CT scan (96.7 and 96.5 %), MRI (41.6 and 41.9 %),

and echocardiographic studies (39.2 and 44.5 %) was

similar. Other findings related to the frequency of the dif-ferent lacunar syndromes, complications during hospital-

ization or the percentage of patients who were symptom-

free at discharge (absence of neurological deficit) was also

similar. Prolonged hospital stay ([12 days) was more fre-quent in women than in men (38.4 vs. 25.3 %, P \ 0.000)

and a significantly higher percentage of women as com-

pared with men were transferred to convalescence orrehabilitation units after discharge (7.7 vs. 3.8 %,

P = 0.020). Three women and one man died, with an in-

hospital mortality rate of 1 % in women and 0.2 % in men(P = 0.412). Causes of death were respiratory complica-

tions in two, sudden death in one, and unknown cause inone.

After multivariate analysis (Table 2), obesity, hyper-

tension, age, and prolonged hospital stay were indepen-dently associated with lacunar infarction in women.

Peripheral vascular disease, COPD, renal dysfunction, and

heavy smoking were independent clinical predictors asso-ciated with lacunar infarction in men.

Discussion

In the present series, the incidence of lacunar infarction inwomen was 11.4 %. Stroke was the leading cause of death

in women of 65 years of age or older in the autonomous

community of Catalonia (7 million inhabitants in north-eastern Spain) during the period from 1993 to 1998 [17]. In

addition, emerging evidence suggests that some cell death

pathways are sex-specific and the gender-based therapeuticinterventions may well hold promise for greater neuro-

protection in adult ischemic brain injury [18]. On the other

Table 1 continued

Women Men P value

Length of stay, days, mean(SD)

12.62 (7.55) 11.49 (8.31) 0.060

Prolonged hospital stay[12 days

119 (38.4) 107 (25.3) 0.000

Clinical differences in age, vascular risk factors, clinical features,lacunar stroke subtype, and early outcome between men and womenwith first-ever lacunar infarction

Data expressed as numbers and percentages in parenthesis unlessotherwise stated

Table 2 Results of logistic regression analysis

Variable b SE (b) Odds ratio(95 % CI)

P value

Obesity 1.445 0.391 4.24 (1.97–9.13) 0.000

Prolonged hospitalstay [12 days

0.464 0.181 1.59 (1.11–2.27) 0.010

Hypertension 0.480 0.189 1.50 (1.04–2.17) 0.031

Age 0.056 0.001 1.06 (1.04–1.08) 0.000

Peripheral vasculardisease

-0.680 0.331 0.51 (0.26–0.97) 0.040

COPD -0.776 0.341 0.46 (0.24–0.90) 0.023

Renal dysfunction -2.055 0.667 0.13 (0.03–0.47) 0.002

Heavy smoking([20 cigarettes/day)

-3.306 0.730 0.04 (0.01–0.15) 0.000

Variables independently associated with first-ever lacunar infarction inwomen

b = -4.695, SE (b) = 0.753, goodness-of-fit v2 = 1.819, df = 8,P = 0.986

Area under the ROC curve = 0.758, sensitivity 77.1 %, specificity59.3 %, positive predictive value 58.2 %, negative predictive value78 %, correct classification 66.8 %

Acta Neurol Belg

123

hand, estrogens have a beneficial effect on serum lipids and

coagulation profile and on preventing coronary heart dis-ease. Gender-specific differences disappear in the post-

menopausal age group. However, there is little information

regarding gender-based differences in vascular risk factors,clinical features, and early outcome in women with lacunar

infarction. Lacunar infarct constitutes a homogeneous

subgroup of cerebral infarctions due to the small size of thelesion (maximal diameter \20 mm) and favorable func-

tional prognosis at hospital discharge, characterized by alower in-hospital mortality and functional deficit as com-

pared with other types of ischemic infarctions, such as

those of cardioembolic or atherothrombotic cause [1, 14,19].

In our study, women patients have a different clinical

profile with a significantly older age, higher frequency ofobesity, hypertension and prolonged hospital stay and a

significantly lower frequency of peripheral vascular dis-

ease, COPD, chronic renal disease, and heavy smoking incomparison with lacunar infarction in male patients. As

shown in other studies [20], we found that male gender and

pure motor hemiparesis were more prevalent than femalesand other subtypes of lacunar stroke among stroke patients

hospitalized due to a cerebral infarction of the lacunar type.

However, age and the percentage of very old patients (aged85 years or more) were higher in women than in men.

Estrogens increase cerebral perfusion in women with or

without cerebrovascular disease. A growing body of evi-dence indicates that estrogens have tissue antioxidant

properties, which could contribute to neuroprotection dur-

ing ischemic episodes [21, 22]. After menopause, there is arapid increase in the incidence of stroke events in women

due to estrogen alterations of lipid metabolism. Accord-

ingly, it appears that lacunar stroke in women is mainly adisease of older patients (mean age 77.3 years in our

study). The more advanced age coincides with results

reported by Asplund et al. [23] with a mean age at the timeof the first stroke as 66.5 in male diabetics and 73.2 in

female patients.

Obesity, particularly abdominal obesity, is otherimportant independent vascular risk factor including lacu-

nar stroke in women. Obese persons have higher levels of

blood pressure, blood glucose, insulin resistance, and ath-erogenic serum lipids [24]. In the Nurses Health Study, the

incidence of stroke increased directly with body mass

index in women after adjustment for other risk factors, butno such relationship was seen in men [24]. On the other

hand, hypertension is the strongest independent risk factor

predisposing to stroke both in women and in men, Howeverand similar to the findings of Jørgensen et al. [25],

hypertension was more frequent among women.

Heavy smoking and alcohol consumption were lowamong female patients as compared with males, a similar

finding reported in the study of Megherbi et al. [26]

implying that gender may modify behavior and remain theleading preventable causes of cerebrovascular diseases in

men. This fact may also account for the lower frequency of

COPD and peripheral vascular disease in women withlacunar infarction.

Interestingly, early prognosis was similar in women than

in and men, given that there were no significant differences inthe rates of in-hospital mortality, percentage of patients who

were symptom-free at discharge, frequency of the differentlacunar stroke subtypes, or medical complications developed

during hospitalization. Lacunar infarction can be considered

a neurological condition with a relatively favorable func-tional prognosis, we found a significantly higher frequency

of prolonged hospitalization ([12 days) and transfer to

convalescence/rehabilitation units in women than in men.This may have a sociocultural reason because in the tradi-

tional family household, healthy women continue to have

prominent role in the care of male stroke patients, whereaswhen the stroke victim is a woman, social support (which

increases duration of hospital stay) and use of intermediate

care facilities are significantly more frequently needed.Chronic renal disease was less frequent among female

patients. Renal dysfunction has been associated with poor

long-term survival rates after stroke. Measures of renaldysfunction have also been noted to be a prognostic indi-

cator of overall mortality rates in many patient groups [27].

A greater frequency of renal function impairment is inagreement of the study of Wannamethee et al. [28] who

showed that renal dysfunction manifested as elevated

serum creatinine concentration, which was a marker forincreased risk of cerebrovascular disease in both normo-

tensive and hypertensive subjects.

In agreement with the present results, sex differenceswith regard to risk factors and outcome were also observed

in a recent study of clinical features of first-ever lacunar

infarction in Japanese patients [29].Findings of the present study, however, should be

interpreted taking into account some limitations. Lacunar

stroke was defined using clinical and neuroimaging databased on CT and/or MRI studies. Currently, it is generally

recommended that MRI is for this the first choice of

imaging and diffusion-weighted MRI (DWI) to be part ofthe scanning protocol [1] but DWI was not used in our

study. Also, comparative data between lacunar and non-

lacunar ischemic stroke have been reported in a previousstudy of our group [14]. This study included 566 patients

with lacunar stroke and 1,516 patients with non-lacunar

stroke. Patients with non-lacunar stroke were significantlyolder and showed a longer hospital stay, whereas lacunar

stroke patients showed a significantly higher frequency of

hypertension and use of MRI studies for diagnosis. How-ever, in the present study in which assessment of within

Acta Neurol Belg

123

differences (men with lacunar stroke vs women with

lacunar stroke) was the purpose of the study, the inclusionof a comparison control group that, for example, differs in

type of stroke would not have been adequate.

Recently, a position paper summarizing the Standardsfor Reporting Vascular changes on nEuroimaging

(STRIVE) [30] presents a comprehensive update of pro-

posed terms and definitions for neurological features ofsmall vessel disease (SVD), image acquisition standards

and analysis for neuroimaging studies of SVD. This pub-lication has a high scientific interest because the use of a

more precise terminology of SVD and neuroimaging

diagnostic methods in patients with SVD, among otheraspects, will contribute to more reliable comparison of

findings across studies [30].

In conclusion, our findings indicate that women withlacunar infarction differ from men in several aspects. While

male patients suffering from lacunar infarct presented more

frequently with peripheral vascular disease, chronic bron-chitis, and chronic renal disease and were heavy smokers,—

age, obesity, and hypertension were predictors of lacunar

infarction in women. Measures to correct obesity and controlof hypertension in women are particularly important strate-

gies to prevent lacunar infarction as well as early subcortical

vascular dementia, for which lacunar stroke has been iden-tified as a clinically relevant risk factor [1]. Although,

lacunar stroke severity was similar in men and women, some

outcome measures (i.e., prolonged hospitalization, use ofintermediate care facilities) appeared to be influenced by

sociocultural factors, mainly the central role played by

women in the family. Therefore, attention to gender-relateddifferences in patients with lacunar infarction is important,

not only as primary stroke prevention, but also for prevention

of cognitive impairment after lacunar stroke. However,whether these findings in patients with lacunar stroke sub-

type could be explained by differences in gender for ische-

mic stroke in general was not addressed in our study.

Acknowledgments We thank Drs Miquel Balcells and CeciliaTarga for the care of many of the patients included in the study, andMarta Pulido for editing the manuscript and editorial assistance.

Conflict of interest None to be declared.

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! 73!

!

Article!3:!El!perfil!cognitiu!dels!pacients!amb!un!primer!infart!lacunar!amb!i!

sense!lacunes!silents!associades:!un!estudi!comparatiu.!!

!

Antecedents!!

La!detecció!precoç!d’alteracions!neuropsicològiques!com!a!precursor!del!declinant!

cognitiu!d’origen!vascular!en!pacients!amb! infart! lacunar!és!un! tema!de!creixent!

interès.! L’objectiu! d’aquest! estudi! es! valorar! quines! són! les! diferències! en! el!

rendiment!cognitiu!a!partir!d’una!bateria!extensa!de!proves!neuropsicològiques!a!

pacients!que!han!patit!un!primer!IL!amb!i!sense!patologia!múltiple!silent!associada.!

Els!diferents!grups!es!van!constituir!a!partir!de!les!diferències!en!les!imatges!de!la!

Ressonància!Magnètica!cerebral.!!

Mètode!

Un! total! de! 72! pacients! consecutius! van! ser! randomitzats! amb! un! primer! IL! i!

vàrem!ser!estudiats!al!cap!d’un!mes!de!l’alta!hospitalària.!Tots!els!pacients!van!ser!

sotmesos! a! una! valoració! neuropsicològica! complerta,! on! s’incloïa! la! prova! de!

CVLT,!el!test!de!fluència!verbal!fonètica!(PMR),!Test!de!fluència!verbal!semàntica!

(animals),!els!subtest!de!dígits!directes! i! inversos!de!la!Escala!d’Intel·ligència!per!

adults!de!la!Wechsler!(WAISEIII),!i!el!MiniEMental!State!Examination!(MMSE).!!

!

! 74!

Resultats!

Un! total! de! 38! pacients! (52,7%)! va! partir! un! infart! lacunar! múltiple! silent,! i! la!

corona!radiata!va!ser!la!topografia!lacunar!més!freqüent!de!la!nostra!mostra!(P*<!

0.023).!Les!hiperintensitats!de!substància!blanca!(leucoaraiosi)!es!van!observar!en!

el! 81,1%! dels! pacients! amb! clínica! silent! múltiple! davant! del! 50%! que! es! va!

observar! en! aquells! pacients! que! van! patir! un! únic! IL! (P*<! 0.007).! Tot! i! que! els!

pacients! de! tots! dos! grups! van! mostrar! un! nivell! cognitiu! general! segons! les!

puntuacions!en!el!MMSE,!els!pacients!amb!múltiple!infarts!lacunar!van!mostrar!un!

empobrit!rendiment!en!el! test!de! fluència!semàntica!(P*<!0.008)! i!en! la!prova!de!

memòria!verbal!immediata!(P*<!0.001).!En!tots!dos!casos,!la!leucoaraiosi!no!va!ser!

estadísticament! significativa! segons! el! models! de! regressió! lineal! multivariada!

ajustant! les! covariables! de! confusió.! Segons! aquest! model,! els! IL! múltiples! i!

l’educació! son!predictors! independents! del! baix! rendiment! en! el! test! de! fluència!

semàntica!!de!la!memòria!verbal!immediata!dels!pacients!de!la!nostra!mostra.!!

Conclusió!

La! presència! d’infarts! lacunar! silents! múltiples! documentats! a! partir! de! la! RM!

cerebral! en! pacients! amb! un! primer! IL! estan! associats! amb! alteracions!

neuropsicològiques! lleus,!particularment!el! rendiment!de! les! funcions!executives!

(fluència! semàntica)! i! la!memòria!verbal! immediata.! Segons!els!nostres! resultats!

obtinguts,! en! els! estadis! primerencs! de! la! patologia! de! petit! vas,! les! alteracions!

neuropsicològiques! apareixen! relacionades! amb! les! llacunes! a! diferència! de! la!

leucoaraiosi!o!hiperintensitats!perivasculars!d’origen!vascular.!

RESEARCH ARTICLE Open Access

Cognitive profile in patients with a first-everlacunar infarct with and without silentlacunes: a comparative studyLorena Blanco-Rojas1, Adrià Arboix1,2*, David Canovas3,5, Marta Grau-Olivares1, Joan Carles Oliva Morera4

and Olga Parra2,6

Abstract

Background: The detection of early neuropsychological abnormalities as precursors of cognitive decline of vascularorigin in patients with lacunar stroke is a subject of increasing interest. The objective of this study was to assesswhether there were differences in the performance of a battery of neuropsychological tests in first-ever lacunarstroke patients with and without associated silent multiple lacunar infarctions found incidentally on the brainmagnetic resonance imaging (MRI) scan.

Methods: A total of 72 consecutive patients with first-ever lacunar infarction were studied 1 month after stroke. Allpatients underwent a comprehensive neuropsychological evaluation, which included the California Verbal LearningTest (CVLT), Phonetic Verbal Fluency Test (PMR), Semantic Verbal Fluency Test (category “animals”), Digit Span Forwardand Backward from the Wechsler Adult Intelligence Scale (WAIS-III), and Mini-Mental State Examination (MMSE).

Results: A total of 38 patients (52.7%) had silent multiple lacunar infarcts, with corona radiata as the most frequenttopography (P < 0.023). White matter hyperintensities (leukoaraiosis) were observed in 81.1% of patients with silentmultiple lacunar infarcts and in 50% with a single lacunar infarction (P < 0.007). Patients in both groups showed similarscores in the MMSE, but those with associated silent lacunar infarctions showed a poorer performance in the semanticfluency test (P < 0.008) and in short delayed verbal memory (P < 0.001). In both cases, however, leukoaraiosis was notstatistically significant in multivariate linear regression models adjusted by confounding covariates. In these models,multiple silent lacunar infarctions and education were independent predictors of poor performance in the semanticfluency test and in short delayed verbal memory.

Conclusions: The presence of silent multiple lacunar infarctions documented on brain MRI scans in patients withfirst-ever lacunar stroke was associated with mild neuropsychological abnormalities, particularly in the performance ofexecutive functions (semantic fluency) and short delayed verbal memory. According to these findings, in the initialstages of small vessel disease, mild neuropsychological abnormalities appear to be related to lacunes rather than toleukoaraiosis or perivascular hyperintensities of vascular cause.

Keywords: California verbal learning test, Lacunar infarction, Neuropsychological abnormalities, MRI, Semantic fluency,Silent multiple lacunar infarctions, Vascular cognitive impairment

* Correspondence: aarboix@hscor.com1Cerebrovascular Division, Department of Neurology, Capio-HospitalUniversitari del Sagrat Cor, Universitat de Barcelona, C/ Viladomat 288,E-08029, Barcelona, Catalonia, Spain2CIBER de Enfermedades Respiratorias (CB06/06), Instituto Carlos III, Madrid,SpainFull list of author information is available at the end of the article

© 2013 Blanco-Rojas et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of theCreative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use,distribution, and reproduction in any medium, provided the original work is properly cited.

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BackgroundLacunar infarcts (LI) or lacunes account for 20-25% of allischemic strokes [1,2]. According to recent studies, to dis-tinct entities in patients with first-ever LI can be distin-guished: 1) patients with a single LI in whom well knowncardiovascular risk factors are present and 2) patients withmultiple LI, in whom a high frequency of hypertensionand leukoaraiosis have been found [3,4]. Also, mild neuro-psychological abnormalities mainly executive dysfunctionhave been reported in 57% of patients with acute lacunarstroke [5] especially in patients with pure motor hemipar-esis and atypical lacunar syndromes. In these circum-stances, although general cognitive performance is usuallynormal, 55% of cases fulfill criteria of mild cognitive im-pairment of vascular type [6]. Identification of early stagesof subcortical vascular dementia is an important area ofresearch because this form of vascular dementia is one ofthe most common causes of cognitive decline in the eld-erly population [7,8].The potential impact of silent multiple lacunar infarctions

on neuropsychological function in patients with clinicallydocumented LI remains unclear. Therefore, the objective ofthis study was to assess whether there were differences inthe performance of a battery of neuropsychological tests infirst-ever lacunar stroke patients with and without associ-ated silent multiple lacunar infarctions found incidentallyon the brain magnetic resonance imaging (MRI) scan.

MethodsPatientsThe study population consisted of 72 consecutive patientswith first-ever LI admitted to the Department of Neurologyof the Capio-Hospital Universitari Sagrat Cor, in Barcelona,Spain, between January 2006 and December 2011. All pa-tients presented a lacunar syndrome according to the Miller-Fisher’s classification [1]. Patients with cortical and/orsubcortical non-lacunar infarct or intracerebral hemorrhagedocumented by MRI studies were excluded from the studyas were those with severe cardiovascular disease, renalinsufficiency, liver dysfunction, neoplastic or chronic dis-ease, major depression and other psychiatric comorbidity(DSM-IV-R). Patients with impaired cognitive performance(Mini-Mental State Examination [MMSE] score < 24) werealso excluded.The definitions of cerebrovascular risk factors and clas-

sic lacunar syndromes, including pure motor stroke, puresensory stroke, sensorimotor stroke, ataxic hemiparesis,dysarthria-clumsy hand and atypical lacunar syndromes(patients presenting isolated dysarthria, dysarthria withfacial paresis or isolated hemiataxia) were those used inprevious studies [5,6,9]. Prior to conducting the study,approval was obtained from Ethical Committee on ClinicalResearch of the hospital. Written informed consent wasobtained from all patients.

MRI examinationMRI studies were performed using a General Electric 1.5Tesla Sigma system (General Electric, Milwaukee, WI) andthe following sequences: T1-weighted (TR = 479 ms,TE = 13 ms, FOV= 270/1.1, slice thickness 5.0 mm, GAP1.0); T2-weighted (TR = 4885 ms, TE = 120 ms, FOV= 220/1.1, slice thickness 5.0 mm, GAP 2.0); fluid-attenuated in-version recovery (FLAIR) (TR = 8000 ms, TE = 120 ms,FOV= 240/1.1, slice thickness 5.0 mm, GAP 1.2); protonicdensity (TR = 3400 ms, TE = 17 ms, FOV= 240/1.1, slicethickness 5.0 mm, GAP 1.0); and diffusion sequences(TR = 3350 ms, TE = 74 ms, FOV= 250/1.1, slice thickness5.0 mm, GAP 1.0). Two senior radiologists determined thepresence and topography of acute and chronic, single and/or multiple silent lacunar infarcts by visual inspection ofthe T1, FLAIR, and T2 sequences of MRI scans. Patientswere divided into two groups, those with a single LI andthose with a single LI in association with multiple silent la-cunar infarcts. Also, white matter hyperintensities (leukoar-aiosis) were evaluated from T2-weighted, FLAIR anddiffusion sequences and classified as present versus absent.

Neuropsychological studiesA battery of neuropsychological tests [10] was adminis-tered to all patients 1 month after the index admission.These included the California Verbal Learning Test(CVLT), Phonetic Verbal Fluency Test (PMR), SemanticVerbal Fluency Test (category “animals”), and Digit SpanForward and Backward from Wechsler Adult IntelligenceScale (WAIS-III). The Spanish versions of these instru-ments were used [11].The CVLT is a standardized test for verbal learning

and memory function developed to assess both theamount of material learned, recalled, and recognized, aswell as qualitative aspects of how the verbal learning oc-curs or fails. A list of 16 words (List A) is presented fivetimes. The words are equally drawn from four semanticcategories with no consecutive words from the same cat-egory. Immediately after the fifth trial, a new list is readto the participant (List B) and asked to recall it. A shortdelayed recall test is presented immediately after recallof List B, where the participant is asked to recall thewords in List A. A long delayed recall test (CVLT-LongDelayed) is presented after a further 20 minutes interval.Finally, a “yes-no” recognition test consisting in the 16items of List A, eight from List B and 20 random dis-tracter items is presented [12]. The PMR test is used toassess semantic knowledge, retrieval ability and execu-tive functioning. The patients have to say words begin-ning with letter “p” “m” and ”r” in 60 seconds. In theSemantic Verbal Fluency Test (category “animals”), par-ticipants had to say as many words as possible from thesemantic category “animals” in 60 seconds. The finalmeasure is the total number of words. The Digit Span

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Forward and Backward Test is a subtest from WAIS-III,which is used to explore the short delayed verbal mem-ory, working memory, and attention ability. The DigitSpan Forward consists of serial numbers that the patienthas to repeat in the same order than the evaluator. Inthe Backwards Test the patient has to say the serialnumbers in the other way round.

Statistical analysisDifferences in demographics, vascular risk factors, clin-ical features, and results of neuropsychological tests be-tween patients with single LI and those with associatedmultiple silent LIs were analyzed with the Student’s t testfor continuous variables and the chi-square (χ2) test orthe Fisher’s exact probability test (when appropriate) forcategorical data. The degree of association of individual

variables with multiple silent LIs was estimated by theodds ratio (OR) and the 95% confidence interval (CI).Multiple linear regression analysis was performed toassess the effect of leukoaraiosis on neuropsychologicalperformance adjusted by confounding covariates. Statis-tical significance was set at P < 0.05.

ResultsThere were 36 men and 36 women, with a mean (stand-ard deviation, SD) age of 75.4 (9.2) years. Thirty-four(47.2%) patients presented a single LI and in theremaining 38 (52.8%), associated silent multiple LIs weredetected on the MRI scan. Table 1 shows the compari-son of demographic variables, vascular risk factors, clin-ical features, and infarct topography between the groupsof single and multiple silent LIs. Statistically significant

Table 1 Demographic, clinical and cognitive features of patients with single lacunar infarction (LI) and patients withassociated multiple silent LIsVariables Lacunar stroke patients Odds ratio (95% CI) P value t*

Single LI Multiple silent

(n = 34) LIs (n = 38)

Age, years, mean (SD) 73.1 (11.3) 77.3 (7.7) 0.999 −1.834

Women, no. (%) 17 (50) 19 (50) 0.999 0.000

Education, mean (SD)† 8.9 (3.7) 8.4 (2.9) 0.71 0.672

MMSE, score, mean (SD) 27.8 (2.3) 28 (2.0) 0.686 −0.406

High BP >140/90 mm Hg, no. (%) 23 (67.6) 29 (76.3) 1.541 (0.546–4.347) 0.414 −0.812

Diabetes mellitus, no. (%) 10 (29.4) 13 (34.2) 1.248 (0.461–3.381) 0.663 −0.430

Dyslipidemia, no, (%) 10 (29.4) 12 (31.5%) 1.108 (0.405–3.029) 0.842 −0.170

Toxic habits, no. (%)‡ 14 (41.2%) 15 (39.5%) 1.073 (0.418–2.756) 0.883 −0.372

Lacunar syndrome, no. (%) 0.381 0.360

Pure motor hemiparesis 9 (26.5) 10 (26.3) -

Pure sensory syndrome 8 (23.5) 10 (26.3) 1.125 (0.308–4.104)

Dysarthria–clumsy hand 5 (14.7) 9 (23.7) 1.62 (0.392–6.678)

Sensorimotor syndrome 4 (11.8) 1 (2.6) 0.225 (0.021–2.404)

Ataxic hemiparesis 2 (5.9) 0

Atypical lacunar syndrome 6 (17.6) 8 (21.1) 1.2 (0.298–4.816)

Infarct lateralization, no. (%) 0.153 −0.538

Right 15 (44.2) 17 (44.7) -

Left 18 (52.9) 15 (39.5) 0.735 (0.277–1.950)

Bilateral 1 (2.9) 6 (15.8) 5.294 (0.570–49.136)

Infarct topography, no (%) 0.014 −0.883

Basal ganglia 2 (5.9) 6 (15.8) 7.500 (1.039–54.118)

Corona radiata 6 (17.6%) 17 (44.7%) 7.083 (1.601–31.331)

Internal capsule 10 (29.4%) 4 (10.5%) -

Thalamus 9 (26.5%) 9 (23.7) 2.500 (0.567–11.011)

Pons 7 (20.6%) 2 (5.3) 0.714 (0.101–5.035)

Leukoaraiosis, no. (%) 17 (50) 30 (81.1) 4.286 (1.481–12.4) 0.007 −2.886*t: test statistics; †years of formal education; ‡smoking/alcohol consumption.Abbreviations: CI confidence interval, MMSE Mini-Mental State Examination, BP blood pressure.

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differences (P = 0.014) were only found in LI topography,with higher percentages of multiple silent LIs in thebasal ganglia and corona radiata, and the presence ofleukoaraiosis, which was significantly more frequent in pa-tients with multiple silent LIs (P = 0.007). The remainingvariables including clinical types of LI were similarly dis-tributed in the two study groups. The mean (SD) MMSEscore was 27.8 (2.3) in the group of single LI and 28 (2) inthe group of multiple silent LIs (P = 0.686).The results of neuropsychological tests are shown in

Table 2. The group of patients with multiple silent LIsshowed a poorer performance in semantic fluency (meandifference 3.265, 95% CI 0.891-5.638; P = 0.008) andshort delayed verbal memory (mean difference 1.265,95% CI 0.514-2.015; P = 0.001) as compared with thegroup of patients with single LI. Differences in the re-sults of other tests were not statistically significant.There were no differences in the performance of neuro-logical tests between the different lacunar subtypes.In the multiple linear regression analysis to assess in-

dependent variables associated with performance of se-mantic fluency and short delayed verbal memory, thepresence of leukoaraiosis was not statistically significant.In both models, multiple silent LIs and education werethe only statistically significant variables (Table 3). Agealmost reached statistical significance (P = 0.062) in thesemantic fluency model.

DiscussionThe clinical relevance of symptomatic lacunar stroke iswell established but little is known of the impact of si-lent lacunes incidentally found on MRI scans on cogni-tive function. Previous studies have shown that a first

single LI may cause cognitive decline as suggested byimpairment in neuropsychological performance [3-5].The present results indicate that lacunar stroke patientswith associated multiple silent LIs had significantlypoorer performance in some neuropsychological testssuch as semantic verbal fluency and short term memory.These findings are even more interesting consideringthat patients were evaluated shortly after the acute cere-brovascular event (1 month).Our results contribute to justify the presence of two

distinct phenotypic entities (in risk factors, neuroimag-ing and neuropsychological profile) in lacunar strokes:LI caused by one isolated symptomatic lacune and lacu-nar stroke caused by one symptomatic LI in associationwith multiple clinically silent lacunar infarctions [1-4].Also, leukoaraiosis was significantly more frequent inpatients with multiple silent LIs, although a statisticallysignificant role as an independent predictor of perform-ance of semantic verbal fluency and short term memorywas not observed in the multivariate linear regressionanalysis. The underlying small vessel vasculopathy maybe different in the two LI entities [3,13,14]. A diffusearteriopathy of perforating arteries with hyaline depos-ition (lipohyalinosis) in the group of multiple silent LIsand localized small vessel microatheroma at the originof the deep perforating arteries (in single LI group). Al-though speculative, distinguishing these two clinical LIentities may enable more appropriate therapy.In the present study, the neuropsychological impair-

ment in the group of patients with associated multiplesilent LIs probably results from the interruption ofprefrontal-subcortical loops by LIs and white matter le-sions. Interruptions of dorsolateral prefrontal-subcortical

Table 2 Results of neuropsychological tests in patients with single lacunar infarction (LI) and patients with associatedmultiple silent LIsVariables Lacunar stroke patients Mean difference (95% CI) P value t*

Single LI Multiple silent

(n = 34) LIs (n = 38)

Phonetic verbal fluency test (PMR) 25.30 (14.90) 20.30 (10.57) 4.997 (−1.282–11.277) 0.111 1.617

Semantic fluency (animals) 14.84 (5.15) 11.84 (4.72) 3.265 (0.891–5.638) 0.008 2.746

California verbal learning test (CVLT)

CVLT short–delay (trial 1) 4.51 (1.69) 3.25 (1.42) 1.265 (0.514–2.015) 0.001 3.366

CVLT learning (trial 1–5) 4.66 (2.74) 5.5 (2.138) −0.833 (−2.066–0.399) 0.182 −1.349

CVLT long delay cued recall 5.96 (3.05) 5.08 (3.25) 0.896 (−0.634–2.407) 0.249 1.163

CVLT long delay recognition 12.06 (3.14) 11.69 (3.24) 0.376 (−1.170–1.902) 0.636 0.476

CVLT total learning (sum trial 1–5) 36 (10.57) 32.63 (9.5) 3.361 (−1.470–8.192) 0.170 1.389

WAIS–III digit span forward

Direct scores 11.63 (4.24) 11.44 (2.78) 0.191 (−1.555–1.939) 0.823 0.224

Scaled scores 11.12 (3.37) 11.88 (2.61) −0.767 (−2.210–0.675) 0.292 −1.062*t: test statistics; CI: confidence interval.Data expressed as mean (standard deviation, SD) unless otherwise stated.

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loop results in executive dysfunction [15,16]. Patientswith multiple silent LIs showed a poorer cognitive per-formance related to short delayed verbal memory andfrontal functions than patients with a single LI. For thisreason, some studies have suggested that this type of si-lent lacunes had a significant individual contribution tothe risk of cognitive impairment and motor speed andexecutive functions, while global cognitive functions andmemory functions remained unaffected [17,18]. On theother hand, cognitive impairment associated with vascu-lar disease frequently does not fulfill the traditional cri-teria for degenerative dementia, because the criteria ofAlzheimer’s disease requires the presence of prominentmemory impairment, which in contrast is not the mainsign of vascular cognitive impairment. Patients with vas-cular dementia show a better long-term memory andgreater deficits in frontal executive functioning than pa-tients with Alzheimer’s disease [18]. The neuropsycho-logical assessment reveals planning, organization andabstraction impairment, as well as deficits in categoryfluency initiation, reasoning, mental flexibility, sequen-cing, fine motor performance, or attentional allocationsource [19-21].It may be argued that multiple silent LIs may be asso-

ciated with a higher risk of cognitive impairment in themid- and long-term [22]. However, further studies areneeded to assess differences in prognosis regarding cog-nitive function in patients with single LI versus patientswith multiple silent LIs. Cognitive stimulation and phys-ical activities could be recommended to improve affectedcognitive functions. In the LADIS (Leukoaraiosis andDisability) study, physical activity reduced the risk ofcognitive impairment, mainly vascular dementia, in olderpeople living independently [23].

A limitation of the study is the fact that leukoaraiosiswas assessed qualitatively as presence versus absenceand not quantified using a quantitative measure (e.g.Scheltens scale, Wahlund scale, Fazekas scale). In a com-munity sample of asymptomatic participants aged 50 to65 years, it has been shown that only deep white matterhyperintensities, not periventricular hyperintensitieswere related to diminished cognitive function in middle-aged individuals [24]. The LADIS study [25] has shownthat white matter hyperintensity volume was the stron-gest predictor of cognitive decline in cerebral small ves-sel disease, but also incident lacunes on MRI parallel asteeper rate of decline in executive functions and psy-chomotor speed. Accordingly, in addition to white mat-ter lesions, lacunes determine longitudinal cognitiveimpairment in small vessel disease. Although the indi-vidual contribution of lacunes on cognition was modest,they cannot be considered benign findings, but indicatea risk of progressive cognitive impairment. In thepresent study carried out in patients with first-ever lacu-nar stroke and without cognitive impairment (MMSEmean score of 27.8 and 28 in the groups of single LI andmultiple silent LIs, respectively), early neuropsycho-logical alterations could be initially related to lacunes. Asubsequent increase in leukoaraiosis may cause moresignificant neuropsychological alterations of the type ofsubcortical cognitive impairment. Subcortical LIs havebeen identified as the cause of mild cortical atrophy [26]and, although this was not analyzed in the present study,may also influence on mild incipient neuropsychologicalalterations observed in our patients.The fact that some patients were included in a clinical

trial (SPS3 randomized trial) of secondary prevention ofcerebral ischemia (aspirin 325 mg/day versus aspirin

Table 3 Variables related to performance of semantic fluency and short delayed verbal memory in the multiple linearregression analysisVariable Coefficient (ß) Standard error t-statistic P value

Semantic fluency model*

Constant 19.845 4.825 4.112 0.000

Multiple silent lacunar infarcts −2.255 1.027 −2.194 0.031

Leukoaraiosis −1.312 1.180 −1.112 0.270

Age −0.109 0.057 −1.896 0.062

Education 0.677 0.166 4.073 0.0001

Short delay verbal memory model†

Constant 6.039 1.619 3.729 0.0004

Multiple silent lacunar infarcts −0.996 0.344 −2.889 0.005

Leukoaraiosis −0.351 0.395 −0.887 0.378

Age −0.028 0.019 −1.453 0.151

Education 0.195 0.056 3.500 0.0008*Adjusted R-squared: 0.3903; P value: 2.802.†Adjusted R-squared: 0.3463; P value: 2.365.

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325 mg/day plus clopidogrel 75 mg/day) may be view asa limitation of the study. However, participation in thetrial did not interfere with radioimaging and neuro-psychological studies of the patients because all those in-cluded in the present study presented a first-everlacunar stroke.

ConclusionsThe presence of multiple silent LIs documented on brainMRI scans in patients with first-ever lacunar stroke1 month after the acute cerebrovascular event was asso-ciated with mild neuropsychological abnormalities, par-ticularly in the performance of executive functions(semantic fluency) and short delayed verbal memory. Ithas been shown that silent lacunes themselves exert anindependent effect on cognitive function [27]. In the ini-tial stages of small vessel disease, mild neuropsycho-logical abnormalities appear to be related to lacunesrather than to leukoaraiosis or perivascular hyperintensi-ties of vascular cause.

AbbreviationsCI: Confidence interval; CVLT: California verbal learning test; LI: Lacunarinfarction; MMSE: Mini mental state examination; MRI: Magnetic resonanceimaging; OR: Odds ratio; SD: Standard deviation; SVD: Subcortical vasculardementia; WAIS-III: Wechsler adult intelligence scale version III.

Competing interestsThe authors declare that they have no competing interests.

Authors’ contributionsLB was the principal investigator, designed the study, collected the data, didthe neuropsychological assessments, contributed to analyze the data,interpreted the results and wrote the paper. AA diagnosed and took care ofthe patients, participated in the study design, analysis and interpretation ofdata and wrote the part of the paper related to the neurological issues. He isalso the corresponding author. DC participated in the collection of data,medical care of the patients and review of the manuscript for intellectualcontent. MGO contributed to write the paper, edited the manuscript andprovide editorial assistance, including the selection of the journal. JCSM andOP participated in the collection of data, medical care of the patients andreview of the manuscript for intellectual content. All authors have read andapproved the final draft.

AcknowledgmentsWe thank Elisenda Grivé, MD, from the Neuroradiology Service for herassistance in the neuroimaging location of lacunar infarcts, Oscar Benavente,MD, and Ana Roldan, MD, for their contribution to the article with somepatients included ‘Secondary Prevention of Small Subcortical Strokes’ (SPS3)trial, Maria Mataró, MD, from the University of Barcelona for valuablescientific commentaries and Marta Pulido, MD; for editing the manuscriptand editorial assistance.

Author details1Cerebrovascular Division, Department of Neurology, Capio-HospitalUniversitari del Sagrat Cor, Universitat de Barcelona, C/ Viladomat 288,E-08029, Barcelona, Catalonia, Spain. 2CIBER de Enfermedades Respiratorias(CB06/06), Instituto Carlos III, Madrid, Spain. 3Department of Neurology,Hospital Parc Taulí, Sabadell, Barcelona, Catalonia, Spain. 4Fundació Parc Taulí,Corporació Sanitària Universitària Parc Taulí, Universitat Autònoma deBarcelona, Sabadell, Barcelona, Catalonia, Spain. 5Universitat Autònoma deBarcelona, Cerdanyola del Vallès, Barcelona, Catalonia, Spain. 6Department ofPneumology, Capio-Hospital Universitari del Sagrat Cor, Universitat deBarcelona, Barcelona, Catalonia, Spain.

Received: 27 November 2012 Accepted: 11 December 2013Published: 16 December 2013

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25. Jokinen H, Gouw AA, Madureira S, Ylikoski R, van Straaten EC, van der FlierWM, Barkhof F, Scheltens P, Fazekas F, Schmidt R, Verdelho A, Ferro JM,Pantoni L, Inzitari D, Erkinjuntti T, LADIS Study Group: Incident lacunesinfluence cognitive decline: the LADIS study. Neurology 2011,76:1872–1878. doi: 10.1212/WNL.0b013e31821d752f.

26. Smith EE, Arboix A: Focal cortical thinning is caused by remote subcorticalinfarcts: spooky action at a distance. Neurology 2012, 79:2016–2017.

27. Arboix A: Lacunar infarct and cognitive decline. Expert Rev Neurother 2011,11:1251–1254.

doi:10.1186/1471-2377-13-203Cite this article as: Blanco-Rojas et al.: Cognitive profile in patients with afirst-ever lacunar infarct with and without silent lacunes: a comparativestudy. BMC Neurology 2013 13:203.

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Cognitive Impairment in Ischaemic Lacunar Stroke

Adrià Arboix1 and Lorena Blanco-Rojas2

1. Head, Cerebrovascular Division, Department of Neurology; 2. Neuropsychologist, Department of Neurology, Hospital Universitari del Sagrat Cor,

Universitat de Barcelona, Barcelona, Spain

AbstractIschaemic cerebral small-vessel disease (SVD) can be visualised on brain magnetic resonance imaging (MRI) scans as lacunar infarcts, white matter hyperintensities and cerebral microbleeds, and has been recognised as the most frequent cause of cognitive impairment of vascular origin. Lacunar infarction is the most common manifestation of SVD and accounts for approximately 25 % of all brain infarctions. In patients with first-ever lacunar infarction, more than half of cases show impairment of the executive functions and meet criteria of mild vascular cognitive impairment. Lacunar stroke is an important predictor of post-stroke cognitive decline and vascular dementia. In the well-characterised cohort of 1,636 lacunar stroke patients of the Secondary Prevention of Small Subcortical Strokes (SPS3) trial, mild cognitive impairment was present in nearly half of participants and was an important complication of lacunar stroke more prevalent than physical disability. The cognitive profile identified to be associated with ischaemic cerebral SVD includes preserved memory with attention deficits and executive functioning impairment. However, in a recent systematic review of cognitive impairment in lacunar ischaemic stroke, impaired cognition appears less selective than previously thought, involving episodic memory and all major cognitive domains. Brain atrophy is also a feature of ischaemic cerebral SVD. Cognitive dysfunction in lacunar stroke sufferers is frequently overlooked in routine clinical practice and may be as common and clinically relevant as motor and sensory sequelae.

KeywordsLacunar infarct, brain atrophy, prognosis, cognitive impairment, neuropsychology, cerebral small-vessel disease, brain atrophy

Disclosure: The authors have no conflicts of interest to declare.

Acknowledgements: The authors thank Marta Grau-Olivares for her contribution in searching the literature and helpful constructive comments and Marta Pulido for editing the manuscript and editorial assistance.

Received: 16 February 2013 Accepted: 20 April 2013 Citation: European Neurological Review, 2013;8(2):144–8

Correspondence: Adrià Arboix, Cerebrovascular Division, Department of Neurology, Hospital Universitari del Sagrat Cor, C/ Viladomat 288, E-08029 Barcelona, Spain. E: aarboix@hscor.com

Lacunar ischaemic infarctions, white matter lesions (WML) (hyperintensities) or leukoaraiosis and cerebral microbleeds constitute the spectrum of ischaemic cerebral small-vessel disease (SVD) documented on magnetic resonance imaging (MRI) studies. History of ischaemic SVD is frequently present in patients with cognitive impairment of vascular origin.1–4 Cerebral lacunes are small infarctions of less than 20  mm in diameter localised in the vascular territory of penetrating arterioles, and represent the most-frequent manifestation of cerebral SVD (see Figure 1).5,6

Clinically, ischaemic lacunar stroke presents five well-recognised features, including pure motor hemiparesis,7 pure sensory syndrome,5,8 sensorimotor syndrome,5,9 dysarthria clumsy-hand10 and ataxic hemiparesis.5,11 Atypical lacunar syndrome is occasionally observed.12 Hypertension and diabetes are well-known cardiovascular risk factors for lacunar stroke.2,5 Other presenting forms of cerebral infarction of the lacunar type are silent lacunar infarcts and transient cerebral ischaemia.2

Deep or penetrating arterioles 100–400 µm in diameter that originate directly from a large cerebral artery are typically involved in the pathogenetic mechanism of lacunar infarct.13 These arterioles, without terminal anastomoses or collateral branches, provide blood supply to the deepest and nearest territories to the middle cerebral hemispheres

and the brainstem. Lacunes are frequently found at the level of the lenticular branches of the anterior and middle cerebral arteries, the thalamoperforating and thalamogeniculated branches of the posterior cerebral artery and the paramedian branches of the basilar artery.

Symptomatic lacunar infarctions are commonly related to microatheromatosis or branch atheromatous disease.13 Patients with hypertension frequently present multiple asymptomatic lacunar infarctions usually due to lipohyalinosis. In different series, silent lacunes have been reported to occur in 52 % and 77 % of cases.5,13

Also, silent lacunes have been detected by MRI in about 30 % of patients with first-ever lacunar stroke.1,14 Contributing factors to vascular cognitive impairment in patients with lacunar infarction are summarised in Table 1.

This review is focused on the clinical evidence and mechanisms underlying the relationship between cognitive impairment and lacunar stroke. The description of neuropsychological consequences of haemorrhagic lacunar stroke15 or the role of ischaemic cerebral SVD to the development of Alzheimer disease16 is not discussed in detail, although this remains an intriguing area of research and overlaps with the topics covered in this review.

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Cognitive Impairment in Ischaemic Lacunar Stroke

Neuropsychological Deficits Symptomatic Lacunar InfarctionsThe clinical relevance of symptomatic lacunes as a causative factor of motor or sensory deficits has been extensively researched, but the degree of which cerebral symptomatic or silent lacunes may affect cognitive function remains unclear, except for subcortical dementia associated with multiple lacunes – the état lacunaire of Pierre Marie – which has been recognised for over a century, and perivascular leukoaraiosis associated with clinically multiple lacunar infarcts (Binswanger disease).2,17 Some classic studies have shown that during the symptomatic acute phase of lacunar stroke, neuropsychological deficits are usually absent. By contrast, neuropsychological abnormalities including verbal fluency, dysmnesia and abulia or spatial heminegligence, atypical aphasia and alteration of cognitive performance have been reported in patients with single lacunar infarctions in the dorsomedial and anterior thalamic region.4,18–20

Recently, it has been observed that ischaemic lacunar infarction is an important predictor of post-stroke cognitive decline and vascular dementia. In a previous study of 40 patients with lacunar infarction and studied 1 month after stroke, mild neuropsychological disturbances were found in 57.5 % of patients, being especially common among patients with pure motor hemiparesis and atypical lacunar infarction. Also the mean score of the Mini-Mental State Examination (MMSE) was 28.4.21

The cognitive profile generally considered to be associated with ischaemic cerebral SVD involves preserved memory with impairment in attention and executive functioning.17,18 Moreover, dysfunction of the frontal system is relatively frequent in cases of multiple subcortical lacunar infarcts.22 Vascular dementia has been reported in 11 % of patients after 2 to 3 years of the initial lacunar infarct and in 15 % of patients after 9 years.14,17 Symptomatic lacunar infarctions are particularly relevant as a predisposing factor for progression to subcortical dementia of the vascular type, and this risk increases with recurrent lacunar events and the presence of concurrent white matter disease.

In a study of 122 patients with recurrent lacunar stroke, cognition was studied in a subset of 59 patients, cognitive impairment, defined as an MMSE score <24, was detected in 16  % of patients with first lacunar infarction recurrence and in 40 % of those with multiple lacunar infarction recurrences.23 Adequate management of lacunar stroke patients is the first step to prevent vascular dementia associated with stroke recurrence.

In summary, recurrent ischaemic lacunar stroke, silent progression of SVD and perivascular leukoaraiosis in cases of clinically symptomatic multiple lacunar infarctions are associated with an increased risk of cognitive impairment.24

Silent (Asymptomatic) Lacunar Infarctions Silent (or asymptomatic) lacunar infarctions are very common. In subjects older than 65 years, 20–28  % of lacunar infarctions are incidentally discovered on MRI studies. It has been shown that silent lacunar infarctions are risk factors for cognitive impairment and recurrent lacunar stroke.14,25 Between 10  % and 50  % of patients with a history of asymptomatic lacunar infarcts present new silent lacunar infarctions on the MRI examination at 3 years, which confirms asymptomatic progression of lacunar disease.26 On the other hand, 40  % of patients with lacunar stroke present progression of leukoaraiosis. The risk of vascular recurrence and cognitive impairment is particularly important in elderly healthy individuals with silent ischaemic cerebral SVD.25–27

The Leukoaraiosis and Disability Study (LADIS)28 investigated whether incident lacunes on MRI determined cognitive changes in elderly subjects with WML. The main finding was that a longitudinal increase in new lacunes on MRI was significantly associated with steeper longitudinal decline in specific cognitive domains, independently of the baseline WML, volume, number of lacunes and progression of WML. In particular, incident lacunes had a significant individual contribution to the deterioration of mental and motor speed and executive functions, while global cognitive function and memory functions remained unaffected. Asymptomatic progression of small-artery disease was a characteristic feature. The individual contribution of silent lacunes on cognition was modest, but the asymptomatic lacunes found on MRI should not be considered a benign vascular condition, but rather a potentially severe disease as a risk indicating progressive cognitive decline requiring adequate and rigorous therapeutic control and medical follow up.28

However, this clinical and neuropsychological aspect is still poorly studied. Long-term follow-up studies with large samples should be carried out to assess the outcome of patients with silent lacunes and to determine clinical and neuroimaging predictors of cognitive decline.

White Matter HyperintensitiesWhite matter hyperintensities (WMH) (also known as white matter changes or leukoaraiosis) are frequently documented in computed tomography (CT) and MRI studies of patients with lacunar stroke, elderly subjects with cerebrovascular risk factors and in cognitively impaired subjects. WMHs are believed to be caused by incomplete white matter infarction

Figure 1: Cerebral Infarction of Lacunar Type of Thalamic Topography Shown by Diffusion Magnetic Resonance Imaging

Table 1: Factors Contributing to Cognitive Impairment of Vascular Type in Patients with Lacunar Infarction

Number of symptomatic lacunar infarcts

Presence and number of clinically asymptomatic (silent) lacunar infarcts

Presence and extension of leukoaraiosis

Presence and number of microbleeds

Presence and degree of brain atrophy

Recurrence of ischaemic stroke

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associated with SVD24,29 and a reflect of haemodynamic ischaemia of the white matter secondary to atherosclerotic thickening of the perforating arteries supplying the white matter.30 Some authors have suggested that patients with lacunar infarcts have more severe WML than patients with ischaemic infarcts of the non-lacunar subtype. Baseline WMH volume has been shown to be the strongest predictor of future cognitive decline in ischaemic cerebral SVD.28

MicrobleedsCerebral microbleeds are small dot-like hypointense lesions corresponding with hemosiderin deposits in the cerebral microvascular perivascular spaces. These lesions are commonly observed in patients with lacunar ischaemic stroke and hypertension.31,32 Echo-planar gradient-echo T2-weighted MRI has high sensitivity for detecting cerebral microbleeds, which are most frequently observed in the basal ganglia (68  % of cases), although they are also common in the frontal, parieto-occipital and temporal regions.32 The occurrence and the number of cerebral microbleeds are associated with the degree of cerebral white matter abnormalities as well as with lacunar stroke and hypertension. On the other hand, cerebral microbleeds have been related to executive dysfunction and cognitive impairment. The results of a recent systematic review suggest that rather than being clinically silent, cerebral microbleeds might be a factor inducing cognitive function decline and the assessment of cerebral microbleeds should be included in the evaluation of patients with vascular cognitive dysfunction.31,32

Mild Vascular Cognitive Impairment In a recent quantitative systematic review (12 cross-sectional studies) of domain-specific cognitive impairment associated with symptomatic lacunar infarcts, Edwards et al.33 reported impairment in the domains of attention/working memory and executive functioning as well as

impairment in other additional domains, including memory, language and visuospatial abilities, thus extending previous characterisations of subcortical vascular cognitive impairment.

In a study of our group, more than half of patients with first-ever lacunar infarction showed cognitive impairment of the executive functions and fulfil criteria for mild cognitive impairment of vascular origin.34 In these patients voxel-based morphometry was used for assessing grey matter atrophy.35 It was observed that grey matter shrinkages mainly affected the following cerebral regions: bilaterally the temporal lobes, parietal and frontal regions and the left cerebellum as well as bilaterally the parahippocampal gyro and the right hippocampus (the latter two regions emerged when region of interest analysis was restricted to these specific regions) (see Figure 2). These findings may be interpreted as corroborating those of the functional neuroimaging literature in which the remote effects of subcortical damage beyond the immediate area of infarction were described.34

Within the Secondary Manifestations of ARTerial disease-Magnetic Resonance (SMART-MR) study,36 a prospective cohort on MRI changes in patients with symptomatic atherosclerotic disease, 565 patients without large infarcts had vascular screening and 1.5 T MRI at baseline and after a mean follow-up of 3.9 years. The presence and progression of periventricular WML and lacunar infarcts were associated with greater progression of brain atrophy, independent of vascular risk factors.

In a longitudinal follow-up study, Nikunan et al.37 showed that the rate of atrophy in patients with SVD, presenting with lacunar stroke and leukoaraiosis, is approximately 1 % per annum and twofold that found in age-matched control subjects.

In another recent study, Duering and colleagues38 reported compelling proof-of-principle evidence that small subcortical infarcts in patients with hereditary stroke (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]) have remote consequences on grey matter volume. Using MRI scans acquired before and after an incident subcortical infarct, it was shown that the appearance of a new subcortical infarct was associated with cortical thinning in connected brain regions. The authors hypothesised that the new infarct would cause focal cortical thinning in connected brain regions. Indeed, the remote ‘action at a distance’ may be the key to solving the riddle of why small subcortical infarcts have such large consequences on cognition.39

Brain atrophy can be the end-stage of multiple pathological processes and is a well-recognised feature of many neurological diseases, including Alzheimer disease and multiple sclerosis. Ischaemic cerebral SVD should be associated with greater progression of brain atrophy.

Subcortical Vascular DementiaIn clinical studies, the proportion of dementia caused by SVD ranges between 36 % and 67 %.17 Dementia is a leading cause of dependency after stroke and has devastating impact on post-stroke quality of life. Subcortical vascular dementia related to ischaemic lacunar stroke probably results from the interruption of prefrontal-subcortical loops by the lacunar infarcts and WML. Interruption of the dorsolateral prefrontal-subcortical loop results in executive dysfunction.39 Brain atrophy and other neurodegenerative changes have been documented in patients with subcortical vascular dementia and cognitive impairment, suggesting that the pathogenesis of the cognitive deficits is variable and may reflect a combination of degenerative and ischaemic causes.17,34,40,41 However, relatively few studies

Figure 2: Region of Interest Analysis Showing Reduced Right Hippocampus Volume in Lacunar Ischaemic Stroke Patients with Mild Cognitive Impairment of Vascular Origin Compared with Patients without Cognitive Impairment

Clusters are scaled, with the yellow–white regions being more significant than the red ones. The scale represents t-values derived from a voxel-based analysis. The depicted results are representative of between-group comparison but are displayed on a normalised brain image of a single subject.

Cognitive Impairment in Ischaemic Lacunar Stroke

EUROPEAN NEUROLOGICAL REVIEW 147

have investigated longitudinal changes in cognitive function following lacunar stroke. Long-term follow-up studies (more than 3  years) with large samples should be carried out to assess the outcome of patients with mild cognitive impairment of the vascular type and to determine clinical and neuroimaging predictors of vascular subcortical dementia.

Strategic infarct dementia is unusual and is caused by isolated infarcts in regions that are important for cognition of the brain, such as the thalamus, hippocampus, caudate or genu of the internal capsule. It is characterised by the abrupt onset of cognitive or behavioural changes, which vary depending of the infarct location.42

In a recent clinical study, Duering et al.43 applied a voxel-based lesion-symptom mapping approach to data from 215 patients with CADASIL, and identified strategic locations for subcortical ischaemic lesions, which affect processing speed, as a major cognitive aspect of vascular cognitive impairment. Significant clusters were found for both lacunar lesions and WMH and identify the anterior thalamic radiation and the forceps minor as major anatomical structures.

The mid- and long-term prognosis of lacunar ischaemic stroke patients with subcortical vascular dementia is generally poor because of the high frequency of adverse outcomes, such as cognitive and functional deterioration, nursing home placement and death.14

Recent Advances and Therapeutic StrategiesThe Secondary Prevention of Small Subcortical Stroke (SPS3)44 phase III study is the first double-blind, multicentre stroke prevention trial focusing specifically on a large group of patients (n=3,020) with recent symptomatic, confirmed MRI lacunar infarcts. Its aims to define the optimal interventions (antiplatelet therapy of either enteric-coated aspirin 325  mg/day or aspirin plus clopidogrel 75  mg/day) to target levels of systolic blood pressure (either intensive <130 mm Hg or usual 130–149  mm  Hg) to prevent stroke recurrence, cognitive decline and major vascular events in this population. The secondary prevention of lacunar stroke as detected by the use of MRI has not previously been the focus of a randomised trial. After a mean follow-up of 3.4 years, the first published data showed that adding clopidogrel to aspirin did not reduce recurrent stroke and increased bleeding in lacunar stroke.45

All English-speaking participants in SPS3 underwent neuropsychological testing at baseline (n=1,636).46 A total of 47  % of the cohort met psychometric criteria for mild cognitive impairment with amanestic deficits as prevalent as non-amnestic.46 Younger age, male gender, less education, post-stroke disability and impaired activities of daily living were independently associated with mild cognitive impairment. The observation of impaired processing speed, motor dexterity and executive function was consistent with the impairment pattern hypothesised for subcortical ischaemic disease.46 On the other hand, the observation of episodic memory deficits was a novel aspect of the study given that incident lacunes have been reported to impact processing speed and motor control but not memory.46 The authors emphasised that mild cognitive impairment found in half of the participants is an important clinical sequela of lacunar stroke, which in turn is more prevalent than physical disability defined by m-Rankin score ≥2 (33 %) and present in

41 % of patients with no significant disability (m-Rankin score 0-1’ Barthel index score 100). It is speculated that the cognitive effects of lacunar stroke are at least as important as disability related to motor or sensory deficits, and can occur in their absence.

Regardless of the paucity of data for cognitive end-points, adherence to current guidelines for primary stroke prevention with smoking cessation, Mediterranean-type diet, physical activity, weight control and control of cardiovascular risk factors, mainly hypertension and diabetes, as well as secondary stroke prevention with antiplatelet therapy, are first-line pharmacological strategies in the management of patients with ischaemic lacunar stroke subtype.1–3,47–49

Recently, cognitive stimulation has been advocated as one of the tasks of neuropsychological rehabilitation with the aim of improving cerebral neuroplasticity based on a set of stimuli for an integral improvement of cognitive, emotional, physical and inter-relationship skills with a final benefit of a better quality of life. Cognitive stimulation may act on some of the three processes involved in neurorepair, such as angiogenesis, neurogenesis and synaptic plasticity.50 Biomaterials for promoting brain protection, repair and regeneration are new hot targets in lacunar ischaemic stroke patients.

Concluding RemarksThe cognitive effects of acute ischaemic lacunar stroke have been identified in half of the patients and are at least as important as disability related to motor or sensory deficits, and occur in their absence. The classic cognitive profile involves preserved memory with impairment in attention and executive functioning. However, in a recent systematic review, impaired cognition appears less selective than previously thought, involving all major cognitive domains and episodic memory impairment may appear as an equally neuropsychological central feature in acute lacunar stroke.

Recurrent lacunar ischaemic stroke is one of the major factors involved in producing vascular subcortical dementia. Brain atrophy can be the end-stage of multiple pathological processes and is a well-recognised feature of many neurological diseases, including Alzheimer disease and multiple sclerosis. Atrophy is another feature recently associated with cerebral small vessel diseases.

Some aspects of cognitive impairment related to lacunar infarction are not definitively established. Further research in the following fields include: a) the investigation of relevant genetic forms and suitable animal models would be valuable for exploring the pathogenesis as well as the prevention of the lacunar stroke causes of cognitive impairment; b) diffusion tensor imaging MRI and cerebral microbleeds in relation to prognosis of lacunar stroke; c) assessment of the role of cerebral volume in cognitive impairment suffered by patients with lacunar infarction. The vascular basis of loss of neuronal and dendrosynaptic integrity in relevant cortical lobes also needs further investigation, and d) the inclusion of cognition as an outcome in future prospective observational studies and clinical trials is urgently required. Ischaemic lacunar stroke offers a target for beneficial interventions to preserve cognition in older people. Q

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37. Nikunan A, Lanfranconi S, Charlton RA, et al., Brain atrophy and cerebral small vessel disease. A prospective follow-up study, Stroke, 2011;42:133–8.

38. Duering M, Righart R, Csnadi E, et al., Incident subcortical infarcts induce focal thining in connected cortical regions, Neurology, 2012;79:2025–8.

39. Smith EE, Arboix A, Focal cortical thinning is caused by remote subcortical infarcts: spooky action at a distance, Neurology, 2012;79:2016–17.

40. Arboix A, Lacunar infarct and cognitive decline, Expert Rev Neurother, 2011;11:1251–4.

41. Lipsanen JH, Schmidt R, Fazekas F, et al., Brain atrophy accelerates cognitive decline in cerebral small vessel disease: The LADIS study, Neurology, 2012;78:1785–92.

42. Lee AY, Vascular dementia, Chonnam Med J, 2011;47:66–71.43. Duering M, Zieren N, Herve D, et al., Strategic role of frontal

white matter tracts in vascular cognitive impairment: a voxel-based lesion-symptom mapping study in CADASIL, Brain, 2011;134:2366–75.

44. Benavente OR, White C, Pearce I, et al., The Secondary Prevention of Small Subcortical Stroke (SPS3) study, Int J Stroke, 2011;6:164–75.

45. SPS3 Investigators, Benavente OR, Hart RG, et al., Effects of clopidogrel added to aspirin in patients with recent lacunar stroke, N Engl J Med, 2012;367:817–25.

46. Jacova C, Pearce LA, Costello R, et al., Cognitive impairment in lacunar strokes: The SPS3 Trial, Ann Neurol, 2012;72:351–62.

47. Modir R, Gardener H, Wright C, Blood pressure and white matter hiperintensity volume. A review of the relationship and implications for stroke prediction and prevention, US Neurology, 2012;8:33–6.

48. Douiri A, Rudd AG, Wolfe CD, Prevalence of poststroke cognitive impairment: South London Stroke Register 1995–2010, Stroke, 2013;44:138–45.

49. Dichgans M, Zietemann V, Prevention of vascular cognitive impairment, Stroke, 2012;43:3137–46.

50. Font A, Arboix A, Krupinski J, Angiogenesis, neurogenesis and neuroplasticity in ischemic stroke, Current Cardiol Rev, 2010;6:238–44.

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!! Les! repercussions! cognitives! associades! als! IL,! definits! com! a!malaltia! de!

petit! vas,! han! estat! infradiagnosticades! a! causa! del! bon! pronòstic! clínic! que!

presenten! a! curt! termini.! Però! la! importància! de! les! alteracions!

neuropsicològiques!de!les!malalties!vasculars!cerebrals!resideix!principalment!en!

el! pronòstic! a! llarg! termini,! especialment! en! el! deteriorament! cognitiu! d’origen!

vascular.! Els! professionals! clínics!hem!de! tenir!present!quines! són! les!principals!

característiques!clíniques,!demogràfiques,!els!factors!de!risc,!la!etiopatogenia!i!els!

tractament!òptim!per!tal!de!millorat!la!qualitat!de!vida!del!pacients!amb!IL.!!!

!

A! continuació! detallarem! la! discussió! específica! per! a! cadascuna! de! les!

quatre!publicacions!per!tal!donar!resposta!a!les!hipòtesis!plantejades!i!valorar!!els!

objectius!plantejats!en!aquesta!tesis!doctoral.!!

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! 92!

!Primera! publicació.! Advancements! in! understanding! the! mechanism! of!

symptomatic!lacunar!ischemic!stroke:!translation!of!knowledge!to!prevention!

strategies.!!

Adrià!Arboix,!Lorena!BlancoERojas,!Josep!Lluis!MartíEVilalta.!

Expert*Rev.*Neurother.*14(3),*261–276*(2014)!

!

! Els! IL! constitueixen! un! de! cada! quatre! infarts! isquèmics! i! solen! ser! el!

resultat! de! l’oclusió! d’una! arteriola! perforant! cerebral! principalment! a! causa! de!

dos! mecanismes! com! són! la! microateromatosi! i! la! lipohialinosi,! i! d’altres!

mecanismes! més! infreqüents! com! l’ateromatosi! de! branques! arterials!

intracraneals!de!més!gran!calibre!!i!fins!i!tot!d’un!origen!embòlic!ocasionalment.!La!

diferenciació!d’aquestes!entitats!patològiques!pròpies!dels!IL!es!considera!de!gran!

rellevància!per!a!determinar!les!estratègies!preventives!terapèutiques!

! Els!IL!han!estat!considerats!com!a!ictus!de!pronòstic!excel·lent.!No!obstant,!

estudis! recents! han! mostrat! repercussions! funcionals! amb! un! risc! d’alteracions!

neuropsicològiques!a!mig! i! llarg!termini!que!fins!ara!havien!estat! infraestimades.!

Els! IL! recurrents! són!més! freqüents!de! lo!que!es! considerava! inicialment! i! estan!

associats! a! diferents! quadres! clínics! severs! especialment! amb! l’estat! lacunar! i! la!

demència! subcortical! vascular.! L’evolució! de! la! RM! amb! imatges! d’alta! resolució!

ens!permet!aprofundir!en!el!coneixement!fisiopatològic!dels!IL.!Per!exemple,!s’ha!

demostrat! un! paper! etiopatogènic! en! l’ateromatosi! intracraneal! amb! l’oclusió!

secundària! de! les! artèries! perforants.! La! microateromatosi! és! el! mecanisme!

associat! als! IL! simptomàtics.! En! canvi,! la! lipohialinosi! que! afecta! arterioles!

perforant! de! petit! calibre! i! sembla! estar! més! relacionada! amb! les! llacunes!

asimptomàtiques! i! la! leucoaraiosi! (HSB).! La! HTA! que! és! el! factor! de! risc! més!

! 93!

important! i! modificable! és! la! causants! del! dany! a! les! artèries! de! la!

microvasculatura! especialment! de! les! arteries! perforants.! Els! agents!

antihipertensius! constitueixen! el! tractament! clau! per! a! la! prevenció! dels! IL,!

principalment!els!inhibidors!de!l’enzim!convertidor!de!la!angiotensina.!Però!també!

juguen!un!paper!important!els!agents!hipolipemiants,!no!solament!emprats!per!a!

disminuir!les!concentracions!plasmàtiques!lipídiques,!sinó!perquè!tenen!un!efecte!

pleiotròpic!i!neuroreparador.!!

! En! aquest! revisió! es! pretén! fer! una! actualització! dels! tractaments! i!

estratègies!preventives!per!als!IL.!!

! Els! IL! només! en! rares! ocasions! s’han! considerat! com! a! objectiu! principal!

d’assajos! clínics.! En! les! principals! guies! terapèutiques! els! IL! es! tracten! ! amb!

antiagregació! plaquetària! amb! aspirina! i! dipiridamol! en! combinació! o! amb!

clopidogrel!o!aspirina!en!monoteràpia!o!també!amb!trifusal!(88).!Però!no!hi!havia!

una!evidència!clara!de!quin!era!el!fàrmac!de!prevenció!secundària!més!adient!per!

als!IL!i!si!era!millor!la!monoteràpia!o!la!doble!antiagregació!plaquetària!(24).!!

! Inicialment! es! varen! inferir! pautes! terapèutiques! a! partir! d’assajos! clínics!

realitzats! en! el! grup! d’infarts! cerebrals! analitzats! de! forma! conjunta! i!

posteriorment!s’observava!el!subgrup!de!pacients!amb!IL!de!forma!secundària.!En!

l’estudi! francès! Accidents* Ischémiques* Cérebraux* Liés* à* l’Athérosclérose! es!

comparava! l’aspirina! en! monoteràpia! o! combinada! amb! dipiridamol! vers! el!

placebo!(89).!Es!va!a!aconseguir!una!reducció!de!69%!de!recurrència!en!el!subgrup!

d’IL!en!aquells!pacients!tractats!amb!aspirina!amb!o!sense!dipiridamol.!En!l’estudi!

Ticlopedine!CanadencEAmericà!(ticlopedine!versus!placebo)!es!va!observar!en!una!

mostra!de!275!pacients!una!reducció!del!50%!en!relació!al!risc!de!recurrència!i!a!la!

mortalitat! per! any! analitzat! (90).! També! en! un! estudi!Chinese*Acute*Stroke*Trial!

! 94!

(aspirina! versus! placebo)! amb! una! mostra! de! 6120! pacients! es! va! aconseguir!

reduir! el! risc! relatiu!de! recurrència!o!de!mortalitat!durant! els!primers!30!dies! a!

l’infart.! Però! aquest! assaig!mostra! els! resultats! a! curt! termini! i! s’ha! de! tenir! en!

compte! que! les! estratègies! preventives! òptimes! han! d’estar! enfocades! a! la!

prevenció!de!recurrència!vascular!cerebral!a!més!llarg!termini!(91).!!!

! En! l’estudi! de! Cilostazol* Stroke* Prevention* Study! comparant! el! fàrmac!

cilostazol! 100! mg/dia! vers! placebo! es! va! trobar! una! reducció! dels! risc! de!

recurrència!en!un!43,4%!d’una!població!de!810!pacients!amb!IL!(92).!En! l’estudi!

Warfarin[Aspirin*Recurrent*Stroke*Study!amb!una!mostra!de!1237!pacients!amb!IL!!

es!va!mostrar!una!taxa!de!recurrència!o!de!mort!d’un!8%!en!els!pacients!tractats!

amb!aspirina!comparats!amb!el!9%!dels!grup!tractat!amb!warfarina!(93).!Per!tant!

es!va!evidenciar!que!el!tractament!amb!anticoagulants!no!és!efectiu!en!els!IL.!Per!

altra!banda,!en!el!African*American*Aspirin*Stroke*Prevention*Study!(n=1221)!no!es!

va!poder!demostrar!una!reducció!significativa!en!el!risc!de!recurrència!i!mortalitat!

en!els!pacients!tractats!amb!ticlopidine!versus!els!tractats!amb!aspirina!(94).!

! El!maneig!de!l’aterotrombosi!amb!clopidogrel!en!pacients!amb!un!alt!risc!de!

AIT!o!infarts!en!l’estudi!MATCH!(clopidogrel!75!mg!versus!clopidogrel!75!mg!més!

aspirina)!el!tractament!combinat!es!va!associar!amb!una!reducció!no!significativa!

d’infart!cerebral,!infart!de!miocardi,!mort!o!!reingrés!hospitalari!de!causa!vascular!

(95).! També! varen! augmentar! les! complicacions! hemorràgiques! intracranials! i!

extracranials!en!els!pacients!amb!doble!antiagregació!plaquetària.!Per!altra!banda!

el! tractament! amb! estatines! és! recomanable! en! pacients! amb! infarts! no!

cardioembòlics!tal!i!com!s’observa!en!els!resultats!de!l’estudi!The*Stroke*Prevention*

by*Agressive*Reduction*of*Cholesterol*Levels*(SPARCL).*Les!estatines!i!altres!teràpies!

! 95!

antiinflamatòries! juguen! un! rol! important! en! la! inhibició! de! la! inflamació! i!

estabilitzen!les!plaques!d’aterosclerosi!(96).!!

! L’estudi! SPS3! (Secundary! Prevention! of! Small! Subcortical! Strokes),! un!

assaig! clínic! de! fase! III! va! ser! el! primer! estudi! de! doble! cec! i!multicèntric! en! la!

prevenció! secundària! d’! IL! confirmats! mitjançant! RM! cerebral! (97).! L’objectiu!

principal!d’aquest!estudi!va!ser!definir!la!teràpia!òptima!(aspirina!325!mg/dia!amb!

recobert!entèric!versus!aspirina!325!mg/dia!més!clopidogrel!75!mg/dia)!i!dividir!

així!mateix!la!mostra!en!dues!branques!en!relació!al!nivell!de!tensió!arterial!(TA)!

recomanat.!En!un!grup,! !el!control!de!la!TA!era!intensiu!(<!130!mmHg)!i!l’altra!el!

control!era!l’habitual!(130E149!mmHg).!L’!objectiu!era!analitzar!la!millor!estratègia!

per!a!la!prevenció!de!la!recurrència!de!l’IL!i!del!deteriorament!cognitiu.!A!remarcar!

que!l’ús!de!la!RM!cerebral!en!tots!els!pacients!amb!IL!de!l’estudi!va!augmentar!la!

qualitat!de!l’estudi.!En!la!cohort!de!3020!pacients!amb!una!mitja!d’edat!de!63!anys,!!

el! 63%! eren! homes,! i! després! de! 3,4! anys! de! seguiment! es! va! demostrar! que! la!

combinació! de! clopidogrel! i! aspirina! no! redueix! de! forma! significativa! la!

recurrència! vascular! cerebral! i! incrementa! el! risc! d’hemorràgia! major! (2,1%! a!

l’any!en!el!grup!amb!doble!antiagregació!plaquetària!i!en!un!1,1%!en!el!grup!amb!

monoteràpia! amb! aspirina)! i! de! mortalitat.! Tot! i! els! resultats! negatius! es! va!

observar! que! l’efecte! de! la! teràpia! dual! antiplaquetària! ! estava! associada! a! una!

tendència! en! la! reducció! dels! infarts! d’origen! ateroscleròtic! però! no! en! la!

recurrència! global! dels! infarts.! Per! tant! l’eficàcia! dels! agents! antiplaquetaris! és!

diferents! en! funció! dels! diferents! tipus! de! malaltia! cerebrovascular.! Aquests!

resultats!explicarien!que!la!aterotrombosi!pot!tenir!un!rol!menor!en!les!oclusions!

de! les! arterioles! petites! penetrants.! En! definitiva,! l’assaig! SPS3! va! mostrar! que!

l’aspirina! era! la! teràpia! antiplaquetària! d’elecció! en! els! IL! simptomàtics! i! va!

! 96!

suggerir! que! potser! els! IL! no! es! relacionaven! amb! una! malaltia! ateromatosa!

intracranial!sinó!una!malaltia!arterial!per!disfunció!endotelial!en!la!qual!l’efecte!de!

la!doble!antiagregació!plaquetària!no!hauria!estat!demostrat.!

! En! l’actualitat! hi! ha! una! sèrie! de! teràpies! antiplaquetàries! emergents! que!

semblen! potencialment! més! potents.! Hi! han! estudis! que! suggereixen! efectes!

prometedors!amb!fàrmacs!com!són!el!prasugrel,!ticagrelor!i!cangrelor!com!a!agent!

de!nova!generació!de!receptors!antagonistes!del!P2Y12!(98).!Però!la!seva!eficàcia!i!

seguretat!encara!ha!de!ser!encara!estudiada.!Cal!que!en!els!estudis!futurs!es!tingui!

present!que!hi!ha! IL!que!no!es!relacionen!amb! l’ateroma!sinó!amb!una!disfunció!

endotelial! de! les! parets! arterial,! i! per! altra! banda! hi! ha! una! associació! amb!

microhemorràgies! i! amb!un! risc!més! elevat!d’hemorràgies!majors! amb! lo!que! la!

doble!antiagregació!plaquetària!no!es!consideraria!un!tractament!d’elecció.!!

! La!neuroprotecció!inclou!una!sèrie!d’estratègies!!dedicades!al!bloqueig!dels!

processos! bioquímics! causats! per! l’infart! com! a! conseqüència! de! la! necrosi! i!

apoptosi!de!les!àrees!de!penombra!isquèmica.!Com!a!novetat!s’ha!demostrat!que!el!

magnesi!té!efectes!sobre!la!substància!blanca!subcortical!en!models!d’isquèmia!ja!

sigui! per! l’efecte! de! la! reducció! de! la! tensió! arterial! o! per! que! actua! com! a!

vasodilatador! endotelial! i! no! tant! com! a! neuroprotector! (99,! 100).! Per! aquest!

motiu! es! requereixen! més! assajos! clínics! controlats! per! a! confirmar! els! efectes!

potencialment!beneficiosos!dels!magnesi!en!la!malaltia!vascular.!!

Aquestes! perspectives! obren! la! possibilitat! que! els! pacients! amb! IL! siguin!

considerats!com!un!grup!diana!adequat!i!específic!per!a!valorar!la!utilitat!de!nous!

fàrmacs! antigregants! plaquetaris,! neuroprotectors! o! estabilitzadors! de! l’endoteli!

arterial!en!els!IL.!

!

! 97!

Segona!publicació.!Clinical!characteristics!of!acute! lacunar!stroke! in!women:!

emphasis!on!gender!differences.!!

Adrià!Arboix,!Lorena!BlancoERojas,!Montserrat!Oliveres,!Luis!GarcíaEEroles,!Emili!

Comes,!Juan!Massons.!!

Acta* Neurol* Belg.* 2014* Jun;114(2):107[12.* doi:* 10.1007/s13760[013[0257[8.* Epub*

2013*Nov*6.!

! Existeixen! diferències! clíniques! significatives! entre! les! homes! i! les! dones!

que!han!patit!un!IL?!Al!Registre!de!Malalties!Vasculars!Cerebrals!de!l’Hospital!del!

Sagrat!Cor!de!Barcelona!van!!ser!diagnosticades!310!dones!i!423!homes!amb!un!IL!!

d’un!total!de!3.808!pacients!i!es!va!realitzar!un!anàlisi!comparatiu!per!determinar!

si! hi! ha! diferències! clíniques! entre! ambdós! sexes! i! així! poder! respondre! a! la!

pregunta!plantejada!al!principi!del!text!(101).!!

L’! Infart! cerebral! va! constituir! una! de! les! principals! causes! de!mort! en! dones! a!

partir!dels!65!anys!d’edat!a!Catalunya!entre!els!anys!1993!i!1997!(102).!Per!altra!

banda,!els!estrògens!tenen!un!efecte!beneficiós!en!el!sèrum!lipídic,!en!el!perfil!de!

coagulació!i!en!la!prevenció!de!malalties!cardíaques!coronàries.!Però!els!beneficis!

nomenats! desapareixen! en! el! grup! de! dones! post! menopàusiques! i! per! tant,!

s’iguala!el!risc!de!patir!una!malaltia!vascular!amb!el!grup!d’homes.!!

! La! nostra! publicació! determina! quines! són! aquelles! característiques!

clíniques!que!diferència!el!patró!clínic!de!les!dones!versus!els!homes!davant!d’un!

infart! cerebral! lacunar.! Les! dones! que! representaven! el! grup! d’estudi! eren!

significativament!més!velles!que!els!homes!(77,3!versus!71,79!anys),!presentaven!

una! alta! freqüència! d’obesitat! (31! IMC! versus! 16! IMC),! una! major! freqüència!

d’hipertensió! arterial! (75,8%! versus! 68,6%)! i! una! estància! hospitalària! més!

prolongada! en! més! de! 12! dies! (38,4%! versus! 25,3%)! .! Aquesta! última!

! 98!

circumstància!és!justificar!en!part!!per!la!influència!sociocultural!de!les!dones!dins!

de!la!família!tradicional!ja!que!adopten!el!rol!de!cuidadores!principals!dels!homes!

malalts!i!de!la!resta!de!familiars.!Quan!la!dona!pateix!la!malaltia!vascular!cerebral,!

el! suport! social! i! l’ús! de! serveis! de! salut! s’incrementen! significativament! davant!!

d’aquesta!situació.!!

! Per!altra!banda,!els!homes!va!presentar!una!taxa!més!elevada!de!malalties!

vasculars! perifèriques,! malaltia! pulmonar! obstructiva! crònica,! alteració! renal!

crònica!i!tabaquisme.!!Una!dada!interesant!és!que!les!dones!més!grans!de!85!anys!

van! presentar! un! percentatge! més! elevat! d’ingrés! hospitalari! que! els! homes.!

Aquesta!situació!es!podria!explicar!en!part!pel!fet!que!els!estrògens!augmenten!la!

perfusió! cerebral! en! les! dones! amb! o! sense! malaltia! cerebrovascular.! Aquestes!

hormones! sexuals! tenen! propietats! antioxidants! per! el! teixit! cerebral! i! com! a!

conseqüència! actuen! com! a! neuroprotectors! durant! els! episodis! d’isquèmia!

cerebral.!Després!de!la!menopausa,!s’incrementa!la!taxa!de!les!dones!que!pateixen!

un! infart! cerebral! degut! al! dèficits! d’estrògens! i! per! aquest!motiu,! la!malaltia! de!

petit!vas!cerebral!s’incrementaria!a!partir!d’aquest!període!menopausa.!

! L’obesitat,!especialment! l’obesitat!abdominal!constitueix!un!altre! factor!de!

risc!vascular!independent!!en!els!IL!en!dones.!Les!persones!obeses!tenen!un!major!

risc!de!patir!HTA,!hiperglucèmia!i!resistència!a!la!insulina!entre!d’altres!patologies.!

Per!altra!banda,!la!HTA!és!el!factor!de!risc!independent!més!potent!que!predisposa!

tant!als!homes!com!a!les!dones!a!partir!un!infart!cerebral.!!

! La!disfunció!renal!greu!està!associada!amb!una!baixa!taxa!de!supervivència!

després! de! patir! un! infart! cerebral! i! constitueix! un! element! pronòstic! relacionat!

amb!la!taxa!de!mortalitat!en!els!pacients!amb!aquest!tipus!de!malaltia!vascular.!En!

l’estudi! de!Wannamethee* et* al.! (103)! demostren! que! la! disfunció! renal! també!

! 99!

constitueix!un!marcador!important!ja!que!incrementa!el!risc!de!patir!una!malaltia!

cerebrovascular! tant! en! el! grup! de! pacients! normotensius! com! d’hipertensius.!

Doncs!els!resultats!mostraven!que!la!malaltia!renal!crònica!és!menys!freqüent!en!

dones!que!en!homes.!!

! Com!a!dada!remarcable,!cal!assenyalar!que!el!pronòstic!de!la!malaltia!va!ser!

similar! en! homes! i! en! dones! ja! que! no! es! van! trobar! diferències! en! la! taxa! de!

mortalitat,! ni! en! els! percentatges! dels! pacients! amb! limitació! funcional! a! l’alta!

hospitalària,!ni!en! la! freqüència!dels!diferents!subtipus!d’infart!cerebral! !o!en! les!

complicacions!mèdiques!que!van!desenvolupar!al!llarg!de!la!seva!estància.!! !

! En!resum,!els!nostres!resultats!indiquen!que!les!dones!amb!un!IL!presenten!

diferències! clíniques! respecte! als! homes.! ! Les! variables! com! l’edat,! l’obesitat! i! el!

HTA!són!factors!clínics!relacionats!de!forma!independent!amb!el!sexe!femení.!En!

canvi,!la!bronquitis!crònica,!la!patologia!vascular!perifèrica,!alteració!renal!crònica!

i!fumar!son!factors!predictors!de!IL!en!homes.!Les!mesures!per!a!corregir!l’obesitat!

i!les!teràpies!farmacològiques!per!a!controlar!la!HTA!en!les!dones!són!estratègies!

importants!per!a!la!prevenció!de!l’IL!i!la!demència!vascular!subcortical!ja!que!l’IL!

es! considera! un! factor! de! risc! clínicament! rellevant! (10).! Per! altra! banda,! els!

resultats!van!mostrar!que!la!severitat!funcional!del!quadre!vascular!va!ser!similar!

entre! ambdós! gèneres! i! que! algunes! mesures! com! l’estància! hospitalària! entre!

d’altres!estan!influenciades!per!factors!socioculturals!on!la!dona!juga!el!paper!més!

important! en! la! família.! El! coneixement! de! les! diferències! del! gènere! en! els!

pacients!que!han!patit!un!IL!no!solament!és! important!per! la!prevenció!primària!

sinó!per!la!prevenció!del!deteriorament!cognitiu!secundari!a!l’IL.!!

! 100!

!Tercera! publicació.! Cognitive! profile! in! patients! with! a! firts>ever! lacunar!

infart!with!and!without!silent!lacunes:!a!comparative!study.!!

Lorena! BlancoERojas,! Adrià! Arboix,! David! Cánovas,! Marta! GrauEOlivares,! Joan!

Carles!Oliva!Morera!and!Olga!Parra!

Blanco[Rojas*et*al.*BMC*Neurology*2013,*13:203*

!

! Les!malalties! vasculars! cerebrals! menors,! com! són! ara! els! IL! clínicament!

silents,!les!HSB,!els!IL!i!els!AIT,!encara!que!tenen!un!bon!pronòstic!a!curt!termini,!

poden! contribuir! de! forma! directa! al! deteriorament! cognitiu! de! tipus! vascular.!

Aquest! terme! va! ser! descrit! per! Schandev! amb! l’objectiu! d’assenyalar! la!

importància! i! la! gravetat! de! les! seqüeles! cognitives! produïdes! per! la! patologia!

vascular! cerebral! en! general! (104).! El! terme! ‘deteriorament! cognitiu! de! tipus!

vascular’! abasta! des! del! deteriorament! cognitiu! lleu! (DCL)! fins! a! la! demència!

vascular.! La! prevalença! del! DCL! oscil.la! entre! el! 15! %! i! el! 20%! i! es! poden!

reconèixer!diferents!patrons!cognitius.!Un!primer!perfil!cognitiu!està!associat!a!la!

demència! vascular! clàssica! segons! els! criteris! de! la! International* Statistical*

Classification*of*Disease!(105):!alteracions!cognitives!associades!a!les!síndromes!de!

l’hemisferi! dominant! (afàsia! de! Broca,! afàsia! de! Wernicke,! afàsia! motora!

transcortical,!apràxia!constructiva!o!gestual,!acalcúlia)!o!les!que!es!relacionen!amb!

l’hemisferi! no! dominant! (associat! amb! diferents! graus! d’heminegligència,!

anosoagnosia,! hemiasomatoagnosia,! apràxia! constructiva,! desorientació!

topogràfica!o!apràxia!del!vestirEse).!En!canvi!un!segon!perfil!cognitiu,!és!de!tipus!

subcortical! i! es! caracteritza! per! la! bradipsíquia! i! bradicinèsia,! síndromes!

disexecutius! i!dificultats!de! la!memòria!d’evocació! i!aprenentatge!mentre!que! les!

! 101!

altres! funcions! cognitives! superiors! com! el! llenguatge,! les! praxis! i! les! gnòsies!

romanen! conservades.! Aquest! últim! perfil! associat! amb! els! IL! són! d’especial!

interès!per!a!aquesta!tesi!doctoral.!!

! Des!dels!estudis!patològics!s’han!suggerit!dos!tipus!de!malaltia!cerebral!de!

petit!vas!i! la!seva!distinció!es!realitza!a!través!de!les!tècniques!d’imatge!cerebral.!

Un! subtipus! és! l’arteriopatia! difusa! de! les! artèries! perforants! a! causa! de! la!

lipohialinosi! (malaltia! de! petit! vas! difusa)! associada! amb! els! IL!múltiples! silents!

clínicament!i!hiperintensitats!de!substància!blanca.!Per!altra!banda,!l’existència!de!

microateromes!originats!a!les!parets!de!les!arteries!profundes!cerebrals!(malaltia!

de! petit! vas! focal)! associada! als! infarts! lacunars! únics! simptomàtics.! La!

patogènesis! d’aquestes! malalties! radica! en! la! disfunció! endotelial! de! la! malaltia!

difusa!de!petit!vas!(106).!!

! Aquests!dos!fenotips!no!solament!es!distingeixen!radiològicament!sinó!que!

trobem!que!aquest!dos! tipus!de!pacient!presenten!perfils! cognitius!diferents.!Els!

nostres! resultats! contribueixen! a! justificar! l’existència! d’aquestes! dues! entitats!

fenotípiques! diferents! a! partir! dels! factors! de! risc,! la! neuroimatge! i! el! perfil!

cognitiu.!Per!tant!es!determina!l’existència!dels!IL!causat!per!un!únic!IL!aïllat!i!per!

altra!banda,!els!IL!simptomàtics!associats!a!múltiples!IL!silents!clínicament.!!

! En! l’! estudi! clínic!prospectiu! realitzat!per! el!nostre!grup!de! recerca,! es! va!

mostrar!que!el!50%!dels!pacients!amb!un!IL!únic!i!simptomàtic,!van!classificarEse!

posteriorment!de! la!ressonància!magnètica,!com!a!pacients!amb!múltiples! infarts!

lacunars!silents.!Aquests!pacients!presentaven!alteracions!de!la!substància!blanca!

de!major!gravetat!i!amb!una!major!freqüència!tant!a!les!àrees!periventriculars!com!

als!ganglis!basals!(73).!En!el!nostra!tesi!es!confirma!que!la!freqüència!de!les!HSB!en!

els! pacients! amb! múltiples! IL! però! actua! com! a! predictor! independent! de!

! 102!

alteracions! neuropsicològiques! referides! a! la! memòria! verbal! immediata! i! a! la!

fluència!verbal!semàntica.!Es!a!dir,! les!alteracions!neuropsicològiques!detectades!

en!la!fase!aguda!de!la!malaltia!són!conseqüència!de!la!pròpia!lesió!lacunar!i!no!de!

la!patologia!de!substància!blanca!cerebral.!Aquesta!troballa!és!important!ja!que!les!

HSB! s’associen! a! llarg! termini! amb!deteriorament! cognitiu,! i! en! diversos! estudis!

s’han!trobat!que!aquestes!lesions!de!la!substància!blanca!es!troben!més!sovint!en!

pacients!dements!que!en!els!controls.!La! leucoaraiosi!s’associa!especialment!amb!

dèficits!del!lòbul!frontal!com!són!ara!les!funcions!executives!que!estan!implicades!

en! la! resolució! de! problemes,! el! raonament! conceptual,! els! patrons! de! conducta!

inhibitoris! apresos! i! de! la! modificació! de! la! conducta! quan! es! rep! la! nova!

informació! del!medi! (flexibilitat! cognitiva),! i! com! a! conseqüència! les! disfuncions!

amb! aquesta! àrea! es! relacionen! amb! alteracions! conductuals! (conducta!

desorganitzada)!i!amb!deteriorament!cognitiu.!Per!tant,!les!HSB!contribueixen!a!la!

disrupció!del!sistema!neuronal!frontal!en!addicció!a!les!disrupcions!produïdes!per!

els! infarts! focals! que! augmenten! l’extensió! de! la! desconnexió! cortical.! Aquests!

resultats!van!en!concordança!amb!l’estudi!de!Leukoaraiosis*and*Disability*(LADIS)!

que!van!incloure!pacients!amb!diferents!perfils!clínics!van!reportar!que!el!nombre!

de!llacunes!prediu!un!empitjorament!de!les!funcions!executives!(107).!!

!

! Els! pacients! diagnosticats! d’un! primer! IL! únic! es! caracteritzen! per!

l’alteració! de! les! funcions! cognitives! superiors! a! la! fase! aguda! de! la! malaltia!

principalment!si!s’associen!a!IL!silents.!Ocasionalment!s’han!descrit! !casos!clínics!

únics!on!la!topografia!estratègica!dels!IL!aïllats!ha!pogut!ocasionar!algun!!tipus!de!

disfunció!neuropsicològica!específica.!Per!exemple!hi!han!sèries!que!han!analitzat!

els!infarts!capsulars!i!la!seva!repercussió!cognitiva,!com!ara,!pèrdues!de!memòria!

! 103!

greus!i!alteracions!neuropsicològiques!relacionades!amb!demència!(108),!amnèsia!

contextual!(109)!i!pèrdues!de!memòria!recurrents!(110).!En!els!estudis!d’Appelros*

et* al.! es! posa! de! manifest! la! correlació! entre! llacunes! en! els! ganglis! basals! i!

alteracions!cognitives!(111).!Aquest!disfuncions!són!degudes!a!la!interrupció!dels!

circuits! prefrontoEsubcortical,! produïda! pels! infarts! en! el! nucli! estriat,! globus!

pàl·lid!o! tàlem,!o! també,!per! lesions!de! la! substància!blanca!que! interrompen! les!

connexions!entre!la!escorça!prefrontalEsubcortical!dorsolateral.!!

Respecte! a! la! recuperació! de! la! focalitat! neurològica! dels! pacients! amb! IL!!

tenen! un! bon! pronòstic! a! curt! termini.! Exceptuaríem! els! casos! que! presenten!

alteracions! cognitives! severes! prèvies! o! focalitats! neurològiques! presents! en! els!

seu!estat!premòrbid.!La!persistència!d’aquestes!seqüeles!neuropsicològiques!com!

alteracions! atencional! i! dèficits! en! la! velocitat! de! processament! actuen! de!

detriment!de!la!qualitat!de!vida!d’aquest!tipus!de!pacients.!!

En!el!nostre!treball!s’ha!objectivat!de!forma!clara!que!els!pacients!amb!un!

primer! IL! associat! a!múltiples! IL! silents! clínicament!presenten!un!perfil! cognitiu!

diferent! i! pitjor! en! comparació! amb! els! pacients! amb! un! infart! primer! IL! únic.!

Aquest!IL!silent!s’associen!amb!disfuncions!del!lòbul!frontal!en!absència!de!criteris!

diagnòstics!clínics!de!demència.!!

Com! a! conclusió,! diversos! estudis! suggereixen! que! els! infarts! múltiples!

contribueixen!a!una!major!disrupció! funcional!del!sistema!frontal!que! les! lesions!

úniques.!Per!aquest!motiu!es!probable!que!les!lesions!subcortical!tenen!un!efecte!

multiplicatiu!en!la!interrupció!de!vies!neurals!i!com!a!conseqüència!produeixin!una!

disfunció!frontal!major!!que!els!pacients!que!han!patit!un!únic!IL!(108).!!

!

! 104!

Quart!article.!Cognitive!impairment!in!ischaemic!lacunar!stroke.!

Adrià!Arboix!and!Lorena!BlancoERojas!

European*Neurological*Review,!2013;8*(2):*144[8.!

! La! causa!més! freqüent! d’alteració! cognitiva!d’origen! vascular! es! relaciona!

amb!els!IL,!la!HSB!i!les!microhemorràgies!documentades!en!els!pacients!a!partir!de!

les! imatges! de! la! RM! cerebral.! Aquestes! tres! entitats! patològiques! constitueixen!

l’espectre!fenotípic!i!morfològic!de!!la!malaltia!de!petit!vas!cerebral.!!

! Les! seqüeles! cognitives! en! la!malaltia! isquèmica!de!petit! vas!han! adquirit!

una!gran!importància!en!els!darrer!anys.!Els!IL!simptomàtics!es!relacionen!amb!els!

mecanismes! de! microateromatosi! o! una! alteració! ateromatosa! de! branques!

arterials! de! calibre! gran.! Per! altra! banda,! els! pacients! que! han! patit! episodis!

crònics! d’hipertensió! arterial! solen! presentar! IL! múltiples! asimptomàtics! i! es!

relacionen!amb!mecanismes!de! lipohialinosi.!Aquesta!revisió!bibliogràfica!pretén!

identificar! la! evidència! clínica! i! els! mecanismes! subjacents! relacionats! amb! el!

deteriorament!cognitiu!i!els!IL.!!

! De! les! diferents! seqüeles! funcionals,! les! alteracions!motores! i! els! dèficits!

sensitius!dels! IL! simptomàtics!han!donat! lloc!a!una!elevada!quantitat!de! treballs!

científics!però,!el!grau!d’afectació!cognitiva!tant!dels!infarts!simptomàtics!com!dels!

infarts!silents!genera!una!certa!controvèrsia.!A! la! literatura!hi!ha!estudis!que! fan!

referència!a!!la!demència!subcortical!associada!a!IL!múltiples,!entitat!que!ja!que!va!

ser! reconeguda! clàssicament! com! “état! lacunaire”! per! Pierre!Marie! .! Però! també!

trobem! altra! entitat! que! relaciona! IL! múltiples! amb! alteracions! extenses! de! la!

substància!blanca:!és!la!malaltia!de!Binswanger.!Ambdues!entitats!serien!típiques!

de!la!malaltia!de!petit!vas!cerebral!evolucionada!(82).!

! 105!

! Des! de! la! Neuropsicologia! s’havien! evidenciat! controvèrsies! i! manca! de!

coneixement!respecte!a!la!presència!o!no!d’afectació!cognitiva!en!els!pacients!amb!

un! primer! IL.! En! un! primer! moment! es! considerava! que! les! alteracions!

neuropsicològiques! dels! IL! solen! ser! mínimes! o! absents! a! la! fase! aguda! de! la!

malaltia.! En! canvi! hi! han! altres! estudis! que! especifiquen! anomalies!

neuropsicològiques! que! es! relacionen! amb! una! alteració! de! la! fluència! verbal,!

dismnèsia! i! abúlia! o! heminegligència! espacial! i! afàsia! atípica,! entre! d’altres!

anomalies,!especialment!en!els!IL!situats!estratègicament!en!la!regió!dorsomedial!i!

anterior!del!tàlem!(108,!109,!111).!!

! En! estudis! recents! s’ha! demostrat! que! els! IL! isquèmics! simptomàtics!

constitueixen! un! factor! predictor! de! deteriorament! cognitiu! i! de! demència!

vascular.!En!un!estudi!del!nostre!grup!amb!una!mostra!de!40!pacients!amb!IL!que!

van!ser!avaluats!al!mes!de!l’alta!hospitalària!es!va!determinar!que!el!57,5%!de!la!

mostra!va!presentar!alteracions!cognitives!lleus!especialment!aquells!pacients!amb!

la! síndrome! hemiparèsia! motora! pura! i! en! els! infarts! lacunars! atípics.! Aquest!

treball!va!aportar!una!mostra!suficientment!gran!com!per!a!considera!les!troballes!

cognitives!com!inherents!als!IL!(73).!

! El!perfil!cognitiu!general!associat!a! la!malaltia!vascular!de!petit!vas!no!sol!

ocasionar!!en!fases!inicials!trastorns!de!memòria,!en!canvi!els!pacients!presenten!

alteracions! atencionals! i! síndrome! disexecutiva.! La! presència! d’alteracions!

neuropsicològiques!referides!a!les!àrees!frontals!és!freqüent!en!els!casos!de!infarts!

lacunars! subcortical! múltiples.! La! demència! vascular! es! va! reportar! en! un! 11%!

entre!els!2!i!3!anys!posteriors!a!l’IL,!i!augmenta!a!un!15%!en!els!9!anys!posteriors.!

Els!IL!simptomàtics!són!importants!com!a!factor!predictor!per!a!la!progressió!de!la!

! 106!

demència! subcortical! vascular,! i! a! l’hora,! augmenta! el! risc! de! IL! recurrents! i! la!

presència!d’alteracions!de!la!substancia!blanca!cerebral!(leucoaraiosi).!!

! Per! altra!banda,! els! IL! silents! es! troben!de! forma! incidental! entre!un!20! i!

28%!a! les! imatges!de!RM!realitzades! a!pacients! asimptomàtics!des!d’un!punt!de!

vista!neurològic.!Hi!han!estudis!que!han!demostrat!que!els! IL!silents!clínicament!

constitueixen!un!factor!de!risc!de!deteriorament!cognitiu!i!IL!recurrent!(23,!68).!Hi!

han!estudis!que!han!trobat!entre!un!10!i!el!50%!dels!pacients!amb!IL!silents!van!

presentar! nous! IL! a! la! RM! tres! anys! posterior! a! l’infart! (80).! Per! altra! banda,! el!

40%!dels!pacients!amb! IL!presenten!una!progressió!de! la!malaltia!de! substància!

blanca.!Per!tant,!s’ha!mostrat!que!hi!ha!un!risc!elevat!de!deteriorament!cognitiu!i!

de!IL!recurrents!en!aquests!pacients!amb!IL!encara!que!siguin!silents!clínicament.!

! L’estudi! LADIS! (The*Leukoaraiosi*and*Disability*Study)! van! demostrar! que!

les!lesions!lacunars!recurrents!a!la!RM!determinen!canvis!cognitius!en!els!pacients!

d’edat!avançada!amb!HSB.!Els!autors!van!mostrar!que!les!noves!llacunes!trobades!

a! les! imatges! de! RM! es! relacionen! significativament! amb! el! deteriorament! de!

funcions! cognitives,! independentment! del! grau! d’HSB! basal,! de! les! llacunes!

incidentals,!del!nombre!de!llacunes!i!de!la!progressió!de!la!HSB!i!conclouen!que!els!

IL! incidentals!contribueixen!al!deteriorament!mental,!a! la!velocitat!motora!i!a! les!

funcions! executives,! tot! i! que! les! funcions! cognitives! generals! i! la! memòria! no!

apareixen! afectades! (81).! Les! lesions! asimptomàtiques! observades! a! la! RM!

constitueix!un!factor!de!risc!precipitant!de!la!progressió!de!la!malaltia!de!petit!vas,!

i! per! tant,! de! deteriorament! cognitiu! vascular.! Els! aspectes! neuropsicològics!

d’aquest! tipus! de! malaltia! no! han! estat! suficientment! estudiats,! especialment,!

aquells! estudis! que! inclouen! seguiments! a! llarg! termini! i! mostres! grans! de!

subjectes.! Les! línies! d’investigació! futures! apunten! a! la! valoració! i! estudi! de! les!

! 107!

seqüeles!cognitives!dels!IL!silents! i!a! l’!anàlisi!dels! factors!predictors!de!seqüeles!

neuropsicològiques!a!partir!de!la!neuroimatge!funcional.!!

! Una! altra! entitat! important! son! les! HSB! que! són! causades! per! infarts!

incomplerts! associats! a! la! malaltia! de! petit! vas! que! reflexa! alteracions!

hemodinàmiques!de! la! substància!blanca! secundària! a!un!procés! arterioscleròtic!

de! les! arterioles! que! vascularitzen! les! àrees! cerebrals! subcortical! (112).! Alguns!

autors!han!suggerit!que!els!IL!s’associen!a!una!HSB!més!extensa!que!la!observada!

en!els! infarts!no! lacunars! i!el! fet!d’establir!un!volum!basal!de!HSB!constitueix!un!

bon!factor!predictor!de!deteriorament!cognitiu!(81).!

! Per!altra!banda,!les!microhemorràgies!cerebrals!són!aquelles!lesions!petites!

i! hipointenses! que! corresponen! amb! dipòsits! d’hemosiderina! en! els! espais!

perivasculars! i! microvasculars.! Són! lesions! que! acompanyen! als! IL! i! són! molt!

freqüents! en! pacients! que! presentes! HTA.! Les! imatges! de! la! RM! en! seqüències!

d’Eco!gradient!T2!són!especialment!sensibles!en!la!detecció!d’aquest!tipus!de!lesió.!

En!un!68%!dels! casos!es!poden!observar!en!els!ganglis!basals,! encara!que!altres!

regions! comuns! són! les! àrees! frontals,! parietoEoccipital! i! temporal! (113).! El!

nombre!de!microhemorràgies!estan!associat!amb!el!grau!de!HSB,!d’IL! i!d’HTA.!A!

nivell!neuropsicològic!aquest!tipus!de!lesió!també!s’han!relacionat!amb!alteracions!

executives!i!deteriorament!cognitiu.!Diversos!estudis!han!suggerit!la!necessitat!de!

la! inclusió! de! les! microhemorràgies! com! a! nou! factor! predictor! d’! alteracions!

neuropsicològiques!(113,!114).!!

En!resum,! les!seqüeles!cognitives!de! la!MPV!(IL,!HSB! i!microhemorràgies)! !estan!

relacionades!amb!el!deteriorament!cognitiu!lleu!i!amb!un!risc!potencial!d’evolució!

posterior!a!demència!vascular!subcortical.!!

! 108!

! L’anàlisi!del!deteriorament!cognitiu!de! tipus!vascular! lleu!va!ser! l’objectiu!

d’una! revisió! de! 12! estudis! amb! tall! transversal! en! els! quals! es! varen! observar!

alteracions!cognitives!associades!als!IL!simptomàtics,!principalment!alteracions!de!

l’atenció! i! de! la! memòria! de! treball! així! com! disfuncions! executives.! També! es!

descriuen! altres! alteracions! cognitives! addicionals! que! inclouen! els! àmbits!

relacionats!amb!la!memòria,!el!!llenguatge!i!les!habilitats!visuoespacial!(115).!!

En! un! estudi! del! nostre! grup,!més! de! la!meitat! dels! pacients! amb!primer! IL! van!

presentar!alteracions!neuropsicològiques,!especialment!de!les!funcions!executives!

i!complien!criteris!de!deteriorament!cognitiu!lleu!d’origen!vascular!(83).!En!aquest!

estudi!es!va!utilitzar!la!morfometria*de*vòxel!(“voxel!based!morphometry”)!per!a!la!

valoració!del! volum!de! la! substància!grisa!d’aquest!pacients!que!van!mostrar!un!

cert! grau! d’atròfia! cerebral! en! determinades! àrees! com! els! lòbuls! temporals!

bilateralment,! regions! frontals! i! parietals,! la! part! esquerre! del! cerebel,! el! girus!

parahipocampal!bilateral!i!el!hipocamp!dret.!Aquestes!troballes!posen!de!manifest!

la! hipòtesi! d’una! possible! afectació! remota! d’altres! àrees! cerebrals!més! enllà! de!

l’àrea!lesional!infartada.!

! Un! altra! factor! important! a! tenir! en! compte! és! la! presència! de! atròfia!

cerebral! que! es! pot! considerar! com! el! final! d’un! procés! patològic! a! partir! de!

diversos!trastorns!neurològics!i!que!podrien!incloure!la!Malaltia!d’Alzheimer!(MA),!!

l’esclerosis!múltiple!i!la!malaltia!de!petit!vas!cerebral.!

! Diversos! estudis! han! mostrat! que! la! proporció! de! demència! vascular!

subcortical!causada!per!la!malaltia!de!petit!vas!oscil.la!entre!el!36%!i!el!67%!i!els!

autors! determinen! que! és! causada! per! la! interrupció! dels! circuits! frontoE

subcorticals! com! a! conseqüència! dels! IL! i! la! presència! de! les! HSB! (82).! Les!

alteracions! produïdes! al! circuit! prefrontal! dorsolateral! s’han! relacionat! amb! les!

! 109!

alteracions! executives! i! de! velocitat! de! processament! (116).! ! S’apunta! a! la!

demència!com!a!la!causant!principal!de!dependència!funcional!i!que!comporta!un!

devastador!impacte!sobre!la!qualitat!de!vida!del!pacient.!La!patogènesi!dels!dèficits!

cognitius!subjacents!a!la!demència!subcortical!són!producte!de!la!combinació!tant!

de!seqüeles!degeneratives!com!isquèmiques!(82,!117,!118).!El!seguiment!d’estudis!

a!llarg!termini!(més!de!tres!anys,!com!a!mínim!seria!una!bona!recomanació)!amb!

mostres!grans!de!pacients!constitueixen!línies!d’investigació!futura!en!l’estudi!del!

DCL!per!determinar!més!factors!predictius!de!demència!subcortical.!

! Els!avenços!en!les!estratègies!terapèutiques!sobre!la!MPV!pretenen!definir!

intervencions!òptimes!per!a!la!prevenció!d’infarts!recurrents!i!de!declivi!cognitiu!!

en! aquest! tipus! de! població.! En! l’estudi! SPS3! (119),! un! assaig! clínic! de! fase! III,!

multicèntric!i!doble!cec!amb!una!mostra!de!3.020!pacients!amb!IL!i!un!seguiment!

de!3,4!anys!!es!va!concloure!que!la!combinació!de!clopidogrel!de!75!mg!i!aspirina!

de! 325! mg! no! demostra! una! major! efectivitat! en! la! recurrència! vascular! en!

comparació!amb!l’aspirina!com!a!tractament!únic!(97).!Pel!que!fa!a!l’anàlisi!de!les!

dades!neuropsicològiques,!al!analitzar!la!mostra!de!parla!anglesa!el!47%!complien!

criteris! d’alteració! cognitiva! lleu! amb! dèficits!mnèsics! en!major! nombre! que! els!

dèficits!no!mnèsics! (120).!El!deteriorament!cognitiu! lleu! (DCL)!era!més! freqüent!

en! els! pacients! joves! i! homes,! amb! un! nivell! inferior! educacional,! amb! seqüeles!

funcionals!post!infart!i!presentaven!disfuncions!en!les!activitats!bàsiques!de!la!vida!

diària! (120).! EL! autors! van! observar! que! les! alteracions! de! la! velocitat! de!

processament,!de!l’habilitat!motora!i!les!funcions!executives!eren!consistents!amb!

el! patró! d’aquest! ! tipus! de! deteriorament! cognitiu! vascular.! Per! altra! banda,! els!

resultats!demostren!que!la!meitat!de!subjectes!presenten!alteracions!de!memòria!

que!a!priori!no!coincideix!amb!aquest!patró!de!deteriorament!vascular!clàssic.!Són!

! 110!

pocs! els! estudis! que! reporten! alteracions! de!memòria! en! pacients! amb! llacunes!

incidentals!ja!que!normalment!s’associen!alteracions!disexecutives!i!de!la!velocitat!

de! processament! però! no! amb! alteracions! mnèsiques.! La! magnitud! d’aquestes!

alteracions! de! memòria! episòdica! faria! pensar! en! la! possible! coexistència! de! la!

MPV! amb! la! Malaltia! d’Alzheimer.! Tot! i! que! la! memòria! de! reconeixement! es!

mantén! preservada,! aquestes! alteracions! en! el! record! diferit! de! la! informació!

suggereixen!que! la! causa!està! relacionada!amb! la!disrupció!del! còrtex!prefrontal!

associat! a! la! recuperació! estratègica! de! la! informació! més! que! a! la! hipòtesi! de!

l’alteració!dels!circuits!de!l’hipocamp!relacionada!amb!la!MA.!En!resum,!aquestes!

dades! són! important! en! la! pràctica! clínica! ja! que! les! alteracions! cognitives! són!

comunes!en!el!pacient!amb!IL!i!són!tant!significatives!com!les!seqüeles!motores!i/o!

sensitives!associades!a!la!MPV.!!!

! La!primera!línia!d’estratègia!terapèutica!en!el!maneig!dels!pacients!amb!IL!

està! relacionada! amb! l’adherència! a! les! Guies! per! a! la! prevenció! primària! de!

l’infart,!evitar!el! !tabaquisme,!recomanar!la!dieta!mediterrània,! l’activitat!física,!el!

control!del!pes,!i!el!control!dels!factors!de!risc!cardiovascular,!especialment!la!HTA!

i! la! diabetis,! al! igual! que! la! prevenció! secundària! de! l’infart! amb! teràpia!

antiplaquetària!(10,!24).!

!! Actualment,!la!estimulació!cognitiva!s’ha!considerat!com!una!de!les!tasques!

de! rehabilitació! cognitiva! amb! l’objectiu! de! millorar! la! neuroplasticitat! cerebral!

basada! en! una! sèrie! d’estímuls! que! milloren! la! capacitat! cognitiva! de! manera!

integral,! emocional,! física! i! millora! les! relacions! interpersonals! amb! la!

conseqüència! d’una!millora! en! la! qualitat! de! vida! dels! pacients.! ! La! estimulació!

cognitiva! actua! sobre! els! tres! processos! implicats! en! la! neurorreparació:!

l’angiogènesi,!la!neurogenesi!i!la!plasticitat!sinàptica!(121).!!

! 111!

! En!definitiva,!alguns!aspectes!neuropsicològic!referits!als!IL!no!estan!encara!

prou!definits!i!per!això!calen!línies!d’investigació!futura:!!

a) estudis!genètics!i!amb!models!animals!per!aprofundir!en!el!coneixement!de!

l’etiologia!i!en!l’estudi!de!les!alteracions!cognitives!

b) l’ús! protocol·litzat! de! les! modernes! tècniques! de! neuroimatge! amb! RM!

funcional!en!l’estudi!dels!IL.!

c) avaluar! el! grau,! el! tipus! i! el! nombre! de! disfuncions! neuropsicològiques!

ocasionades!o!associades!als!IL!en!particular!i!a!la!malaltia!cerebral!de!petit!

en!general.!!!

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6.#Conclusions!

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!! Les!conclusions!d’aquesta!tesi!doctoral!són!les!següents:!

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1. Existeixen!diferències!clíniques!en!els!IL!en!relació!al!sexe.!Les!dones!tenen!

una!edat!més!avançada,!i!més!freqüència!d’obesitat!i!d’hipertensió!arterial.!

Per! altra! banda,! els! homes! presenten! una! major! freqüència! de! malaltia!

vascular!perifèrica,!bronquitis! crònica,!malaltia! renal! crònica! i! un! consum!

més! elevat! de! tabac.! La! intervenció! diagnòstica! i! terapèutica! i! el! control!

adequat! d’aquests! factors! de! risc! vascular! cerebral! constitueix! una!

estratègia!preventiva!de!primera!elecció.!

!

2. En!la!malaltia!vascular!cerebral!de!petit!vas!els!factors!que!contribueixen!al!

deteriorament!cognitiu!de!tipus!vascular!son!els!següents:!!

! Presència!i!nombre!d’!IL!simptomàtics!

! Presència!i!nombre!de!IL!silents!clínicament!

! Presència!i!extensió!de!la!leucoaraiosi!o!HSB!

! Presència!i!grau!d’atròfia!cerebral!

! Presència!i!nombre!de!microhemorràgies.!!

! Recurrència!de!nous!IL.!

!

3. La! presencia! de! IL! clínicament! silents! en! pacients! amb! un! primer! IL! està!

associat! amb! alteracions! neuropsicològiques! lleus,! particularment!

amb!disfuncions!executives! (fluència! semàntica)! i!de! la!memòria! verbal!

immediata.! Aquestes! disfuncions! cognitives! estan! relacionades! amb! les!

llacunes!i!no!amb!les!alteracions!o!hiperintensitats!de!la!substància!blanca.!

! 116!

4. La!meitat!dels!pacients!amb!IL!presenten!criteris!de!deteriorament!cognitiu!

lleu!sent!una!complicació!clínica!tant!important!com!la!discapacitat!física.!El!

perfil!cognitiu!associat!als!IL!isquèmics!no!sols!presenten!alteracions!de!les!

funcions! executives! i! atencionals,! sinó! que! s’evidencien! alteracions! de!

memòria!episòdica! i!de! les! funciones!cognitives!superiors.!Les!disfuncions!

cognitives!en!els!IL!han!estat!infravalorades!en!la!pràctica!clínica!i!són!més!

comuns!i!clínicament!tan!rellevants!com!les!seqüeles!motores!i!sensitives.!!

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7.#Bibliografia!

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