vasospasme post-hsa

R Manet(1), S Chatard-Baptiste(2) , S Saleme(2) , L Gergelé(3),

P Gromolard(3), C Nuti(1), FG Barral(2)

(1) Service de neurochirurgie – CHU Saint Etienne

(2) Service de radiologie – CHU Saint Etienne

(3) Département anesthésie-réanimation – CHU Saint Etienne

Cours DES neurochirurgie – 22 avril 2011

• Epidémiologie – pronostic

• Physiopathologie

• Diagnostic

– Clinique

– Monitoring

– Imagerie (S. Chatard-Baptiste)

• Prise en charge

– Traitements médicaux

– Traitements interventionnels (S. Saleme)

• Chronologie

– Précoce (<48h ) : 10% des HSA. Physiopathologie différente

mais morbidité similaire ? (Baldwin, Stroke, 2004);

– Incidence max: J5 – J14;

– Jusqu’à 4 semaines.

• Incidence (Charpentier, Stroke, 1999)

– Vasospasme angiographique : 30 -70% des HSA;

– Vasospasme symptomatique : 17 - 40% des HSA.

(Ischémie Cérébrale Différée: ICD)

• Facteurs de risque:

– Age jeune (Rabb Acta Neurochir 1994; Charpentier, Stroke, 1999 );

– HTA pré-existante (Ohman, J Neurosurg, 1991);

– Tabagisme actif (Lasner, J Neurosurg, 1997);

– Sévérité du tableau clinique initial (Lasner, J Neurosurg, 1997;

Charpentier, Stroke, 1999);

– Insuffisance cardiaque initiale (Friedman, Neurosurgery, 2003);

– Sévérité tomodensitométrique initiale (Claassen, Stroke, 2002);

– Hyperglycémie (Charpentier, Stroke, 1999);

– Nécessité d’une dérivation du LCR (Charpentier, Stroke, 1999).

…QUANTITE DE SANG SOUS-ARACHNOIDIEN

• Facteurs de risque

Clinique initiale & TDM initiale

Claassen, Stroke, 2002

Fisher Infarctus

0 0 %

1 6 %

2 14 %

3 12 %

4 28 %

Hunt&Hess ICD

1 22 %

2 33 %

3 52 %

4 53 %

5 74 %

Greenberg, Handbook Neurosurg, 2010

Complication la plus grave chez les survivants d’une HSA:

• L’ICD est un facteur de risque indépendant de séquellesneurologiques à 6 mois (Charpentier, Stroke, 1999);

• Meilleur pnc neurologique chez patients ne développant pas d’ICD(Dorsch, J Clin Neurosci, 1994);

• 30% de mortalité chez patients avec vasospasme (Dorsch, J Clin

Neurosci, 1994).

Décrit en 1951 Ecker, J Neurosurg, 1951;

Compréhension relativement incomplète;

HSA => hypoperfusion cérébrale:

Dépression hémodynamique immédiate

+/- aggravée secondairement par vasospasme

Tb hémodynamiques & microcirculatoires

* = p < 0,05

Tb hémodynamiques & microcirculatoires

Tb autorégulation / couplage métabolique

PPC AutorégulationCouplage

métabolique

Tb hémodynamiques & microcirculatoires

Tb autorégulation / couplage métabolique

Yundt, J Cereb Blood Flow Metab, 1998

Jaeger, Stroke, 2007

PPC AutorégulationCouplage

métabolique

Ischémie

Tb hémodynamiques & microcirculatoires

Phénomènes microthrombotiques

Aggrégation plaquettaire => micro-infarctus;

Akopov, Cerebrovasc Brain Metab, 1996

Consommation plaquettaire à la phase aigüe d’HAS = facteur prédictif;

indépendant d’ICD Hirashima, J Neurosurg, 2005

Ttt antiplaquettaire => amélioration non significative du pnc neuro.

Dorhout, Stroke, 2008

Tb hémodynamiques & microcirculatoires

Phénomènes microthrombotiques

SAH => Inflammation => Hypercoagulabilité;

Marqueurs plasmatiques de l’ activité thrombine & fibrinolyse corrélés

avec grade HSA et pnc mais pas de corrélation retrouvée entre ces

marqueurs et ICD/infarctus;

Ilveskero, Neurosurgery, 2005

Activité thrombine dans LCR corrélée à infarctus par ICD.

Kasuya, Acta Neurochir, 1998

Inflammation / Stress oxydatif

Inflammatory mediators ( stroke) Potential therapeutic interventions

Stress oxydatif

i NOS neurotoxicité Relargage NO

Chow M, Neurosurgery, 2002

Ng, Neurosurgery,2001

↑Endothéline-I

Vasoconstriction

Prolif endothéliale & m lisse

Inflammation

DIS ?

Pdts dégradation HB COX-2 => PG

Inflammation

Vasoconstriction

Lésion BHE

Bilirubine

Biliverdine

Hème

BOXesVasospasme angiographique

DIS ?

Woszczyk, Acta Neurochir, 2003

NO

ET-I

Péroxydation

lipidique

BOXes

Pilitsis, J Neurosurg, 2002

Clark, J Cereb Blood Flow Metab, 2006

ICD ?

ICD ?

Stress oxydatif: péroxydation lipidique

Levels of CSF F2-IsoPs (specific

marker of lipid peroxidation) levels

during the first 8 days after

surgery (15SAH/10controls).

(A)Non-SAH controls (n=10).

(B)DIND patients (n=3)

Stress oxydatif

Inflammation

↓CBF Stase leucocytaire ↑ infiltration leucocytaire

Lucas, Br J Pharmaco, 2006

Lindsberg, Ann Neurol, 1996

Rothoerl, Cerebrovasc Dis, 2006

Hallenbeck, Stroke, 1986

Dommages locaux Activation microglialeMacrophages

Cytokines

Complément

C3a C5a MAC

Hémolyse

Lésions neuronales

Médiateurs

proinflammatoires

?

Molécules d’adhésion cellulaireI-CAM (ICAM1) V-CAM

Sélectines (P-selectin E-selectin)

Intégrines

Adhésion & infiltration leucocytaire

Mellergård, Neurosurgery, 2011

Inflammation

IL1β

IL6

IL10

Apoptose

P53 / activité caspase

Inhibition P53 chez rat => ↓mortalité ↓rupture BHE ↑pnc neuro

Apoptose

endothéliale

Apoptose

neuronale

Rupture BHE

Cahill, Stroke, 2006

Influx cationique/hydrique passif massif dépassant les capacités de

transport mbr => dépolarisation « galopante » lente (2-5mm/min)

Situation physiologique

Suractivation des transporteurs ATP-dépendants=> conso énergie ++

=> réponse hémodynamique hyperhémique

Normalisation en qlq min (5-15min)

Agression aiguë (HSA)

=> absence de réponse hémodynamique adaptée = ischémie

=> Spreading ischaemia Dreier, Brain, 2009

Durable / auto-entretenue

Cortical spreading depolarization

Cortical spreading depolarization

Dreier, Brain, 2009

Dreier, Brain, 2009

Cortical spreading depolarization

Dreier, Brain, 2009

Apoptose

Tb

hémodynamiques

Stress

oxydatifInflammation

Réduction DSCDécouplage

métaboliqueTb autorégulation

Spreading

depolarization

Souffrance cérébrale

Apoptose

Tb

hémodynamiques

Stress

oxydatifInflammation

Réduction DSCDécouplage

métaboliqueTb autorégulation

Spreading

depolarization

Souffrance cérébrale

Vasospasme post-HSA = Ʃ phénomènes pathologiques complexes

dont l’une des expressions est la réduction de diamètre des

vaisseaux.

Déficit Neurologique

Ischémique Différé

Infarctus

cérébral

Clinique

Dégradation neurologique différée survenant entre J5 et J21:

Tb des fonctions supérieures / Désorientation temporo-spatiale;

Tb de la vigilance;

Ʃd méningé;

Apparition ou aggravation d’un déficit neurologique focal:

- ACA => Ʃd frontal (+/- bilatéral si ACoA);

- ACM => mono/hémiparésie, aphasie, apraxie…

Signes systémiques: hyperthermie, hyponatrémie…

Diagnostique différentiel

• Resaignement;

• Hydrocéphalie;

• Œdème cérébral;

• Epilepsie;

• Tb métaboliques;

• Sepsis;

• …

Monitoring non-invasif

Doppler transcrânien Seiler, J Neurosurg, 1986

VELOCITES MOYENNES VASOSPASME

80 - 120 cm/s Discret

120 - 200 cm/s Modéré

> 200 cm/s Sévère

Augmentation > 50 cm/s/j ATTENTION

Lindegaard (Vm ACM / Vm ACI)

> 3 Vasospasme

> 6 Vasospasme sévère

Lindegaard, Acta Neurochir, 1988

Monitoring non-invasif

Doppler transcrânien

Problèmes: intermittent (=> monitoring continu)

interprétation difficile / opérateur dépendant ++

faible sensibilité (50-67%)

exploration des gros vaisseaux

Monitoring non-invasif

cEEG / qEEG:

Diminution de l’amplitude du signal EEG;

Labar, EEG clin Neurophys, 1991

Diminution relative de l’activité α (6-14 Hz).

Vespa, EEG clin Neurophys, 1997

Diminution du ratio Alpha/Delta (ADR).

Claassen, Clinical Neurophysiology, 2005

Monitoring non-invasif

cEEG / qEEG:

Monitoring non-invasif

cEEG / qEEG:

Monitoring non-invasif

cEEG / qEEG:

♀ 57years. SAH/PCoA. Hunt–Hess grade 4

Post-op (SAH day 2) GCS14, no infarct on CT[…]

SAH day 6: ADR progressively decreased […]

Flow velocities in the right MCA were marginally

elevated (144 cm/s).

SAH day 7: GCS dropped from 14 to 12

=> CTscan + Angiography: vasospasm ++

=> intra-arterial Papaverine/Nicardipine

Monitoring non-invasif

NIRS:

(A) 6 patients (5 WFNS V and 1 WFNS II): only

small changes in CoSO2 (5%) / No vasospasm

on DSA;

(B) 8 patients (5 WFNS V and 3 WFNS II)

showed decreases in CoSO2 by more than 5%

reduction between 5 and 9 days after SAH. 6

exhibited severe vasospasms extending to the

peripheral MCA on DSA. TCD failed to detect in

4 cases.

(A)

(B)

Monitoring invasif

Microdialyse:

15 patients

J Neuroradiol. 2005 Dec;32(5):348-51.

Monitoring invasif

Multimodal

Hourly means ± SD of microdialysis and

PbtO2 measurements 24-hours preceding

CT-scans

- without new infarction (N = 55),

- with new ipsilateral frontal infarction (N = 8)

- with new infarction distant to the monitoring

devices (N = 4)

Biologie

Protéine S100b

LCR Wiesmann, Acta Neurochir, 1997

Plasmatique Takayasu, J Neurosurg, 1985

Autres:

F2-IsoPs LCR Lin, Free Rad Biol Med, 2006

Axe hypothalamo-hypophysaire ? Weant, Neurosurgery, 2008

…

Imagerie

Polygone Angio-imagerie

Micro-circulation (?) Imagerie de perfusion

• Imagerie de premier passage d’un bolus intraveineux d’un agent

exogène non diffusible ( pdc iodé ) dans le réseau capillaire

encéphalique

• Paramètres hémodynamiques cérébraux

• Données qualitatives : cartographies

• Données quantitatives.

TDM perf

TDM perf

TDM perf: cartographie

TDM perf = données quantitatives

Ca bloqueurs: Nimodipine NIMOTOP®

Kazda, Acta Neurochir, 1982 (7 essais randomisés depuis)

→ IVSE / relais Per Os dès que possible

Optimisation rhéologique…

…3H thérapie ? (Hypertension-Hypervolémie-Hémodilution)

Traitements médicaux

3H thérapie (préventive / curative)

• Aucun essai contrôlé randomisé montrant bénéfice.

• Tendance actuelle =

– Normovolémie

– Hypertension contrôlée PAM ≈ 100mmHg - 120mmHg

– Hémodilution est très discutable

– +/- monitoring hémodynamique

Traitements médicaux

• Ca bloqueurs: Nicardipine Haley J Neurosurg 1993

• Antagonistes des rNMDA: SELFOTEL ® Grotta, Stroke, 1995

• Antagonistes des rETA: CLOZANTAN ® Barth, Acta Neurochir, 2007

• Free radical scavengers: FREEDOX® Kassell J Neurosurg 1996

• Nitroprussiate intratéchal Thomas, Stroke, 1999

• Magnésium Veyna, J Neurosurg, 2002

• HBPM Wurm, Clin Neurol Neurosurg, 2004;

• Statines Vergouwen, Stroke, 2010

…

? ? ?

Traitements médicaux

Traitements chirurgicaux

• Epuration des espaces sous-arachnoïdiens (mécanique,

fibrinolytiques, drainage LCR).

• Sympathectomie cervicale Hori, Acta Neurochir, 1979

• Pontages intra-extracrâniens Batjer, Neurosurgery, 1986

• Stimulation du ggl sphénopalatin Yarnitsky, Surg Neurol, 2005

Takahashi, J Neurosurg, 2010

Traitements interventionnels

Traitements endovasculaires

• Angioplastie mécanique;

• Vasodilatation pharmacologique in-situ

• …

Traitements interventionnels

Angioplastie transluminale mécanique

• Zubkov, Acta Neurochir, 1984.

• Muizelaar, J Neurosurg, 1999.

• Rationnel: endommagement vasculaire / destruction des fibres de

collagène et des myocytes Smith, J Vasc Interv Radiol, 2000.

• Pb: complications rares mais généralement dramatiques…

Traitements interventionnels

Papaverine intra-artérielle:

Un des premier produit utilisé.

Nombreuses publications concernant des effets délétères

Mathis, Neuroradiology, 1997

Polin, Neurosurgery, 1998

Smith, Stroke, 2004

…

Traitements interventionnels

Smith, Stroke, 2004

Traitements interventionnels

Papaverine intra-artérielle:

Traitements interventionnels

Ca bloqueurs intra-artériels:

Nimodipine NIMOTOP Biondi, AJNR, 2004

Nicardipine LOXEN Badjatia, AJNR, 2004

Inhibiteur PDE-3 intra-artériels:

Milrinone COROTROPE ® Khajavi, Neurosurgery, 1997

Amrinone INOCOR ® Yoshida, AJNR, 1997

Autres molécules de mecanisme d’action similaire non rapportée dans

le ttt du vasospasme post-HSA:

Enoximone

Imazodan

Piroximone

Traitements interventionnels

Traitements interventionnels

Traitements interventionnels

Contrôle HSA CORO cisternal CORO ia

Histologie tronc basilaire

HES

Immuno

Histo

AMPc

Animaux tués à J7 (après ttt le cas échéant)

Traitements interventionnels

Déficit Neurologique

Ischémique Différé

Infarctus

cérébral

TDMDTCClinique

Pas d’argument

Surveillance

≥ 1 argument

Artériographie

conventionnelle

Echo cœur

Optimisation volémie

Pas de

vasospasmeVasospasme

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