Stroke Snapshot: Acute Ischemic Stroke

Stroke is a leading cause of morbidity and mortality in the US and globally, making research in this area important both to neurology and public health. This short review covers recent advances in care for acute ischemic stroke (AIS) treatment with an emphasis on advances that have affected standards of care and are influencing current stroke research (Table).

Acute Thrombolytic Therapy

Every neurologist involved in acute stroke care within the last 26 years is likely familiar with what is arguably the most important advance in stroke care—the use of tissue plasminogen activator (tPA) in AIS—shown in 1995 to improve stroke outcomes if given within 3 hours of symptom onset.¹ tPA is now standard of care for AIS in individuals meeting specified criteria. The window of 3 hours from symptom onset has since been challenged and modified by multiple studies, including a randomized controlled trial in 2008 that showed tPA improved outcomes when used within 4.5 hours of symptom onset.²

Most recently, in 2018, a randomized controlled trial of tPA use in AIS with unknown time of symptom onset used brain MRI to guide treatment decisions.³ Most participants, although not all, had “wake-up strokes,” meaning that they woke up from sleep with AIS symptoms. All had brain MRI, and if there was a mismatch between diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) imaging, they were randomly assigned to receive tPA or placebo. Those who received tPA had better functional outcomes at 3 months poststroke without a statistically significant increase in the number of symptomatic intracranial hemorrhages (sICH). This finding has significantly changed the management of individuals with AIS at stroke centers with immediate MRI availability.

Tenecteplase vs Alteplase

The clinical trials referenced above all used the tPA alteplase, which is often mistaken as the only form of tPA, although there are multiple drugs in that class, including tenecteplase. Multiple clinical trials and meta-analyses comparing tenecteplase to alteplase, for any AIS as well as specifically for AIS with large vessel occlusions (LVOs), have shown that tenecteplase is noninferior—at least as safe and effective as—alteplase.⁴ In a large meta-analysis of individuals who had AIS with LVO, however, tenecteplase provided significantly better recanalization and improved functional outcomes 3 months poststroke with no differences in safety profile compared with alteplase.⁵ The multicenter, randomized, double-blind, placebo-controlled TIMELESS trial^a is evaluating use of tenecteplase in people with AIS with LVO who present for care 4.5 to 24 hours after symptom onset. The results of this trial and any resulting changes to standard of care are eagerly awaited.

Endovascular Thrombectomy

Another recent and significant advance in AIS care includes extension of the window for endovascular thrombectomy (EVT) beyond the previously designated 6 hours after symptom onset.^6,7 Clinical trials showed EVT for AIS from internal carotid artery (ICA) or proximal middle cerebral artery (MCA) occlusion within 6 to 24 hours of symptom onset with standard medical care improved functional and disability outcomes compared with standard medical care alone. Safety analysis in both trials showed there was no increase in sICH after thrombectomy. In these trials, perfusion studies were used to identify participants prior to randomization.

Stent Retrievers

The introduction of stent retrievers was a major advancement in EVT for AIS, increasing navigability and rapid recanalization of a stent with fewer long-term complications. The Food and Drug Administration (FDA) has approved 2 stent retrieval devices for treatment of AIS due to LVO; these are the Solitaire FR (Medtronic) and Trevo (Stryker) retrievers.

The Solitaire Flow Restoration device improved disability outcomes, reduced sICH mortality, and increased successful recanalization. Solitaire recanalization site-determined rates were 88% to 92% compared with 48% to 55% with the Merci device.⁸ The Trevo stent retriever has also shown better clinical outcomes at 24 hours, including better reperfusion to a thrombolysis in cerebral infarction (TICI) score of 2 or more compared with the Merci stent retriever, shorter hospital stays, and increased poststroke independence.⁹

A prospective cohort study showed individuals who had AIS due to LVO with large core infarcts on either noncontrast head CT or CT perfusion studies and underwent EVT had better outcomes. Individuals with discordant imaging profiles had lower odds of good functional outcomes and higher adverse events.¹⁰ The SELECT 2 trial^b is a randomized clinical trial that is ongoing to further study the results of EVT in patients with LVOs and large core infarcts.

Mobile Stroke Units

Mobile stroke units (MSUs) are specialized ambulances with imaging capabilities that are brought to the scene of the patient with stroke symptoms. MSUs are still uncommon in the US, with less than 2 dozen in service to date. Typically, an MSU is dispatched by paramedics initially on scene. Upon arrival, providers on the MSU can decide if a patient is appropriate for the very specialized care they provide. Noncontrast head CT and CT angiograms can be done on the MSU in real time. Because time to treatment directly correlates with brain tissue survival (ie, time is brain), MSUs are also equipped to give tPA in the field, when imaging findings indicate it is appropriate. In a large multicenter trial, MSU vs standard ambulance care improved outcomes as measured by the utility-weighted modified Rankin Scale (mRS).¹¹ These findings may drive increased development of MSUs in the US and globally.

Telestroke Care

Telestroke is another significant advance in stroke care, specifically for rural areas and smaller hospitals systems with few vascular neurology services available. Telestroke has increased access to AIS care, including use of thrombolysis and appropriate transfer of patients to comprehensive stroke centers, and has improved poststroke outcomes.¹² Ongoing efforts to monitor the quality of telestroke care are important to track the efficacy of the program, as well as opportunities to make it better and more widely available.

Artificial Intelligence–Assisted Imaging

To increase the sensitivity and specificity of rapid imaging interpretation, which is essential to guide appropriate stroke treatment, artificial intelligence-assisted imaging (eg, RapidAI, Viz.ai, Brainomix, Avicenna.ai, and Aidoc) has been developed and can be a very useful screening tool. For AIS, artificial intelligence-assisted imaging is useful for identifying emergent LVO, calculating grading scores, determining mismatch on perfusion scans, and allowing for real-time image processing.¹³ Such software potentially decreases time to final diagnosis and thus could reduce time to thrombolysis and thrombectomy. As this technology continues to improve and becomes less expensive, it is hoped it will continue to grow and become more readily available in conjunction with MSUs and telestroke care to improve AIS outcomes around the world.

Antiplatelet Use

Antiplatelet use in individuals with AIS but low National Insitutes of Health Stroke Scale (NIHSS) scores or high-risk transient ischemic attacks (TIAs), specifically aspirin plus clopidogrel or ticagrelor for 21 days, followed by clopidogrel or ticagrelor monotherapy vs aspirin alone has been shown beneficial.^14,15 There was an increased risk of hemorrhagic transformation or other hemorrhages. Thus, use of dual antiplatelet therapy is time limited for most individuals, typically 21 to 30 days for those who had a minor stroke or high-risk TIA and 90 days for people with large artery disease.

Prehospital use of antiplatelet drugs before mechanical thrombectomy has also been studied. The use of antiplatelet agents prior to thrombectomy has been associated with higher rates of successful recanalization and is shown to be safe, with no significant increase in sICH.¹⁶

Neuroprotective Agents

Multiple potentially neuroprotective agents have been studied as possible therapy for AIS with the hope for improved outcomes, lowering the disability burden of stroke. As the major excitatory neurotransmitter, glutamate is thought to play a major role in ischemic injury, via the N-methyl D aspartate receptor (NMDAR). However, in a small randomized controlled trial of the NMDAR antagonist dextromethorphan, no improvement in poststroke outcomes was observed at 3 months.¹⁷ Further studies have continued to search for a strong neuroprotective agent.

It has also been hypothesized that magnesium sulfate, when started in the hyperacute phase of AIS, improves outcomes, but a clinical trial showed no significant difference in AIS outcomes at 90 days with magnesium sulfate use and no significant difference in mortality or adverse events either.¹⁸

Nerinetide is an eicosapeptide thought to interfere with postsynaptic density protein 95 and act as a neuroprotectant. Preclinical trials suggested nerinetide might improve reperfusion, but did not improve outcomes in a large, randomized control trial, including reperfusion and disability at 90 days.¹⁹

Poststroke Rehabilitation

Stem Cell Therapy

Animal models have demonstrated potential use of stem cells in poststroke rehabilitation, including mesenchymal, embryonic, inducible pluripotent, and neuronal stem cells. There have only been a few randomized clinical trials studying this, with varying results.

A study of intravenous bone-marrow–derived stem cells showed no improvement in functional outcomes at 3 months, although 1-year post-hoc analysis showed a significant improvement in outcomes in those treated with stem cells.²⁰ Other studies using surgical implantation and injection of stem cells showed improvement in stroke scale scores but no improvement in functional outcomes at 3 months.²¹ Stem cell research is ongoing with great interest as the technology for these treatments continues to develop.

Fluoxetine

Early treatment with fluoxetine and physiotherapy after AIS for those with moderate-to-severe motor deficits was shown to enhance motor recovery after 3 months in a randomized controlled trial with 118 participants. This was hypothesized to occur via a neuroprotective anti-inflammatory effect. A more recent trial with 1,280 participants, however, showed no improvement in functional outcome with fluoxetine and demonstrated increased risk of falls and other safety concerns.²²

Monoclonal Antibodies

A humanized monoclonal antibody to myelin-associated glycoprotein with disabled Fc region considered to improve post stroke motor recovery when given within 72 hours of stroke, has shown no improvement in gait velocity compared with placebo.²³

Other Advances

There are many other areas of research in the attempt to improve stroke rehabilitation, such as mirror therapy, transcranial magnetic stimulation, constraint-induced movement therapy, growth factor therapy, robotics, brain-computer interfaces, and virtual reality.²⁴

Conclusion

Over the past 2 decades, there has been a huge increase in advances in the world of stroke treatment and rehabilitation. This review only briefly summarizes some of these achievements, and we hope it serves to enlighten the future generation of neuroscientists to continue in that same endeavor.