Stroke is a major cause of death worldwide. Fortunately, reperfusion therapies have changed the outcome of many patients with acute ischemic stroke, preventing death and incapacity. Although intravenous (IV) recombinant tissue plasminogen activator (rtPA) is safe and effective in reducing disability in patients with acute ischemic stroke, several limitations prevent its more widespread use, including its narrow therapeutic time window and poor effect in the recanalization of large vessels. Recently, endovascular therapy has been proven a safe and effective therapy for patients with large vessel occlusion who do not respond to or are ineligible for IV thrombolysis. The pivotal clinical trials of mechanical thrombectomy for acute ischemic stroke focused on a time window of up to 6 to 8 hours from symptom onset and have used a broad range of neuroimaging modalities for patient selection.
More recently, the concept of “tissue window” versus time window has proved useful for selecting patients for mechanical thrombectomy up to 24 hours from symptom onset. An essential premise in the development and optimization of endovascular therapies for acute ischemic stroke is the notion of ischemic penumbra, essentially described as the area of brain tissue that is still viable but is critically hypoperfused and will progress to infarct in the absence of timely reperfusion (case 4-1). Even though the paradigm of “time is brain” has been vital to strengthen the importance of rapid treatment in acute stroke, several investigations have demonstrated that other factors contribute to the degree of ischemic injury at any point in time. The different behaviors relative to the time/ischemia construct are now better delineated, allowing for the possibility of improving the selection of patients for acute reperfusion therapies. This article reviews the indications and supporting evidence for endovascular therapy in acute ischemic stroke as well as how this treatment can be offered to a greater number of patients after the linear concept of time of ischemia has evolved into the tissue window paradigm.
A 50-year-old man with a history of hypertension and diabetes mellitus had a sudden onset of dysarthria, left hemiplegia, hemineglect, and sensory loss. His daughter witnessed the first symptoms, but as they live in a rural area, he arrived at the hospital 11 hours after symptom onset.
His National Institutes of Health Stroke Scale score at hospital admission was 17. His noncontrast head CT had an Alberta Stroke Program Early CT Score (ASPECTS) of 6 (hypodensities at the caudate, lentiform nucleus, insula, and internal capsule). CT angiography confirmed a right middle cerebral artery occlusion with excellent collateral flow (score of 3 in the Souza collateral grading system) (figure 4-1). His core ischemic lesion was 18 mL (cerebral blood flow, less than 30%), and his hypoperfused area was 201 mL (mismatch ratio, 11.2). He was successfully treated with mechanical thrombectomy (modified thrombolysis in cerebral infarction [TICI] score, 3) (figure 4-2). His modified Rankin Scale score at discharge was 2 (mild left hemiparesis, 4/5 muscle strength).
This case illustrates the notion of the ischemic penumbra. Even in a late time window (11 hours after symptom onset), based on the presence of salvageable tissue determined by the use of advanced neuroimaging, this patient was successfully treated with mechanical thrombectomy.
DEFINING THE ISCHEMIC PENUMBRA
Following an intracranial large vessel occlusion, three zones of injury can be identified: the ischemic core zone (tissue irreversibly injured even if blood flow is reestablished), the ischemic penumbra (ischemic but still viable cerebral tissue that is the main target of reperfusion therapy), and the zone of benign oligemia (an area with a milder reduction in tissue perfusion that does not actually place the tissue at risk) (figure 4-3).
In the ischemic core zone, blood flow less than 10% to 25% of the normal cerebral blood flow with consequent loss of oxygen and glucose results in rapid depletion of energy stores, leading to necrosis of neurons and glial cells. It is estimated that 1.9 million neurons are lost during each minute of ischemia. The duration of the penumbra in humans varies substantially, depending on factors such as degree of collateral blood flow supply, cerebral perfusion pressure, susceptibility of tissue to ischemia and ischemic preconditioning, location of the vessel occlusion, and other specific factors such as hyperglycemia, body temperature, and oxygen delivery capacity (case 4-2). Nonetheless, cells in the penumbra area will eventually die if perfusion is not reestablished because collateral circulation is inadequate to maintain the neuronal demand for oxygen and glucose indefinitely.
A 62-year-old woman with a history of atrial fibrillation and dyslipidemia was admitted to the hospital 5 hours after the sudden onset of a mild expressive aphasia and a right facial droop.
Her National Institutes of Health Stroke Scale (NIHSS) score at admission was 3. Her noncontrast head CT had an Alberta Stroke Program Early CT Score (ASPECTS) of 8 (hypodensities at the caudate and left M4). CT angiography confirmed a left middle cerebral artery occlusion with excellent collateral flow (score of 3 in the Souza collateral grading system). Her core ischemic lesion was 5 mL (cerebral blood flow, less than 30%) and her hypoperfused area was 6 mL (mismatch ratio, 1.2) (figure 4-4). The patient was admitted to the stroke unit and managed conservatively.
Nine hours after hospital admission, the patient became aphasic and developed a right hemiplegia (NIHSS score, 18). Given the severe clinical deficits, CT perfusion was not repeated, and she was immediately treated with mechanical thrombectomy with a modified thrombolysis in cerebral infarction (TICI) score 2b recanalization (figure 4-2).
A follow-up MRI showed a 30-mL infarct in the left middle cerebral artery territory. Her 3-month modified Rankin Scale score was 3.
This case illustrates the dynamic of the collateral circulation in acute ischemic stroke. The patient initially had mild neurologic symptoms despite a large vessel occlusion; therefore, mechanical thrombectomy was not offered. Even with the best medical treatment, collateral failure happened 9 hours after hospital admission. Neurologic surveillance was of utmost importance in this case, as it allowed quick identification of worsening and immediate reperfusion therapy.
In patients with proximal cerebral artery occlusions, no single practical and reliable imaging biomarker predicts infarct growth into the surrounding penumbra; however, the principles of clinical-imaging mismatch and perfusion-imaging mismatch have revolutionized the evaluation of patients with acute ischemic stroke.
UNDERSTANDING THE COLLATERAL CIRCULATION
Survival of brain tissue supplied by an occluded or very stenotic artery depends on (1) the status of the obstruction (circulation may be restored either spontaneously or by active treatment to dissolve or mechanically remove the blockage); (2) in case of partial occlusions, the ability of the systemic circulation to adequately supply the ischemic region through augmented flow either spontaneously or through therapeutic interventions such as induced hypertension; and (3) the presence and strength of collateral blood supply.
The cerebral collateral circulation constitutes an adjuvant chain of vascular pathways that sometimes preserve cerebral perfusion when the primary vessel supplying the region in question becomes occluded. Hypoperfusion due to hemodynamic failure, thrombotic or embolic events, or a combination of these factors may result in the recruitment of collaterals. Recruitment of collateral circulation possibly relies on the chronological course of several compensatory metabolic, hemodynamic, and neural responses. The persistence of these protective vascular channels may influence the severity of the ischemic injury.
Collateral circulation comprises extracranial sources of cerebral blood flow and intracranial pathways of ancillary perfusion. Cerebral collaterals can be broadly divided into the short bypass segments at the circle of Willis and the elongated leptomeningeal anastomotic routes able to deliver retrograde perfusion to adjacent vascular territories. The term primary collaterals refers to the circle of Willis, secondary collaterals to the ophthalmic and leptomeningeal arteries, and tertiary collaterals to newly developed vessels through angiogenesis.
Blood flow through the anterior communicating artery and reversal of flow in the proximal anterior cerebral artery can provide collateral support in the anterior portion of the circle of Willis. The posterior communicating arteries can equally provide flow in one or the other direction between the anterior and posterior circulations. Blood flow reversal within the ophthalmic artery is an important source of secondary collateral support in cases of proximal carotid occlusion. Distal anastomoses can provide an alternative supply into a major arterial territory, mostly between the anterior, middle, and posterior cerebral arteries but also across the cerebellar arteries in case of vertebrobasilar disease. The leptomeningeal collateral circulation is a chain of blood vessels supplying the brain that follows a diffuse course over the superficial surface of the brain. Within major pial arterial territories, microscopic anastomoses may help regulate alternative vascular supply to local cortical tissue fields.
The anatomy of the circle of Willis varies considerably. Anatomic studies describe an azygos anterior communicating artery (unpaired anterior communicating artery) in up to 5% of patients, absence of the anterior communicating artery in 1% of patients, absence or hypoplasia of the proximal anterior cerebral artery in 10% of patients, a fetal posterior circulation artery (arising from the internal carotid arteries) in 20% to 30% of patients, and absence or hypoplasia of either posterior communicating arteries in 30% of patients.figure 4-5 summarizes the collateral circulation of the brain. Such anatomical variations may become even more important when blood flow is dependent on collaterals.
The collateral circulation also has long been recognized as a factor in modifying stroke risk in patients with carotid stenosis. Collateral capacity in patients with internal carotid artery (ICA) occlusive disease as measured by angiography predicts the presence of CT infarction in patients with transient ischemic attacks. In one study, the absence of collateral flow in patients with ICA occlusions as measured by angiography correlated with low oxygen extraction fraction on positron emission tomography (PET) scanning and increased frequency of brain infarcts. In a series of patients with unilateral ICA occlusions, the presence of a posterior communicating artery that measured at least 1 mm correlated with the absence of border-zone hemispheric infarction.
The natural history of proximal intracranial arterial occlusion usually indicates a poor outcome. However, clinical severity at presentation (eg, baseline National Institutes of Health Stroke Scale [NIHSS] score) and the presence of collateral flow seem to be more important than the level of proximal intracranial arterial occlusion in determining the prognosis. In other words, an occlusion of the middle cerebral artery (MCA)-M2 segment in a patient presenting with an NIHSS score of 14 and poor collaterals will, in general, have a worse outcome than an occlusion of the ICA terminus in a patient presenting with an NIHSS score of 6 and good collaterals. Collateral circulation has also been found to be important in determining the outcome of various acute reperfusion treatments (IV and intraarterial thrombolysis and mechanical clot retrieval) in patients with acute brain ischemia. The presence and adequacy of collateral circulation supplying the brain distal to arterial occlusions is a key prognostic factor. In several studies, delayed recanalization together with poor collateral vessels correlated with poor outcome when compared with early recanalization and good collaterals. Conversely, patients with acute ischemic stroke presenting at later time windows may still benefit from endovascular therapy if good collaterals are present. This highlights that, although time to treatment is, on average, a good predictor of treatment response, it should not dictate treatment decisions in isolation because collateral flow prolongs the time of tissue viability.
The role of collateral circulation in selecting patients for endovascular therapies should not be underestimated. An accurate assessment of the cerebral collateral circulation is a very important prerequisite for the appropriate management of patients with acute ischemic stroke. Recently, various imaging criteria have been developed to grade the collateral status in patients with stroke. The structure of the cerebral collateral circulation can be assessed by using transcranial Doppler (TCD), transcranial color-coded duplex ultrasonography, CT angiography (CTA), MR angiography (MRA), and digital subtraction angiography (DSA).
TCD is a noninvasive method that can measure real-time cerebral blood flow velocities, collateral status, and cerebrovascular reactivity. However, the accuracy of TCD in diagnosing vessel occlusion and collateral status highly relies on the experience of the examiner. MRA is also noninvasive and can be used to evaluate the structure of cerebral collateral circulation. The accuracy of time-of-flight MRA to evaluate leptomeningeal collaterals is limited because of its relatively low spatial resolution. Moreover, evaluating unstable patients with acute ischemic stroke by using MRI can be cumbersome because of longer examination times and the inability to evaluate patients with a metallic prosthesis or pacemaker. Recent advances in 7-Tesla MRI have made possible the evaluation of pial branches in cerebral arterial disease, opening a new avenue for assessing leptomeningeal collaterals with high-resolution MRA. However, this technique is not feasible in the acute setting.
CTA is another noninvasive method that has a high accuracy in assessing the presence of proximal arterial occlusions. Because blood flow via collaterals may be delayed when compared with normal antegrade flow, traditional single-phase CTA may miss the more delayed phases required to optimally capture collateral opacification and, as such, may underestimate collateral flow. In order to overcome this limitation, multiphase CTA (or dynamic CTA) is being increasingly used to assess cerebral collateral status.
DSA is the gold standard to evaluate the collateral anatomy and dynamics. The most largely recognized grading system for collaterals on DSA is the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology collateral scale that classifies the cerebral collateral status to grades 0 to 4 (table 4-1). Grades 0 and 1 are considered poor, grade 2 is moderate, and grades 3 and 4 are good collateral flow.
Several CTA-based collateral scales are useful in predicting the volume of infarct core and the perfusion to diffusion mismatch ratio within the first few hours after an ischemic stroke. Some examples of collateral grading methods based on CTA are shown in table 4-2.
NEUROIMAGING FOR SELECTING PATIENTS FOR ACUTE ENDOVASCULAR THERAPIES
The baseline Alberta Stroke Program Early CT Score (ASPECTS) is a well-known predictor of outcome in patients with acute ischemic stroke. Originally developed for standardized lesion assessment on noncontrast CT, it is a 10-point scoring system with anatomic regions distributed over the MCA territory. Many of the pivotal randomized controlled trials that demonstrated a strong positive effect of mechanical thrombectomy using stent-retriever devices on clinical outcomes used a noncontrast CT ASPECTS for patient selection. Of note, the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) did not use an ASPECTS threshold for patient exclusion and showed a consistent additional effect of intraarterial treatment over all ASPECTS ranges analyzed (0 to 4, 5 to 7, 8 to 10). However, only 30 patients with an ASPECTS of 0 to 4 were evaluated in the trial. A meta-analysis from five early-window thrombectomy trials suggested that, although a lower baseline ASPECTS was strongly associated with lower rates of favorable outcomes, a similar benefit was conferred in patients with an ASPECTS of 9 to 10 and those with an ASPECTS of 6 to 8. However, the effect of endovascular thrombectomy in patients with a baseline ASPECTS of 5 or lower could not be established because most trials excluded such patients (case 4-3). A recent multicenter, pooled analysis of seven institutional prospective registries of patients presenting with an ASPECTS of 0 to 5 who were treated with mechanical thrombectomy showed that successful reperfusion was beneficial without increasing the risk of symptomatic intracerebral hemorrhage, suggesting that a formal clinical trial of mechanical thrombectomy versus best medical treatment in these patients is justified.
A 72-year-old man was admitted to the hospital 4 hours after a sudden onset of left hemiplegia and hemineglect, dysarthria, and forced eye deviation to the right.
His National Institutes of Health Stroke Scale score at hospital admission was 22. His noncontrast head CT had an Alberta Stroke Program Early CT Score (ASPECTS) of 4. CT angiography confirmed a right middle cerebral artery (MCA) occlusion with very poor collateral flow (score of 0 in the Souza collateral grading system) (figure 4-6). His core ischemic lesion was 62 mL (cerebral blood flow, less than 30%), and his hypoperfused area was 114 mL (mismatch ratio, 1.8).
He was treated with IV recombinant tissue plasminogen activator (rtPA) with no improvement. Mechanical thrombectomy was not offered based on the poor collateral flow profile. The patient developed a malignant MCA syndrome. His family decided against hemicraniectomy and comfort measures only were instituted. The patient died 7 days after hospital admission.
This patient had a malignant collateral profile, and, therefore, mechanical thrombectomy was not offered. It is still a matter of controversy of how to treat patients with large cores and large mismatch ratios. Future studies need to address the role of intravenous and endovascular recanalization in this patient population.
The original ASPECTS has some important limitations: interrater reliability is low even among experienced physicians; cerebral small vessel disease and movement of the patient can influence interpretation; most importantly, the template is based on anatomical structures, and, thus, the individual regions cover different amounts of brain tissue with varying degrees of tissue eloquence, and so the score is not a linear scale. Therefore, infarct location and laterality, and not just infarct volume, impact clinical outcomes and can provide additional prognostic value in patients with acute intracranial vessel occlusion.
CT perfusion (CTP) is a widely accessible method and can be combined with nonenhanced CT and CTA data, especially in patients with anterior circulation stroke. CTP requires a 35- to 50-mL bolus of iodinated contrast delivered by power injection into an antecubital vein and a dynamic cine image acquired after a 5- to 7-second delay after the contrast injection. CTP coupled with CTA provides a broad assessment of collateral circulation and functional and anatomic aspects. The physiologic data derived from CTP are displayed in perfusion maps, including cerebral blood flow, cerebral blood volume, and mean transit time. Brain regions with critically reduced cerebral blood volume or cerebral blood flow coincide with the core of the infarction. Areas with prolongation of the mean transit time or its inferred parameters (time-to-peak and time-to-maximum) have been shown to appropriately quantify the penumbra in patients with acute ischemic stroke. It is important to be aware of CTP limitations because delayed cerebral tissue iodine saturation could occur in the setting of cardiac arrhythmias, low cardiac output, cervical internal carotid artery stenosis, or a mixture of these factors, which are not uncommon in patients with acute ischemic stroke.
The success of the pivotal clinical trials demonstrating the efficacy of endovascular stroke therapy is mostly attributable to the use of next-generation mechanical thrombectomy devices, resulting in better recanalization rates, and to more rigid neuroimaging criteria for the choice of endovascular treatment candidates. The SWIFT PRIME (Solitaire With the Intention For Thrombectomy as PRIMary Endovascular Treatment) and EXTEND-IA (Extending the Time for Thrombolysis in Emergency Neurological Deficits–Intra-Arterial) trials included an assessment of penumbra, largely by CTP. Interestingly, both trials had the best outcomes in patients undergoing endovascular treatment within 6 hours from symptom onset with functional independence at 3 months of follow-up in 60% in the SWIFT PRIME trial and 71% in the EXTEND-IA trial. CTP is definitely not essential for endovascular reperfusion candidates in the 0- to 8-hour time window. However, the higher proportion of good outcomes in the trial that used CTP as a selection tool suggests that CTP might be helpful in choosing patients with higher chances of benefiting from the treatment. One should be aware that CTP may cause significant delays in workflow due to the longer acquisition and processing times, and it does not invariably provide accurate information, resulting in both overestimation and underestimation of ischemic core. Furthermore, the adoption of strict CTP criteria might lead to overselection by excluding many patients for whom endovascular therapy could be beneficial.
The use of MRI as a neuroimaging method for hyperacute stroke has been incorporated by some stroke centers. Current stroke MRI protocols can be performed in only 5 to 20 minutes. The diffusion-weighted image lesion volume is directly associated with the degree of collateral flow in acute ischemic stroke. Large lesion volumes and cortical lesion patterns (regardless of the lesion volume) on diffusion-weighted imaging are frequently found in patients with poor collaterals. Even though diffusion-weighted imaging is a more reliable marker for ischemic core than CTP, diffusion abnormalities can still be reversed and fully salvaged with rapid reperfusion in some patients. Therefore, it is important to continue to study patients undergoing reperfusion to establish models that can better predict what will happen in the best-case scenario of early and sustained recanalization.
AUTOMATED PERFUSION READING
Negative trials using the “mismatch” concept have suggested that visual assessment can be unreliable and that thresholds are required to better distinguish benign oligemia from critical hypoperfusion and ischemic core in patients with acute ischemic stroke. Several studies have shown that automated processing of CTP and MRI can provide a quantitative mismatch classification even among inexperienced neuroimaging centers (case 4-1, case 4-2, and case 4-3). Furthermore, in clinical practice, automated CTP processing seems to improve diagnostic confidence by eliminating the need for postprocessing and thus increasing reproducibility of interpretation. Therefore, less experienced centers can take better advantages of its use.
The higher rates of good outcomes in the trials that used automated perfusion reading of CTP in the classical time window of 6 hours from symptom onset (SWIFT PRIME and EXTEND-IA) when compared with those that mainly used noncontrast CT ASPECTS (REVASCAT [Endovascular Revascularization With Solitaire Device Versus Best Medical Therapy in Anterior Circulation Stroke Within 8 Hours], ESCAPE [Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke], and MR CLEAN) suggest that refining selection with CTP imaging may optimize clinical results in the treated patients. However, it is important to understand a critical limitation of this finding because the outcomes were reported only for the treated patients meeting the inclusion criteria for the respective trials. Therefore, it becomes critical to account for the denominator effect. As more patients are excluded from treatment due to more strict selection criteria, the outcomes for the overall population that is initially considered for treatment might actually be worse than if simpler, faster, and more inclusive criteria are used. A simple illustration of this phenomenon is that the control population of EXTEND-IA (100% CTP selection) had better outcomes than the endovascular arm of MR CLEAN (very inclusive treatment criteria).
The time delays that can be potentially caused by CTP imaging, its costs and risks, and the chances of super-selecting patients for endovascular treatment should be further evaluated.
ENDOVASCULAR THERAPY WITHIN 6 HOURS FROM SYMPTOM ONSET
In 2015, the paradigm of acute ischemic stroke treatment for patients with large vessel occlusion shifted definitely to endovascular therapy. Six randomized controlled trials undoubtedly confirmed the benefits of using endovascular thrombectomy on the clinical outcome of patients with stroke compared with those receiving only standard medical care. The trials MR CLEAN, SWIFT PRIME, and EXTEND-IA proved the benefit of mechanical thrombectomy in anterior circulation acute ischemic stroke within the first 6 hours of symptom onset. The THRACE trial (Trial and Cost Effectiveness Evaluation of Intra-arterial Thrombectomy in Acute Ischemic Stroke) added further evidence for thrombectomy up to 5 hours from symptom onset. Finally, the ESCAPE and REVASCAT trials proved the benefit of mechanical thrombectomy for patients with anterior circulation acute ischemic stroke up to 8 hours from symptom onset.
In a meta-analysis of individual patient data (including MR CLEAN, REVASCAT, ESCAPE, SWIFT PRIME and EXTEND-IA [HERMES]), the number needed to treat with endovascular thrombectomy to reduce disability by at least one level on the modified Rankin Scale score for one patient was 2.6. Furthermore, HERMES corroborated the benefit of endovascular thrombectomy across a range of subgroups, including in patients not receiving IV rtPA, elderly patients, and patients arriving later than 5 hours from stroke symptom onset. Based on the selection criteria and results of the six trials discussed herein, the American Heart Association recommends that patients should receive mechanical thrombectomy with a stent retriever if they meet all the criteria described in table 4-3.
The use of mechanical thrombectomy in patients with MCA M2 occlusions within 6 hours from symptom onset may be reasonable for carefully selected patients, as is its use in patients who have a prestroke modified Rankin Scale score greater than 1, ASPECTS less than 6, or NIHSS score less than 6. The benefit of mechanical thrombectomy in patients presenting within 6 hours from symptom onset and occlusion of the anterior cerebral arteries, vertebral arteries, basilar artery, or posterior cerebral arteries remains uncertain.
It is important to highlight that, in all trials previously described, patients received IV thrombolysis as a bridge to mechanical thrombectomy when eligible and that the chances of better outcomes at 90 days within the mechanical thrombectomy group declined with a longer time from symptom onset to arterial puncture. Therefore, observation after IV thrombolysis to evaluate clinical improvement before mechanical thrombectomy should not be performed.
The goal of mechanical thrombectomy should be to achieve reperfusion, not only recanalization. There are several reperfusion scores; however, the modified thrombolysis in cerebral infarction (TICI) score is currently the tool with a better correlation with clinical outcomes and should, therefore, be used (figure 4-2). The final objective of the mechanical thrombectomy procedure should be a reperfusion to a modified TICI score of either 2b or 3.
In all pivotal clinical trials of mechanical thrombectomy in acute ischemic stroke, stent retrievers were used. In the procedure, a catheter is advanced into an artery, and by using x-ray guided imaging, a stent retriever is inserted into the catheter. The stent reaches past the clot, expands to stretch the walls of the artery, and is retrieved, removing the clot. Direct aspiration thrombectomy as first-pass mechanical thrombectomy was proven to be noninferior to stent retrievers for patients treated within 6 hours from symptom onset. Therefore, both second-generation stent retrievers and aspiration devices can be used for mechanical thrombectomy in acute ischemic stroke. Stent retrievers can also be used in combination with aspiration techniques. Local expertise and availability will influence the decision to use either technique (figure 4-7 and figure 4-8).
EXPANDING THE TIME WINDOW
Recently, two clinical trials completely disrupted the time window concept in acute ischemic stroke, showing excellent clinical outcomes in patients treated up to 24 hours from symptom onset. The DAWN (DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention) trial included patients at a median of 12.5 hours from onset and showed the largest treatment effect size in terms of functional outcome ever described in any acute stroke treatment trial (35.5% increase in functional independence). In DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3), patients treated with mechanical thrombectomy at a median of 11 hours after onset had a 28% increase in functional independence and an additional 20% absolute reduction in death or severe disability. These astonishing results led to the question of why the treatment effect was larger in the late-window trials, which has been called the late-window paradox. This is, in part, because large vessel occlusions can respond to IV rtPA, and because both DAWN and DEFUSE 3 randomly assigned patients only after 6 hours from the time last seen well, the vast majority of the controls did not have the benefit of IV rtPA. In fact, the controls of DAWN and DEFUSE 3 had the worst outcomes of any mechanical thrombectomy trial despite the fact that they had small infarcts on presentation. Another factor is that the growth of early ischemic lesions varies substantially among patients. Some patients with very poor collateral circulation develop large ischemic lesions in the first hours after symptom onset whereas other patients present with very small lesions even after 12 hours of stroke symptoms. In nonreperfused patients, lesion volumes usually reach their peak in 3 days. In the DEFUSE 2 study (Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution Study 2), about 30% of the patients presented with a medium growth range (3 mL/h to 10 mL/h), and only 20% had a malignant profile, and growth rates ranged from about 15 mL/h to as high as 100 mL/h. Both studies (DAWN and DEFUSE 3) used automated software to determine the ischemic core. Because of the requirement for small core volumes, most of the patients included in the DAWN and DEFUSE 3 studies had slow progressions. Considering that the median time from symptoms to enrollment was 12.5 hours in DAWN and 11 hours in DEFUSE 3 and core volumes were ≤10 mL, the early growth rates of the infarcts in both studies were ≤1 mL/h before enrollment. Therefore, both trials enrolled patients who were very slow progressors.
Interestingly, effectiveness of late-window thrombectomy was maintained across all subgroups, including those defined by time, age, mode of presentation, and ASPECTS. Patients with witnessed onset of symptoms at 6 to 24 hours derived comparable benefit to patients with wake-up stroke and unwitnessed mode of presentation.
CARE DURING AND AFTER MECHANICAL THROMBECTOMY
There is uncertainty if either general anesthesia or conscious sedation should be used in patients undergoing mechanical thrombectomy. Three single-center randomized clinical trials compared general anesthesia with conscious sedation during acute ischemic stroke endovascular procedures. In none of the trials was general anesthesia superior to conscious sedation for the primary end point, but patients treated with general anesthesia had better outcomes in several clinical secondary end points. However, many retrospective studies suggest that general anesthesia in patients undergoing mechanical thrombectomy is associated with worse functional outcomes, including a post hoc analysis of the MR CLEAN trial.
Blood pressure is probably the most important isolated parameter to be monitored during and after an endovascular procedure for acute ischemic stroke. From the periprocedural period to days later, the cerebral autoregulation is impaired, and the patient is susceptible to complications caused by transient changes in blood pressure levels. Many patients treated with mechanical thrombectomy will have been treated with IV thrombolysis and, therefore, should have their systolic/diastolic blood pressure maintained at ≤180/105 mm Hg. No randomized clinical trials have evaluated ideal blood pressure levels in patients undergoing mechanical thrombectomy. In the trials evaluating patients within 6 hours from symptom onset, as many patients were treated with IV rtPA, blood pressure was maintained at ≤180/105 mm Hg for 24 hours after the procedure. Normal blood pressure levels were recommended once recanalization was achieved in ESCAPE, as well as in the DAWN trial, which recommend systolic blood pressure <140 mm Hg for the first 24 hours in patients who achieve complete recanalization. The ideal blood pressure levels during and after mechanical thrombectomy deserve further investigation.
For patients with acute ischemic stroke and a large vessel occlusion in the proximal anterior circulation who can be treated within 6 hours of stroke symptom onset, mechanical thrombectomy with a second-generation stent retriever or a catheter aspiration device should be indicated whether or not the patient received treatment with IV rtPA in patients with limited signs of early ischemic changes on neuroimaging. Two clinical trials completely disrupted the time window concept in acute ischemic stroke, showing excellent clinical outcomes in patients treated up to 24 hours from symptom onset.
Outcomes after mechanical thrombectomy seem to depend on the interaction of several variables including infarct volume, regional eloquence, age, and baseline functional status. In patients with a mismatch (either clinical-imaging or perfusion-core mismatch), endovascular treatment initiated more than 6 hours and up to 24 hours from time last seen well is a highly effective therapy and not less effective than treatment within 0 to 6 hours. The safety profile in the late time window seems to be similar to mechanical thrombectomy performed in up to 6 hours from symptom onset. Effectiveness is maintained across all prespecified subgroups (across age, mode of presentation, and ASPECTS).
DAWN and DEFUSE3 had demonstrated a strong benefit of thrombectomy in properly selected stroke patients treated within the 6- to 24-hour window. However, as suggested by the large treatment effect size observed in both trials, the clinical-imaging mismatch and the perfusion-core mismatch criteria were very likely too stringent. Future studies should focus on better establishing the minimum boundaries of benefit in this patient population.
- Although IV recombinant tissue plasminogen activator (rtPA) is safe and effective in reducing disability in patients with acute ischemic stroke, several limitations prevent its more widespread use, including its narrow therapeutic time window and poor effect in the recanalization of large vessels.
- An essential premise in the development and optimization of endovascular therapies for acute ischemic stroke is the notion of the ischemic penumbra, essentially described as the area of brain tissue that is still viable but is critically hypoperfused and will progress to infarct in the absence of timely reperfusion.
- The different behaviors relative to the time–ischemia construct are now better delineated, allowing for the possibility of improving the selection of patients for acute reperfusion therapies.
- The duration of the penumbra in humans varies substantially, depending on factors such as degree of collateral blood flow supply, cerebral perfusion pressure, susceptibility of tissue to ischemia and ischemic preconditioning, location of the vessel occlusion, and other specific factors such as hyperglycemia, body temperature, and oxygen delivery capacity.
- In patients with proximal cerebral artery occlusions, no single practical and reliable imaging biomarker predicts infarct growth into the surrounding penumbra; however, the principles of clinical-imaging mismatch and perfusion-imaging mismatch have revolutionized the evaluation of patients with acute ischemic stroke.
- Cerebral collaterals can be broadly divided into the short bypass segments at the circle of Willis and the elongated leptomeningeal anastomotic routes able to deliver retrograde perfusion to adjacent vascular territories.
- The natural history of proximal intracranial arterial occlusion is usually that of poor outcomes. However, clinical severity at presentation (eg, baseline National Institutes of Health Stroke Scale [NIHSS] score) and the presence of collateral flow seem to be more important than the level of proximal intracranial arterial occlusion in determining the prognosis.
- An accurate assessment of the cerebral collateral circulation is a very important prerequisite for the appropriate management of patients with acute ischemic stroke.
- The success of the pivotal clinical trials demonstrating the efficacy of endovascular stroke therapy is mostly attributable to the use of next-generation mechanical thrombectomy devices, resulting in better recanalization rates, and to more rigid neuroimaging criteria for the choice of endovascular treatment candidates.
- CT perfusion might be helpful in choosing patients with higher chances of benefiting from the treatment. However, clinicians should be aware that CT perfusion may cause significant delays in workflow due to the longer acquisition and processing times, and it does not invariably provide accurate information, resulting in both overestimation and underestimation of ischemic core.
- Several studies have shown that automated processing of CT perfusion and MRI can provide a quantitative mismatch classification even among inexperienced neuroimaging centers.
- Recently, two clinical trials completely disrupted the time window concept in acute ischemic stroke, showing excellent clinical outcomes in patients treated up to 24 hours from symptom onset; effectiveness of late-window thrombectomy was maintained across all subgroups, including those defined by time, age, mode of presentation, and the Alberta Stroke Program Early CT Score (ASPECTS).
- Outcomes after mechanical thrombectomy seem to depend on the interaction of several variables including infarct volume, regional eloquence, age, and baseline functional status.
- The safety profile in the late time window seems to be similar to mechanical thrombectomy performed in up to 6 hours from symptom onset.
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