Elsevier

The Lancet Neurology

Volume 12, Issue 6, June 2013, Pages 572-584
The Lancet Neurology

Review
Non-pharmacological strategies for the treatment of acute ischaemic stroke

https://doi.org/10.1016/S1474-4422(13)70091-7Get rights and content

Summary

Early recanalisation and an increase in collateral blood supply are predictors of favourable outcome in acute ischaemic stroke. Since individual responses to intravenous treatment with alteplase are heterogeneous, additional intra-arterial thrombolytic and mechanical endovascular treatment is increasingly given. Despite encouraging findings from single-centre studies, data from randomised clinical trials have not proven the hypothesis that interventional recanalisation leads to a better outcome. Advanced thrombectomy devices, the effect of ultrasound-enhanced thrombolysis, and imaging-guided selection of patients outside the currently approved time-window are all under investigation. Although neuroprotective agents have not shown benefit in clinical trials, non-pharmacological treatment strategies—such as decompressive surgery, therapeutic hypothermia, transcranial laser treatment, or augmentation of cerebral collateral perfusion by different means (eg, partial aortic occlusion or sphenopalatine ganglion stimulation)—are topics of current research. The future of acute stroke therapy relies on evidence for individually tailored, effective, safe, and rapidly accessible treatment probably consisting of combined pharmacological and improved non-pharmacological approaches.

Introduction

In the USA and Europe, stroke has dropped from being the third leading cause of death to the fourth.1 However, stroke remains the leading cause of physical disability and can also lead to post-stroke dementia, depression, personality changes, and sometimes pain. While improved management of risk factors for, and cardiovascular causes of, ischaemic stroke has contributed to a decline in the frequency of both primary and recurrent stroke, intravenous fibrinolysis with alteplase remains the only approved medical treatment specific for patients with acute ischaemic stroke presenting within 4·5 h after symptom onset.2, 3

In 1995, findings of a National Institute of Neurological Disorders and Stroke (NINDS) trial showed a benefit of intravenous thrombolytic treatment if started within 180 min after the onset of symptoms.2 A pooled analysis of data from alteplase trials showed that early treatment led to better outcomes, although benefit was seen up to 4·5 h after onset.4 This finding was confirmed by the ECASS III trial, which showed that intravenous alteplase administered 3–4·5 h after the onset of symptoms significantly improved clinical outcomes in patients with acute ischaemic stroke, compared with placebo.3 Results of the observational SITS-MOST study verified that alteplase is safe in a clinical setting when given 3–4·5 h after the onset of symptoms in patients with acute ischaemic stroke,5, 6 and in November, 2011, the European Medicines Agency (EMEA) approved the use of alteplase within 4·5 h after symptom onset (the US Food and Drug Administration have only approved alteplase for use within 3 h).

However, the heterogeneity of individual responses to intravenous alteplase has led to the use of additional intra-arterial thrombolytic and mechanical endovascular treatments for acute ischaemic stroke. Optimisation of early recanalisation rates, augmentation of collateral blood supply, and, in turn, improvement of clinical outcomes are the challenging goals of non-pharmacological strategies for the treatment of acute ischaemic stroke and the subject of many ongoing studies.

In this Review, we describe current ideas and knowledge about the mode of action of non-pharmacological stroke treatment strategies that aim at recanalisation, reperfusion, neuroprotection, and collateral flow augmentation. Furthermore, we present safety and efficacy data from clinical trials of these non-pharmacological strategies. We discuss surgical procedures that aim to improve survival and outcome in malignant infarction. Finally, we highlight how standard intravenous thrombolysis might be complemented by additional or alternative treatment options.

Section snippets

Pharmacological treatment and the bridging concept

As the only evidence-based and approved treatment strategy for acute ischaemic stroke, administration of intravenous alteplase to patients in whom symptoms started no more than 3 h or 4·5 h earlier is, in general, advised by US and European guidelines, respectively, for stroke management.7, 8 Additional or alternative treatment options are selected on the basis of national or international recommendations and institutional standards. In most centres that offer intravenous thrombolysis for

Intra-arterial thrombectomy with mechanical devices

Table 1 presents data from prospective studies of thrombectomy devices.26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 The first neurovascular system designed for embolectomy—the Merci retriever (Concentric Medical, Hertogenbosch, Netherlands)—was approved by the US Food and Drug Administration (FDA) in August, 2004, for the restoration of blood flow by removal of a thrombus from the neurovasculature. In the prospective, non-randomised MERCI trial,26 the device was used in 141 patients

Ultrasound-enhanced thrombolysis

The idea of using ultrasound to amplify thrombolytic treatment is based on the finding, first described in the 1970s,48 that recanalisation is facilitated by ultrasonic mechanical pressure waves. Microstreaming—the motion of fluid around a thrombus—is another noted effect of ultrasound, possibly enhancing contact with alteplase. However, only a few trials of ultrasound-enhanced thrombolysis have been reported (table 3).11, 12, 49, 50, 51, 52, 53

CLOTBUST was a randomised, open-label, multicentre

Decompressive surgery for malignant stroke

Removal of the cranium to allow space for brain tissue to expand after infarction is a surgical option used for patients who have large supratentorial infarcts that otherwise could lead to death by brainstem herniation (figure 2). Even though decompressive surgery is done in many stroke centres worldwide, the ideal candidates for the procedure, the best time to undertake the treatment, and the technique of the surgery itself are still a matter of debate. Data from three small controlled trials

Conclusions

Here, we have reported several strategies for the treatment of acute ischaemic stroke beyond pharmacological interventions. The need for new therapeutic options is attributable to the inherent limitations of intravenous alteplase, which remains the only evidence-based treatment for patients with acute ischaemic stroke within 4·5 h after the onset of symptoms. Many acute stroke patients do not receive this treatment because of the limited time-window or different approval restrictions;

Search strategy and selection criteria

For the section on intra-arterial thrombectomy with mechanical devices, we searched PubMed between 1965 and March, 2013, with the terms (and synonyms) “acute stroke”, “cerebral ischaemia”, “cerebral infarction”, “interventional”, “mechanical”, “thrombectomy”, and “device”. Abstracts of retrieved citations were reviewed and prioritised by relevant content, particularly the quality of evidence reported. We selected mainly studies with a prospective design or those that reported findings in at

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