Acute stroke treatment Tim Harrington

Important concepts All time loss/wastage results in further neuronal loss/poorer outcome The rate at which neuronal loss occurs is highly variable variations in COW and pial collaterals Penumbra- injured but resurrectable brain Patient selection is critical and is still controversial CTP not reliable, MRP not readily available IV and IA have differing strengths and weaknesses

Variability and reversibility of focal cerebral ischaemia in unanesthetized monkeys Cromwell RM et al Stroke lab, Uni of Massachusetts Neurology October (10): ‘neurologic improvement was common after the release of occlusion. …frequent with 30-min and 4- hour occlusions …was observed even after 16 hours’

CONCEPTS INFARCT CORE ISCHAEMIC PENUMBRA

concepts Core of irreversible injury Penumbra sustained by peripheral collaterals: potentially salvageable with prompt institution of appropriate therapy

Aims Recannalisation Minimal delay Minimal Cx- nb sICH Optimise physiological parameters to minimise cerebral compromise

What do we know? Most of morbidity and mortality comes from large vessel occlusions - 46% of stroke involve large vessel occlusions and these have a poor prognosis (eg Basilar or ICA occlusion have 4.5 fold ↑ risk of death and 3 fold ↓risk of good outcome)- Smith WS et al Stroke 2009 Recanalisation associated with good outcome- 58 vs 25% Rha Stroke 2007 Higher rates of recanalisation with arterial embolectomy than IV tPA especially in the vessels that IV tPA is ineffective

Neuronal loss 32,000 neurones/min Average Individual rates are highly variable and depend mainly on quality/quantity of pial and other collateral other drivers of perfusion such as BP

Time A protocol that allows up to 4.5hrs does not mean that much time should be used up Procedural time is often one of the least important delays in achieving recannalisation

Time A successful acute stroke program will address delays throughout the treatment pathway Public information re nature of stroke and urgency Ambulance diversion to stroke centres Rapid triage and informing of relevant teams Imaging urgency Parallel arrangement of consent, ICU, aneasthetics, bloods whilst waiting for other steps

IV Thrombolysis Almost 20yrs old and still only <20% being treated in western countries- bolus + 1hr infusion Only requires NCCT for triage many contraindications- mainly re bleeding risk not effective in large vessels newer agents more fibrin specific eg Tenectoplase Advanced imaging hoping to improve pt selection

IV Thrombolysis 38% good outcome in NINDS in strokes selected for small size by clinical stroke score recannalisation <10% in ICA, <25% in M1 Approx 9% sICH Tenectoplase- ↑recannalisation, ↑neurological improvement Parsons et al rtPA approved to 4.5hrs

Patient selection Time is a poor surrogate for knowing an individual’s pathophysiology Assessing ‘penumbra’ CTA and CTP whilst not having full validation proving to be useful tools and readily available- adds about 15min to NCCT

NECT Haemorrhage Cytotoxic oedema Dense MCA sign

Lentiform nucleus

Insular stripe

Hyperdense MCA

MRI DWI measures “water motion” Ischaemia: normal cellular ion pumps (eg Na-K) fail Shift of water from extracellular to intracellular space Cytotoxic oedema Restricted diffusion

CT perfusion Can be used to measure perfusion parameters CBV CBF MTT

cerebral blood volume Volume of blood per unit of brain tissue 4-5mL/100g

cerebral blood flow Blood flow per unit of brain tissue per minute 50-60mL/100g/min

MEAN TRANSIT TIME Time difference between arterial inflow and venous outflow

CEREBRAL ISCHAEMIA Decreased CBF Cerebral autoregulation Capillary dilatation

CAPILLARY DILATATION Increased CBV Increased MTT

CRITICAL CBF LOSS Normally 20% Failure of autoregulation Reduction in CBV Reduction in CBF

Imaging the core MRI DWI Visible hypo- attenuation of NECT rarely reverses CBV abnormality on Perfusion

IMAGING THE PENUMBRA Increased MTT Normal CBV

CTA Site of occlusion length of occlusion Tandem lesions- ICA source of embolus Access issues

Level & Access

Imaging Core CBV or DWI Poor chance of good outcome if >25ml Almost no chance of good outcome if >70ml Severe perfusion changes predicts ICH TTP >14sec

Poor collateral/CTP 2hrs

Poor collaterals/CTP

Good collaterals/CTP at 8hrs

Good collaterals/CTP

IA therapy/embolecto my Stentriever- Solitaire, Trevo, others Direct aspiration- Penumbra Combination of above

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What do we know? iv tPA fails to recannalise in most large vessel occlusions-25% success in M1,10% for ICA Most patients do not receive iv tPA- at best 20% - time and other exclusions Imaging can select gps with salvageable brain beyond 3-4.5hr time window Abou-Chebl A Stroke 2010

Efficacy? Recannalisation rates of 80-90% Average times to recann. of 40min Frequent single pass recann-average no of passes 1.8

Outcomes Miteff F- mRS≤2 in 56% ant circ’n 16pts Galimanis A et al-623 pts prospective-48.9% Soize S et al-36pts prospective- 63.9% STAR- prospective registry multinational -58%

83yo female SUDDEN COLLAPSE DYSPHASIA

Blood volume

Mean transit time

PROCEDURE TIME: 15 MIN SINGLE PASS

IV vs IA IMS 111 failed but wrong devices used with unacceptable delays Randomised trials in US, Europe and Aus

Evolving Protocol Clinical then CT work-up NCCT,CTA,CTP IV rTPA in those suitable Endovascular immediately in those with large vessel occlusion

Treatment selection IV tPA has limit on size of vessel/thrombus it can dissolve longer than 8mm embolus has 0 recann should have occurred within 1hr of injection Quick and no skill in delivery, can be used after limited imaging( NCCT as per NINDS) ‘drip and ship’ model

Treatment selection Arterial treatment restricted to large vessels ICA, M1/2,Basilar these are most morbid strokes Technical issues/skill important access difficult in elderly- ?restrict to <80yrs Not interfered with by prior tPA and not limited by tPA limitations

Treatment synergy IV and IA are not really the competitors they are made out to be Interested in different vessels Extend IA- IV vs IV plus IA, similar UK/European studies IMS 111- poor devices and prolonged delays in IA Rx

Treatment selection IV thrombolysis- rTPA, tenectoplase IA stentriever aspiration IA thrombolysis

Thank You