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 occlusion 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 occur (necrotic core)
    • approx. 2 million brain cells are lost per minute
  • penumbral neurons remain viable for minutes to hours (individual therapeutic window) after arterial occlusion, and the process is reversible with early reperfusion
  • the mainstay of acute stroke treatment is early recanalization of the occluded artery and achievement of anterograde reperfusion to rescue hypoperfused tissue
  • in summary, the best outcome is achieved in patients with good collateral circulation and a large penumbra in whom rapid recanalization is achieved
Recanalization in acute stroke

Prognostic factors of a good outcome

The chances for recovery depend on many controllable and uncontrollable prognostic factors

  • early recanalization and reperfusion are crucial for a good outcome
  • 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 3 months  [Smith,2004]  
  • mechanical thrombectomy (MT) has the highest recanalization potential
  • recanalization, however, does not always result in clinical improvement due to:
    • distal embolization (16%)  [Janjua, 2008]
    • reocclusion (18%)
    • no-reflow phenomenon (microcirculation blockage with the 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].
  • the presence of viable hypoperfused tissue (penumbra) is a prerequisite for a successful treatment
  • detection of persistent penumbra (by CTP, PWI/DWI mismatch, or DWI/FLAIR mismatch) allowed treatment of patients beyond standard therapeutic windows
  • relevant trials:
  • another milestone was achieved by trials demonstrating the effect of thrombectomy within 24 hours, even in patients with large cerebral infarcts – these trials will significantly change current practice
  • 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 arterial 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]
  • NIHSS correlates with the likelihood of arterial occlusion and is a predictor of outcome
  • NIHSS ≥ 10 ⇒ high probability of large vessel occlusion (LVO) [Nakajima, 2004]
  • the interval from stroke onset to treatment initiation (OTT) significantly influences the outcome
    • the earlier tPA is administered, the greater the benefit, especially when started within 90 min
    • the chance for a good outcome is twice as high if treatment starts within 90 minutes (OR 2.8) compared to initiation beyond 181 minutes (OR 1.4);  hence the slogan “time is brain” [Hacke, 2004]
    • data from the IMS 3 trial suggest that each 30-minute delay reduces the chance of a good outcome by 10%
  • at the same time, the earlier tPA is administered, the greater the chance of recanalization (the composition of the thrombus and its “resistance” to tPA change in the first few hours)
    • for this reason, it is necessary to reduce transport times and Door-To-Needle Time (DTN time)
  • 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 a severe stroke
  • ASPECT score correlates with the baseline NIHSS value and allows prediction of outcome and risk of symptomatic hemorrhage
    • a score of ≤ 6 is associated with a worse outcome
    • conversely, a score of ≥ 7 predicts a good response to reperfusion therapy (up to 3 times greater chance of achieving independence compared to a score of ≤ 6) [Hill, 2003]
  • recent trials have shown the benefit of MT even in patients with low ASPECTS (SELECT2, ANGEL-ASPECT)

Overview of recanalization methods

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Intravenous thrombolysis (IVT)

Unselected patients ≤ 4.5 hours after stroke onset
  • 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 – preferred according to  ESO guidelines 2021
  • TCD/TCCD monitoring increases the likelihood of recanalization during IVT, but the clinical benefit has not been demonstrated in trials ⇒  sonothrombolysis is not recommended beyond clinical trials

→ intravenous thrombolysis
→ fibrinolysis and fibrinolytic drugs

Unselected patients > 4.5 h after stroke onset
  • except for basilar artery occlusion (BAO), the effect of IVT > 4.5h in unselected patients has not been demonstrated 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 normal NCCT; similar outcomes were reported in patients with witnessed-onset and wake-up strokes and normal CT  (Armon, 2019)
  • negative results have been published with desmoteplase in a 3-9 hour time window – DIAS 3  [Albers, 2015]   DIAS 4  [Kummer, 2016]
Patients selected by multimodal imaging (4.5-9 hours after stroke onset/WUS/uncertain 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 manage distal embolization)

Emergent carotid endarterectomy (CEA)

  • may be considered for 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

  • advanced imaging should not delay the administration of IVT!
    • bolus tPA can be administered immediately after finishing NCCT; followed by CTA/CTP
    • CTA/CTP may sometimes be helpful in the differentiating stroke mimics
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Evaluation of therapy results

  • treatment efficacy is represented by:
  • 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 most commonly used thrombolytic agent is alteplase (tPA) (intravenous and intraarterial)
  • alternatively, tenecteplase (TNK) may be used (ESO Guidelines 2021) (AHA/ASA guidelines 2019 IIb-BR)
  • the use of other thrombolytics is not yet recommended in routine clinical practice

→ fibrinolysis and fibrinolytic drugs

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Recanalization therapy in acute stroke