restoration of flow at the primary occlusion site AOL
 Reperfusion restoration of anterograde flow in the vessels beyond the primary occlusion site (anterograde perfusion) TICI
 Collateral circulation
retrograde perfusion
 Distal embolization new occlusion detected distal to the primary occlusion site
 Reocclusion closure of an already opened artery
Recanalization in acute stroke

Time is brain

  • most ischemic strokes are caused by occlusion of a cerebral artery (up to 80% according to angiographic studies) due to thrombosis or embolization with subsequent hypoperfusion of brain tissue
  • when blood flow decreases from normal values > 50ml/100g/min to values between 12-18 ml/100g/min, reversible functional impairment (penumbra) occurs
  • if perfusion decreases to <10 ml/100g brain tissue/min, irreversible changes follow (necrotic core)
    • about 2 million brain cells are lost every minute
  • penumbral neurons remain viable for minutes to hours (individual therapeutic window) after artery occlusion, and the process is reversible with early reperfusion
  • the mainstay of acute stroke treatment is early recanalization of the occluded artery and achieving anterograde reperfusion to rescue hypoperfused tissue
  • in summary, the best outcome is achieved in patients with good collateral circulation and large penumbra in whom rapid recanalization is achieved
Recanalization in acute stroke

Prognostic factors of a good outcome

The chances for recovery depend on a number of controllable and uncontrollable prognostic factors

  • early recanalization and reperfusion are crucial to achieving good recovery
  • there is a strong correlation between recanalization and good outcome (OR for a good outcome is 4.4 for recanalization)  In recanalized patients, the OR for good clinical outcome is 4.43 [(Rha, Stroke 2007]    [Rha, 2007]
    • patients who recanalize are up to 13 times more likely to be independent at three months  [Smith,2004]  
  • mechanical thrombectomy (MT) has the highest recanalization potential
  • recanalization, however, does not always lead to clinical improvement because of:
    • distal embolization (16%)  [Janjua, 2008]
    • reocclusion (18%)
    • no-reflow phenomenon (blockage of microcirculation – absence of reperfusion)  (Schiphorst, 2021)
    • late reperfusion with HEB disruption ⇒ edema, hemorrhagic transformation of ischemia
Recanalised patients are up to 13 times more likely not to remain disabled after three months [Smith, 2004].
Recanalization therapy in acute stroke
  • advanced age is generally associated with a higher risk of stroke and a worse prognosis
  • patients without occlusion have a better prognosis than patients with proven artery occlusion (OR 5.0)
    • Clot Burden Score (CBS) <10 is associated with a lower chance of a good outcome compared to a CBS of 10
    • odds ratio (OR) is 0.09 for CBS ≤ 5; 0.22 for CBS 6-7 and 0.48 for CBS 8-9 [Puetz, 2008]
  • patients without proven arterial occlusion tend to have a lower baseline NIHSS (median 18 vs. 7)  [Derex, 2002]
  • the longer the thrombus, the lower the chance of achieving recanalization, with IVT having a minimal chance of recanalization for thrombi > 8mm      [Riedel, 2011]
  • NIHS score correlates with the likelihood of artery occlusion and is a predictor of outcome
  • NIHSS ≥ 10 ⇒ high probability of large vessel occlusion (LVO) [Nakajima, 2004]
  • the interval from stroke onset to the start of treatment (OTT) significantly influences the outcome
    • the sooner tPA is given, the greater the benefit; especially if started within 90 min
    • the chance for a good outcome is twice as high as when started within 90 min (OR 2.8) compared to beyond 181 minutes (OR 1.4);  hence the slogan “time is brain” [Hacke, 2004]
    • data from the IMS 3 trial suggest that every 30 min delay reduces the chance of a good outcome by 10%
  • at the same time, the earlier tPA is given, the greater the chance of recanalization (the composition of the thrombus and its “resistance” to tPA change in the first hours)
    • that is the reason why reduction of transport times and Door To Needle Time (DTN time) are required
  • the above also applies to mechanical thrombectomy → start ASAP!
Odds of a favourable 3-month outcome increased as OTT decreased (Hacke, 2004)
  • extensive early ischemic changes indicate severe stroke
  • ASPECT score correlates with the baseline NIHSS value and allows prediction of outcome and risk of symptomatic hemorrhage
    • the worse outcome can be expected with a score of ≤ 6
    • conversely, score ≥ 7 predicts a good response to reperfusion therapy (up to 3 times higher chance of achieving independence compared to score of ≤ 6) [Hill, 2003]

Overview of recanalization methods

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Recanalization therapy in acute stroke

  Intravenous thrombolysis (IVT)

Unselected patients ≤ 4.5 h from onset of stroke symptoms
  • alteplase (ACTILYSE) should be administered ASAP, even if mechanical thrombectomy is planned
  • an alternative to tPA in the < 4.5h window is tenecteplase (TNKase®) (AHA/ASA guidelines 2019 IIb-BR)
    • genetically modified tissue plasminogen activator with enhanced fibrin specificity, allowing bolus administration
    • NOR-TEST trial (bolus 0.4 mg/kg) demonstrated similar results to tPA
    •  EXTEND-IA TNK trial (0.25 mg/kg) showed better results than tPA in patients with LVO and subsequent MT – preferable according to  ESO guidelines 2021
  • TCD/TCCD monitoring increases the likelihood of recanalization during IVT, but the clinical benefit has not been demonstrated by studies ⇒ sonothrombolysis is not recommended outside clinical trials

→ intravenous thrombolysis
→ fibrinolysis and fibrinolytic drugs

Unselected patients > 4.5 h from onset of stroke symptoms
  • except for basilar artery occlusion (BAO), the effect of IVT > 4.5h was not demonstrated in unselected patients in RCTs
  • advanced imaging in the time window of > 4.5h is recommended (ESO guidelines 2021)
    • however, it seems safe to thrombolyse patients with wake-up strokes and a normal NCCT; similar outcomes in patients with witnessed-onset and wake-up strokes and normal CT were reported (Armon, 2019)
  • negative results with desmoteplase in time window 3-9h were published – DIAS 3  [Albers, 2015]   DIAS 4  [Kummer, 2016]
Patients selected by multimodal imaging (4.5-9 hours from onset/WUS/unclear time of onset)
  • advanced imaging modalities are used (CT/MR perfusion, MR DWI/FLAIR mismatch) – see below
  • according to the meta-analysis of the WAKE-UP, EXTEND, THAWS, and ECASS-4 trials, IVT is safe and effective in patients selected by advanced imaging [Thomalla, 2020]

  Endovascular treatment (EVT)

Mechanical thrombectomy (MT)
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Intra-arterial thrombolysis (IAT)
  • therapeutic window < 6h from onset of stroke symptoms
  • now virtually abandoned and replaced by mechanical thrombectomy
  • can be used as a supplement to MT (e.g., to treat distal embolizations)

  Emergent carotid endarterectomy (CEA)

  • can be considered in isolated symptomatic occlusion or significant ICA stenosis without concomitant intracranial artery occlusion (if the hemodynamic cause of the current deficit is assumed or proven by, e.g., TCCD) → see here

The purpose of multimodal imaging in patient selection

  • performing advanced imaging should not lead to a delay in the administration of IVT!
    • tPA bolus can be administered immediately after finishing NCCT; CTA/CTP is performed afterward
    • sometimes CTA/CTP can help to differentiate stroke mimics
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Assessment of therapy results

  • the effectiveness of treatment is represented by:
    • percentage of complete recanalizations with full distal reperfusion (TICI 3)
    • incidence of bleeding (asymptomatic and especially symptomatic)
    • clinical outcome ( mRS ≤ 2 is considered a favorable outcome)

angiographic grading of revascularization therapy

  • ODT  (Onset to Door)
  • DIT  (Door to Imaging)
  • DTN  (Door to Needle)
  • DPT  (Door to Puncture)
  • DRT  (Door to Reperfusion)
  • PRT  (Puncture to Reperfusion)
  • ORT  (Onset to Reperfusion)

Thrombolytic drugs

  • the commonly used thrombolytic agent is alteplase (tPA) (intravenously and intra-arterially)
  • as an alternative, tenecteplase (TNK) can be used (ESO guidelines 2021) (AHA/ASA guidelines 2019 IIb-BR)
  • administration of other thrombolytics is not yet recommended in routine clinical practice

→ fibrinolysis and fibrinolytic drugs

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