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Table of Contents
Year : 2021  |  Volume : 18  |  Issue : 3  |  Page : 166-171

New frontiers in acute stroke management

1 Department of Neurology, Indraprastha Apollo Hospital, New Delhi, India
2 Critical Care Medicine, Holy Family Hospital, New Delhi, India

Date of Submission16-Aug-2021
Date of Decision06-Sep-2021
Date of Acceptance06-Sep-2021
Date of Web Publication18-Sep-2021

Correspondence Address:
Pushpendra Nath Renjen
Indraprastha Apollo Hospital, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/am.am_98_21

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Ischemic stroke is a common emergency presentation to hospital with improving survival rates owing to access to specialist organized stroke care. The approach to the treatment of ischemic stroke has undergone great transformation over the past 20 years. The negativism of older times has given the way to proven treatment strategies to reverse ischemia and prevent patients from severe neurological disabilities or death. Acute stroke care has three main ideologies: (1) timely achievement of occluded artery recanalization and reperfusion of the part of brain that is ischemic, (2) optimization of collateral flow, and (3) avoidance of the secondary brain injury. In this review article, we will focus on the new developments in the management of acute stroke in the past decade.

Keywords: COVID-19, mechanical thrombectomy, stroke, thrombolysis

How to cite this article:
Renjen PN, Garg S, Mishra A, Chaudhari DM. New frontiers in acute stroke management. Apollo Med 2021;18:166-71

How to cite this URL:
Renjen PN, Garg S, Mishra A, Chaudhari DM. New frontiers in acute stroke management. Apollo Med [serial online] 2021 [cited 2021 Dec 6];18:166-71. Available from: https://www.apollomedicine.org/text.asp?2021/18/3/166/326244

  Introduction Top

Ischemic stroke is a common emergency presentation to hospital with improving survival rates owing to access to specialist organized stroke care. There has been considerable advancement in hyperacute stroke treatments in the past decade, which has resulted in improved outcomes and revolutionized acute stroke care from a disease with no treatment to one with multiple proven options.[1] The premise for acute stroke care is to salvage viable ischemic brain tissue (ischemic penumbra) surrounding the irreversibly injured core through reperfusion.[2] Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), a novel coronavirus, first emerged in Wuhan in December 2019 and has evolved into a pandemic which was declared on March 11, 2020.[3] There has been a great transformation in therapeutic approach to acute ischemic stroke over the past 20 years. The availability of established treatment options that can lead to reversal of ischemia and prevent death and even long-term disability in patients is nothing short of a miracle. The process of IV thrombolysis has been commonly implemented for the past 25 years. However, there is now clear evidence that combining endovascular treatment with mechanical thrombectomy can lead to better neurological outcomes in cases where there is a proximal intracranial vessel occlusion.[4]

The mainstays of treatment of acute stroke are recanalization and reperfusion which can reverse neurologic deficits and reduce infarct size. The degree of reopening of the occluded artery and the degree of flow reaching the previously hypoperfused brain region each defines recanalization and reperfusion, respectively. In majority of cases, there an ischemic penumbra is found which is the area of the brain that gets hypoperfused but is not yet infarcted. This tissue is called the ischemic penumbra. Opening the occluded artery promptly reestablishes the blood flow salvaging this area. This tissue at risk can be visualized by advanced brain imaging such as computed tomography (CT) perfusion or magnetic resonance (MR) diffusion/perfusion (penumbra imaging).[5] Two methods employed for achieving reperfusion are intravascular chemical thrombolysis using recombinant tissue plasminogen activator (rtPA), also called alteplase and mechanical embolectomy with a retrievable stent. These have shown proven benefit.[4] A known complication of these therapies is reperfusion injury which can present with hemorrhage and edema. The larger area of established infarction leads to more severe reperfusion injury. It is crucial to select appropriate patients, i.e., those with the absence of a large ischemic core to avoid this complication.

  COVID-19 and Stroke Top

COVID-19 is a SARS caused by a novel coronavirus now named SARS-CoV-2. In recent studies from three hospitals in Wuhan, China, up to 36% of COVID-19 patients manifest neurological symptoms.[6] SARS-CoV-2 infection has also been found to be associated with coagulopathy which causes venous and arterial thrombosis. SARS-CoV-2-associated prothrombotic state causing venous and arterial thromboembolism also leads to elevated D-dimer levels.[7] Proinflammatory cytokines associated with severe COVID-19 lead to endothelial and mononuclear cell activation with the expression of tissue factor which is responsible for coagulation activation and thrombin generation. Unchecked by natural anticoagulants, the circulating free thrombin can activate platelets and lead to thrombosis.[8] It is pertinent to be very careful while selecting acute ischemic stroke patients for mechanical thrombectomy given the difficulties associated with performing invasive procedures on patients suspected or confirmed with COVID-19. Patients who meet the inclusion criteria which were used in clinical trials should be chosen. More favorable outcome is also expected with procedures that can be initiated quickly and performed within a short time period.[6]

  Protected Pathways in the Emergency Room (ER) for Stroke Patients with COVID-19 Top

The current stroke protocols need to be adapted for ER to continue good-quality care of stroke patients and to ensure adequate protection of health-care workers and patients. Thus, patients without suspected infection need one pathway, whereas those with suspected or confirmed infection need a different pathway. Such pathways require the assessment of each patient for suspected or confirmed COVID-19 before admitting into ER. In the screening area, appropriate personal protection equipment must be worn by the health personnel, and a surgical mask worn by the patients all the time. As recommended by the International Expert Panel, it is compulsory to enforce these protected pathways for stroke patients with suspected or confirmed infection to continue good-quality standards of care. Aerosol-generating medical procedures need to be avoided in patients with confirmed or suspected COVID-19 and dedicated CT and US rooms for such patients should be provided. Inpatient telemedicine can be used to monitor the neurological function of these patients which will help reduce person-to-person contact.[9]

  Thrombolysis in Acute Ischemic Stroke Top

Ischemic stroke is a common emergency presentation to hospital with improving survival rates owing to access to specialist organized stroke care. There has been considerable advancement in hyperacute stroke treatments in the past decade, which has resulted in improved outcomes and revolutionized acute stroke care from a disease with no treatment to one with multiple proven options.[1] The premise for acute stroke care is to salvage viable ischemic brain tissue (ischemic penumbra) surrounding the irreversibly injured core through reperfusion.[10] Alteplase (recombinant rtPA) is the only Food and Drug Administration approved tissue plasminogen activator (tPA) in stroke. Unlike the previous thrombolytic agents such as streptokinase and urokinase, alteplase is a fibrin selective analog with a short half-life. It is given at a dose of 0.9 mg/kg up to 90 mg intravenously; 10% given as a bolus followed by infusion for 1 h. rTPA has proven to be beneficial in acute ischemic stroke within 3 h as evidenced by trials such as the European Collaborative Acute Stroke Study (ECASS), the National Institute of Neurological Disorders and Stroke. The ECASS III trial showed that patients who have clearly defined symptom onset between 3 and 4.5 h of onset of stroke benefit also from thrombolysis with alteplase (modified Rankin scale [mRS] 0–1 at 3 months).[11] [Figure 1] depicts the timeline of the evolution of thrombolytic and endovascular therapy in stroke [Figure 1].[11]
Figure 1: Timeline of major stroke trials. (Adapted from Ann Indian Acad Neurol, Vishnu VY, Padma Srivastava MV. Innovations in Acute Stroke Reperfusion Strategies. 2019;22(1):6-12)[13]

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The current guidelines recommend the use of IVT with alteplase (0.9 mg/kg) if treatment is rapidly delivered within 4.5 h of symptom onset, provided ICH has been appropriately excluded and delivery occurs within the context of an organized stroke service with skilled and trained staff to monitor for complications.[12] It should be noted that for the 3–4.5 h subgroup, caution needs to be applied, given that for each patient in whom treatment results in a good outcome (number-needed-to-treat [NNT] 19), one has a symptomatic ICH; therefore, the priority should be to deliver treatment as quickly as possible. The risks of fatal ICH are not insignificant (2%) with IVT and lower doses of alteplase (0.6 mg/kg) have been shown to reduce hemorrhage risk and early mortality but do not deliver equivalent efficacy to conventional doses (0.9 mg/kg).[13]

The WAKE-UP study tested the efficacy and safety of alteplase in MR imaging (MRI)-guided thrombolysis in patients with stroke of unknown time of onset (90% of which were wake-up stroke) using the concept of mismatch.[14] There was an 11% difference in a favorable outcome in preference to the alteplase group with a nonsignificant difference in symptomatic ICH (2% alteplase vs. 0.4% placebo). The NNT to afford favorable outcome in this trial was nine patients, highlighting potential expansion of the ischemic stroke population eligible for recanalization therapy.[10]

  Thrombolysis Beyond 4.5 Hours Top

Meta-analysis of individual patient data from three trials (EXTEND, ECASS-4, and EPITHET) has examined the merits of extending thrombolysis with alteplase to 4.5–9 h including wake-up stroke (9 h from mid-point of sleep) using perfusion imaging to identify salvageable tissue.[15] Two-thirds of the patients had large vessel occlusion (LVO) (but did not undergo MT) and 50% of patients had wakeup stroke. The odds of excellent functional outcome at 90 days were 1.86 (95% confidence interval [CI] 1.15–2.99) in favor of alteplase treatment, and this was consistent with age, time window (4.5–6 h, 6–9 h, and wake-up) as well as in the presence of LVO. A further recent meta-analysis of individual patient data involving alteplase for stroke with unknown time of onset guided by advanced imaging (WAKE UP, EXTEND, THAWS, and ECASS 4) showed an absolute 8% improvement in functional independence despite an increase in symptomatic ICH (3% vs. <1% in control arm).[16] These data suggest that IVT may be useful in bridging therapy in conjunction with MT within this specified time frame as well as being considered as stand-alone therapy in the absence of LVO. The combination of IVT and MT in an extended time window (4.5–24 h) is being tested in the TIMELESS trial using tenecteplase.[17]

  Emergence of Tenecteplase Top

No other thrombolytic agent except for alteplase is approved for use in ischemic stroke. Yet, the value of tenecteplase for treating acute cerebral ischemia patients shows new information. Tenecteplase is a modified form of rtPA but with a longer half-life, greater specificity for fibrin, and higher resistance against tissue plasminogen inhibitor-1.[4] The NOR-TEST (Norwegian Tenecteplase Stroke Trial) included ischemic stroke patients who presented within 4½ h of symptom onset and compared 0.4 mg/kg (up to 40 mg) dose of Tenecteplase versus the standard-dose rtPA.[18] It was given as a single IV bolus. The majority of study participants had mild stroke severity (median NIHSS score of 4). However, the percentage of patients with grave adverse effects such as intracerebral hemorrhage was similar in both groups. So was functional independence at 3 months. However, due to the trial having being designed only to test the superiority of one group over another, it was not possible to give the conclusion that therapy with rTPA and tenecteplase was equivalent. Another trial EXTEND-IA TNK (Tenecteplase Versus Alteplase Before Endovascular Therapy for Ischemic Stroke) compared the efficacy of tenecteplase with rtPA in patients of acute ischemic stroke and block of a proximal intracranial artery presenting in the window period of 4½ h and eligible for mechanical thrombectomy. They were randomly chosen to receive either of the two drugs. Tenecteplase was given at a dose of 0.25 mg/kg, up to 25.[19] They were evaluated with conventional angiography for recanalization/reperfusion which was found to be present in greater proportion in those who received tenecteplase (22% vs. 10% with rtPA). They also had better functional outcomes at 3 months with low rates of symptomatic ICH (1% in both groups). Thus, if these promising results are confirmed by future studies, tenecteplase may become a preferred alternative to rtPA.[4]

  Endovascular Therapy Top

Five trials in 2015 demonstrated the benefit of endovascular thrombectomy over standard medical treatment in patients who presented in the window period of 6 h and were diagnosed with LVO of the anterior circulation. These trials were the following “(Multi-center Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands [MR CLEAN]; Extending the Time for Treatment in Emergency Neurological Deficits-Intra-Arterial [EXTEND-IA]; Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times [ESCAPE]; Solitaire With the Intention For Thrombectomy PRIMary Endovascular Treatment [SWIFT PRIME]; and Randomized Trial of Revascularization with Solitaire FR Device vs. Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting within Eight Hours of Symptom Onset [REVASCAT]).”[20],[21],[22],[23],[24] Involvement of internal carotid artery (ICA) and or M1 branch of middle cerebral artery constitutes anterior circulation stroke. In a meta-analysis of the abovementioned studies, the proportion of functional independence (defined by the mRS score of 0–2) was found to be 46% in thrombectomy group, much more than the 27% found in medical therapy cohort. The NNT came out to be five.[25],[26]

The DAWN trial (“DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo”) used clinical-core mismatch imaging selection in patients presenting 6–24 h from the last time that they remember being asymptomatic. CT perfusion or diffusion MRI was used to identify a comparatively minor area of ischemic core, and it was correlated with the severity of neurological deficit.[27] Another trial named The DEFUSE 3 trial (“Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke”) included patients presenting 6–16 h since they recalled being asymptomatic. CT perfusion or MRI perfusion-diffusion mismatch was used and <70 mL of ischemic core along with the critically hypoperfused region being both >15 mL and >1.8 times the ischemic core was required.[28] In the DAWN and DEFUSE 3 trials, 2.8 and 3.6 were, respectively, the NNT for functional independence (defined as mRS score 0–2).[27],[28] Therefore, international guidelines recommend perfusion imaging selection for the selection of patients for thrombectomy presenting 6–24 h from the last time that they remember being asymptomatic.

Endovascular thrombectomy with or without Intravenous Alteplase in Acute Stroke (DIRECT-MT), a recently published trial, found that the group of patients who were treated with alteplase before thrombectomy showed a better rate of successful reperfusion. No significant differences in When it came to adverse effects including symptomatic intracerebral hemorrhage, it was similar between the groups.[29] The use of alteplase instead of the more effective thrombolytic tenecteplase also confounds the interpretation of the DIRECT thrombectomy trial[19] and potentially alters acute stroke workflow. In most cases, thrombolysis can be administered, whereas the decision of thrombectomy procedure is being made, however, in above trials, there is a delay in commencing thrombolysis as all imaging has to be finished, and the interventionist has to approve the patient for the procedure before they can be included in the study and finally undergo thrombolysis. This reduces the opportunity to induce reperfusion before thrombectomy.[25]

  Mobile Stroke Units Top

There is ample evidence that mobile stroke units (MSUs) are beneficial in decreasing time to reperfusion and eventual disability.[25] An MSU is actually an ambulance which has a CT scanner in it. There is also a specialized team on board for evaluating and managing patients in the public. Those who require thrombectomy are referred to higher centers. With the help of MSU, time saving of 42.5 min (95%CI: 36.0–49.0) in terms of an overall duration from initial dispatch of ambulance to taking place of thrombolysis and of 51 min (95%CI: 30.1–71.9) in duration between initial dispatch of ambulance and the beginning of thrombectomy (arterial puncture) was found in a study from Melbourne, Australia, in patients with large vessel obstruction.[30] Based on the time saved, the estimated disability reduction calculated came out to be 20.9 disability-adjusted life years for 100 patients in the thrombolysis group and 24.6 disability-adjusted life years in the thrombectomy group.[30]

  Clot-Based Radiomics and Endovascular Therapy Top

Recent studies show that successful recanalization is associated with vessel architecture at the place of blockade in the form of the angle of interaction between the aspiration catheter and the clot.[31] The outcome of recanalization with thrombolysis by alteplase can also be predicted by the texture of the clot, as reported by another recent study.[32] Radiomic features (RFs) may indicate important points as to the composition of the clot. Thus, radiological evaluation to determine RF before the procedure is undertaken can influence the outcome of mechanical thrombectomy.[33]

The extent of the clot can be assessed by the clot burden score (CBS) which is calculated using the T2* MRI sequence (T2*-CBS), adapted from the CTA-CBS.[34],[35] There is an association between CBS and functional outcome of patients being subjected to EVT.[36] CBS has a maximum score of 10 and the lower the score, the more extensive is the thrombus.[34] No clot or a clot with no susceptibility vessel sign is implied by a score of 10, whereas a score of zero means full multisegment vessel blockade. Subsequently, the CBS was divided and a cutoff of ≥6-point was put, according to and for comparison with previous studies.[37]

The formation of a leptomeningeal collateral circulation could be indicated by FLAIR vascular hyperintensity (FVH) on baseline MRI and this can be used as a prognostic marker for stroke patients.[37] Derraz et al. found that the association of clot extent with the functional outcome is influenced by the status of collaterals, which can be quantified by the FVH scoring system. The study showed that a high FVH score is independently associated with a good functional outcome at 3 months. Hence, the FVH score can be used to prognosticate, especially in situations where there is nonavailability of contrast-based vascular imaging. How the thrombus extent interacts with the collateral and the underlying mechanism should be assessed by future work.[37]

Kim et al. did a histologic analysis of retrieved clots in AIS with its correlation to Gradient-Echo MRI findings.[38] The histologic composition of clots that were removed from cerebral arteries in acute stroke patients was found to be different between stroke subtypes in this study. Clots retrieved from patients with cardioembolic stroke had a greater proportion of RBC than those from patients of large-artery atherosclerosis, whereas higher fibrin was found in clots from patients with large artery atherosclerosis than those of cardioembolism. In addition, there is an association of susceptibility vessel sign as seen on GRE MRI with a high number of RBCs and a low amount of fibrin as well as platelets in removed clots. In acute ischemic stroke patients, these findings can help guide the clinicians to predict the composition of clot and stroke etiology using GRE imaging even before undertaking endovascular therapy.[38]

  Conclusion Top

The only established approach to decrease disability among ischemic stroke patients is effective and rapid reperfusion. Thrombectomy is newer advancement that continues to have expanding indications. Every minute counts in acute ischemic stroke as it is a medical emergency. Even severe neurologic deficits can be reversed by achieving reperfusion, thus allowing patients to regain function. Systems of care innovations to hasten the management of ischemic stroke are greatly attainable. They are very important to continue to decrease the disability associated with ischemic stroke with LVO. Tenecteplase is the next-generation agent of thrombolysis, which may be superior to alteplase.

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