Stroke in the ED

Context

In England and Wales, over 80,000 people are hospitalised with acute stroke each year, and cerebrovascular disease is the third leading cause of disability in the UK [1].

Until the last decade, there was little in the way of treatment to offer the acute stroke patient.

With the licensing of thrombolysis for acute ischaemic stroke, the lack of evidence-based therapeutic intervention has changed dramatically.

As a result, a suspected stroke must always be treated as a medical emergency.

Emergency department (ED) staff need to have excellent stroke recognition skills, and agreed care bundles in place for the diagnosis, and treatment, of cerebrovascular events.

In addition, there should be an increased awareness that good, basic medical and nursing care is vitally important in preventing complications, and optimising outcomes.

A national stroke strategy was published in 2007 by the UK Department of Health [2].

Learning Bite

Strokes account for 11% of all deaths in England and Wales each year.

Definition

An acute stroke is the clinical result of an interruption of the blood supply to a focal part of the brain causing loss of neurological function or death.

Approximately 85% of strokes are due to cerebral infarction (ischaemic stroke), 10% due to primary haemorrhage and 5% due to subarachnoid haemorrhage [1].

This session deals with ischaemic stroke.

Learning Bite

85% of strokes are due to ischaemia

Introduction

Ischaemic stroke and transient ischemic attack (TIA) are part of a patho-physiological continuum of cerebrovascular disease.

Strokes and TIAs result from one of three main aetiologies:

• Large artery atherothromboembolism (intracranial/extracranial)
• Small vessel disease
• Embolism from a cardiac source

Other causes include:

• Carotid or vertebral artery dissection
• Hypercoagulable states
• Sickle cell disease
• ‘Undetermined’ aetiology

Further details on carotid or vertebral artery dissection are presented later in this session, and also in the following session:

• Cervical Artery Dissection

Ischaemic Stroke

In ischaemic stroke, arterial occlusion leads to the abrupt cessation of distal blood flow.

Brain tissue receiving little or no blood flow is known as the ischaemic core, and is made up of cells that die rapidly.

Typically, 1.9 million neurons are lost for every minute that a stroke goes untreated.

Surrounding the ischaemic core is the ischaemic penumbra. This is tissue that is hypoperfused, functionally impaired and at risk of infarction, but it may be saved if reperfused.

The penumbra contains electrically inexcitable, but viable, cells. The duration of ischaemia, as well as the absolute flow, plays a crucial role in determining the fate of the cells in this penumbra.

The longer that penumbral brain tissue remains untreated, the greater is the chance of it undergoing infarction.

Vascular Anatomy

Here is a diagram of vascular anatomy.

1: Middle cerebral artery

The main branches of the internal carotids are the middle and anterior cerebral arteries (anterior circulation).

Circulation Territories

The anterior and posterior circulations are linked via posterior communicating arteries forming the Circle of Willis – as shown in the image.

The extent of each artery’s territory varies between individuals, as does the presence or absence of collaterals. The signs of stroke depend on the site and size of the ischaemic injury. In anterior cerebral artery (ACA) occlusion, the patient’s leg will be more affected than the face or arm. In middle cerebral artery (MCA) occlusion, the face or arm is more affected than the leg. This reflects the cerebral territory supplied by these vessels.

Relationship between artery territories and motor functions

The image below demonstrates the relationship between artery territories and motor functions.

 

Learning Bite

Stroke patients with a functional deficit greater in the leg than the arm or face have had an occlusion of the anterior cerebral artery. Those whose deficit is greatest in the face and arm, have had an occlusion of the middle cerebral artery.

Minor Arteries

The major arteries give off small, penetrating vessels, which supply areas deep in the brain (sub-cortical areas) such as the internal capsule, thalamus and basal ganglia. Strokes involving these small end arteries are called lacunar strokes. Lacunar strokes involving the posterior limb of the internal capsule are typically associated with only motor signs, whereas those affecting the thalamus produce pure sensory signs. It is important to distinguish between patients who have evidence of cortical involvement and those who do not. Symptoms indicating cortical involvement include:

• Agnosia
• Dysphasia
• Sensory inattention
• Visual field defects

FAST

The key element of stroke assessment is stroke recognition. This includes encouraging the public to react to stroke symptoms and call 999.

A useful tool for pre-hospital assessment of suspected acute stroke is FAST:  Face – Arm – Speech – Test.

There are public awareness campaigns using FAST (‘Stroke – Act FAST’), and patients at high risk of stroke should be given information about calling for immediate help at the onset of symptoms.

This is an important aspect of TIA management in the ED if the patient is to be managed as an outpatient.

FAST

Analysis of Stroke Mimics

In one study of consecutive patients thought to have had a stroke and presenting to an urban teaching hospital ED, about 30% actually had a different pathology/diagnosis [8]. The chart shows the percentage incidence of stroke mimic pathologies.

This study found eight features independently predicted the diagnosis. The table on the next page describes some of the features of stroke mimics. The patient with a previous stroke event is particularly difficult to assess.

Learning Bite

The ability to distinguish true stroke from stroke mimics is an essential skill in the management of stroke patients that cannot be replaced by imaging alone.

Stroke Mimics

This table describes the clinical differences between strokes and stroke mimics.

Non-Contrast CT

Non-contrast computed tomography (CT) is the most readily available imaging technique.

Non-contrast computed tomography (CT) is the most readily available imaging technique.

The main aim is to exclude a bleed as the cause of the focal neurological signs (rather than to see ischaemic changes). Early signs of ischaemia may or may not be seen, for example the loss of differentiation of the grey and white matter interface. CT may also show another cause, such as a brain tumour or subdural haemorrhage.

NICE Guidelines

The current NICE Pathway for acute stroke states that brain imaging should be performed immediately for people with acute stroke if any of the following apply:

• Indications for thrombolysis or early anticoagulation treatment;
• On anticoagulant treatment;
• A known bleeding tendency;
• A depressed level of consciousness (GCS <13);
• Unexplained progressive or fluctuating symptoms;
• Papilloedema, neck stiffness or fever;
• Severe headache at onset of stroke symptoms.

‘Immediately’ is defined as ‘ideally the next slot and definitely within 1 hour, whichever is sooner’ [9].

For all people with acute stroke without one of these indications for immediate brain imaging, scanning should be performed as soon as possible. ‘As soon as possible’ is defined as ‘within a maximum of 24 hours after onset of symptoms.

Non-Contrast CT: MCA Sign/Loss of insular ribbon

The hyperdense MCA sign refers to the appearance of the middle cerebral artery (MCA) on CT. It has been associated with poor outcome.

There is increased attenuation of the proximal portion of the MCA and it is often associated with thrombosis of the M1 MCA segment. It is one of the early signs of an MCA infarct [10].

The sign is typically seen within 90 minutes of the ischaemic event, and thus, it is very important to recognise this sign. This sign has approx. 100% sensitivity, however only 30% specificity.

It is usually associated with another important sign of acute ischaemia: insular ribbon sign. This is a loss of definition of the grey-white interface in the lateral margin of the insular cortex (“insular ribbon”).

MRI

Immediate magnetic resonance imaging (MRI) may be available in some centres.

MRI has a higher sensitivity for early acute ischaemic changes and can image the posterior fossa more reliably.

With diffusion-weighted MRI, diffusion perfusion mismatch may show the area of potentially reversible ischaemia, and better identify patients, beyond the current guidelines, who would benefit from thrombolytic therapy.

Other Tests

Other tests required:

All patients in the ED:

• Full blood count
• Urea and electrolytes
• Coagulation studies
• Blood glucose
• ECG
• Chest x-ray

Selected patients in the ED:

• Toxicology
• Pregnancy test
• LFTs

Introduction

The aims of acute management are:

• Restoration of brain perfusion to reduce the effects of the primary insult and prevent secondary brain injury
• Effective stroke care. Effective stroke care is multi-disciplinary. The stroke team, radiology and the stroke unit should be contacted early.
• Thrombolysis. Patients presenting within a few hours of symptom onset may benefit from administration of the thrombolytic agent tissue plasminogen activator (rt-PA). The patient should, therefore, have a focussed medical history, including exact time of onset of symptoms, and be urgently assessed for the inclusion and exclusion criteria of stroke thrombolysis

In the past, patients were eligible for thrombolysis if they presented within three hours of symptom onset. This was extended to 4.5 hours following publication of the European Cooperative Acute Stroke Study (ECASS) III trial in patients aged 18-80 [11]

Learning Bite

The evidence base for thrombolysis for acute ischaemic stroke indicates benefit if delivered within 4.5 hours.

ABC

All patients will benefit from appropriate management of their airway, breathing and circulation. Close control of temperature and glucose levels can reduce stroke-associated morbidity.

Airway protection and Breathing

A comatose patient may need careful positioning, and even intubation, if unable to maintain or protect an airway.

A patient with significant weakness can slump on the trolley, partially obstructing their airway, so reducing the effectiveness of their breathing. Secondary brain injury due to hypoxia must be avoided.

In general, patients with acute stroke without respiratory co-morbidities may be permitted to adopt any body position that they find most comfortable, while those with respiratory compromise should be positioned as upright as possible, avoiding slouched or supine positions to optimise oxygenation [12]. This must be balanced against the improved cerebral blood flow seen if a patient is lying flat [13].

Supplementary oxygen should not be administered routinely. It should only be given if required to achieve an oxygen saturation of 94-98% (88-92% for patients with co-existing risk of COPD or other risk of respiratory acidosis) [14].

Stroke patients should be nil by mouth until their ability to swallow (and therefore avoid aspiration) has been properly assessed.

Circulation

Patients are often dehydrated following a stroke. A patient may have been on the floor all night or may have swallowing difficulties.

Poorer outcomes occur if systolic BP is less than 100mmHg or diastolic is less than 70mmHg.

Hydration should be assessed and hypovolaemia treated with fluid boluses of 250-500ml of normal saline [15]. Fluid overload should also be avoided as it will exacerbate cerebral oedema – a cause of further brain injury in stroke. The aim is euvolaemia. Other causes of hypotension, such as sepsis or acute myocardial infarction, should be considered.

Hypertension should very rarely be treated in the acute phase [1]. Reasons for doing so include [16]:

• Hypertensive encephalopathy
• Hypertensive nephropathy
• Hypertensive cardiac failure/myocardial infarction
• Aortic dissection
• Pre-eclampsia/eclampsia
• Intracerebral haemorrhage with systolic blood pressure over 200 mmHg.

In patients being considered for thrombolysis, a blood pressure target of less than 185/110 mmHg should be achieved.

Pyrexia

Pyrexia after stroke onset is associated with an increase in morbidity and mortality [17].

No trial has been done to show whether treating the fever improves outcome, but it seems reasonable to give antipyretics, and look for signs of infection such as urinary tract infection.

Line insertion and urinary catheter placement in the ED, should follow infection control principles, but should, as far as possible, be avoided.

Hyperglycaemia

Studies have shown that hyperglycaemia is associated with poor outcomes after ischaemic stroke, including in those patients treated with thrombolytic agents [15]. There is an increased intracranial haemorrhage (ICH) rate.

The effects of hyperglycaemia on long-term outcome are similar to those seen after acute myocardial infarction. Known diabetic patients also have poorer outcomes.

The evidence for improved outcome with treatment of hyperglycaemia is not so clear. Current consensus seems to be that patients with acute stroke should be treated, to maintain a glucose concentration between 5 and 15mmol/l (previously 4-11mmol/l), while being careful to avoid hypoglycaemia [1]. This may require the use of an insulin sliding scale and glucose, or the patient’s own oral hypoglycaemic agents, if the patient can swallow.

Focused Neurological Examination

In order to determine the functional severity of a stroke and allow objective assessment of a patient’s progress, use of a standardised stroke scoring tool is essential.

The most widely adopted tool is the National Institutes of Health Stroke Scale (NIHSS) score, first described in 1989 [18] and modified subsequently.

Although the decision to thrombolyse is not made solely on the basis of this scoring system, it is used in thrombolysis protocols to provide an objective baseline assessment of the neurological deficit against which improvement, or deterioration, can be judged.

The NIHSS for rapid measurement of neurological impairment has an online training programme.

Free training for all healthcare professionals on using the NIHSS scoring system is available at nihss-english.trainingcampus.

Learning Bite

The efficacy of thrombolysis in stroke is inversely proportional to the time since symptom onset. ‘Time = Brain’.

Reperfusion Therapy – Thrombolysis Guidelines

Thrombolysis is recommended by many national guidelines for the treatment of selected patients with acute ischaemic stroke.

Current American guidelines (AHA/ASA) recommend intravenous thrombolysis for selected patients within 4.5 hours of onset of ischaemic stroke [19].

UK NICE Guidelines advise that alteplase is recommended for the treatment of acute ischaemic stroke when used by experienced physicians. ED physicians, if appropriately trained and supported, can administer alteplase provided that patients can be managed within an acute stroke service. Protocols should be in place for the delivery and management of thrombolysis, including post-thrombolysis complications [16].

The most recent Cochrane Review is similarly supportive: the ‘overall benefit [of thrombolytic therapy] was apparent despite an increase in symptomatic intracranial haemorrhage, deaths at seven to 10 days, and deaths at final follow-up’ [20].

The UK Royal College of Physicians 2016 guidelines have loosened eligibility criteria further, suggesting that ‘patients with acute ischaemic stroke, regardless of age or stroke severity, in whom treatment can be started within 3 hours of known onset should be considered for treatment with alteplase’ [1].

By current NICE guidelines, approximately 20% of stroke patients are eligible to receive thrombolysis treatment. In England, Wales and Northern Ireland, 87% of hospital sites offer 24 hours a day, 7 days a week on-site thrombolysis [21]. In Q2 2016, 87.7% of patients eligible for thrombolysis actually received it (3300 patients approximately) [22].

Reperfusion Therapy – Evidence behind the Guidelines

Multiple studies have been carried out on thrombolysis for stroke, each with strengths and flaws. The seminal papers include:

NINDS [23]

This pioneering paper used four primary outcome measures of stroke recovery to assess whether treatment with tPA (tissue plasminogen activator) resulted in clinical benefit at three months in 300 patients. The outcome measures used were scores on the Barthel index, modified Rankin scale, Glasgow outcome scale, and NIHSS. At 3 months there was a 12% absolute difference in the Modified Rankin Score in patients treated with tPA by 3 hours. Symptomatic intracerebral haemorrhage within 36 hours occurred in 6.4% of patients given tPA but only 0.6% of patients given placebo (P <0.001). Mortality at three months was 17% in the tPA group and 21% in the placebo group (P = 0.30).

ECASS-I [24]

Patients were randomised to treatment with tPA or placebo within 6 hours from the onset of symptoms. Primary end points included Barthel Index (BI) and modified Rankin Scale (RS) at 90 days. The trial showed a 6% absolute improvement in modified Rankin Scale, but at the cost of an increase in mortality with tPA (22% vs 15% placebo) and an increase in intracranial haemorrhage.

ECASS-II [25]

Patients were again randomised to treatment with tPA or placebo within 6 hours from the onset of symptoms with changes to blood pressure control, CT criteria and randomisation. There was no statistical difference in modified Rankin Score (the primary end point) or mortality, but again, intracranial haemorrhage was increased in the tPA arm (8.8% vs 3.4%).

ECASS-III [11]

800 patients were randomised to receive tPA between 3 and 4.5 hours after their stroke, with a primary endpoint of disability at 90 days assessed with modified Rankin scores. More patients had a favourable outcome with alteplase (52.4% vs 45.2%) with no significant mortality difference, but with a higher rate of symptomatic intracranial haemorrhage (2.4% vs. 0.2%, P = 0.008).

IST-3 [26]

A large international multicentre open label randomised control trial, it took 10 years to recruit 3000 patients, many of them outside the existing European licence for alteplase at the time. The study did not reach its primary endpoint: it found a non-significant 2% benefit from tPA (alive and independent, as defined by an Oxford Handicap Score) at 6 months. There was an increase in significant intracranial haemorrhage (7% vs 1%) and early deaths but no difference in overall mortality at 6 months. It suggested that more elderly patients could benefit from thrombolysis than previously thought.

Reperfusion Therapy – Concerns about the Evidence

Over 27 trials have been conducted on the immediate hazards and the apparent net benefit of thrombolytic therapy [20].

Concerns remain over evidence quality, particularly amongst Emergency Physicians.

The Royal College of Emergency Medicine issued a position statement in 2015 recognising ‘that there is controversy and some scientific concern about whether to provide thrombolysis for patients who have suffered an acute ischaemic stroke’ [27]. Only 10% of hospitals in the UK have an ED consultant on their thrombolysis rota [21].

The American College of Emergency Physicians also downgraded the use of thrombolysis from a Level A to a Level B recommendation in 2015 [28].

See the NNT.com for a further discussion of the merits of thrombolysis studies [29].

You should be aware of the local policies that apply in your department and discuss any concerns with your local stroke lead.

Reperfusion Therapy – What to tell patients

Communicating this information about the risks/benefits of thrombolysis to patients or their relatives can be difficult. Your department should have a detailed protocol document to guide you on the proper management of acute ischaemic stroke, particularly if ED physicians lead thrombolysis in your local area. There should also be a clear patient information leaflet discussing stroke, alteplase and thrombolysis. Numbers need to treat/harm can help communicate risk.

Reflecting the concerns over the evidence, there is ongoing debate over the accuracy of NNT/NNH figures.

Reperfusion Therapy – Who to thrombolyse

Who to thrombolyse?

The indications for considering thrombolysis are [1]:

• Clinical signs and symptoms consistent with acute stroke
• Clear time of onset
• Presentation within 4.5 hours of onset
• No contra-indications (see next page)
• An individualised risk:benefit assessment favouring thrombolysis

What drug to use?

The recommended medication is:

• Alteplase at 0.9mg/kg body weight (maximum dose 90mg) given as an infusion over 60 minutes, with the first 10% of the total dose administered as a bolus [31]

Reperfusion Therapy – Contraindications

There is a long list of contra-indications for thrombolysis of acute ischaemic stroke with alteplase, as listed in the manufacturer’s summary of product characteristics.

Imaging

Contra-indications found on brain imaging include:

• Intracranial haemorrhage
• Greater than one-third middle cerebral artery territory acute ischaemic change (i.e. very severe stroke)
• Extensive small vessel disease

History

Contra-indications from history include:

• Symptoms began more than 4.5 hours prior to thrombolysis, or unknown time of onset
• Patient already receiving effective oral anticoagulation treatment
• Seizure at stroke onset
• History of stroke or head injury in the last three months
• History of any previous stroke and concomitant diabetes
• History of any previous intracranial haemorrhage
• History consistent with subarachnoid haemorrhage (even if CT is normal)
• History of previous major surgery or significant trauma in the last 3 months
• Previous CNS damage (including spinal/intracranial surgery, neoplasm or aneurysm)
• History of gastrointestinal or urinary tract haemorrhage within 21 days or documented ulcerative gastrointestinal disease in the last 3 months
• Recent (less than 10 days) arterial puncture at a non-compressible site (subclavian/ jugular vein)
• Recent (less than 10 days) traumatic external heart massage or obstetrical delivery
• Recent lumbar puncture
• Heparin treatment within last two days
• Severe liver disease, acute pancreatitis, neoplasm with increased bleeding risk
• Significant bleeding disorder at present or within the past 6 months, or known haemorrhagic diathesis

Investigations

Contra-indications from investigations include:

• Platelets <100*10⁹/l
• INR >1.7/elevated thromboplastin time
• Blood glucose < 50 or > 400 mg/dl

Examination

Contra-indications from examination include:

• Symptoms rapidly improving
• Low NHISS score (four or less) or very high NIHSS score (25 or more)
• Systolic blood pressure consistently >185mmHg

Diastolic blood pressure consistently >110mmHg

Reperfusion Therapy – NOACs and thrombolysis

The Royal College of Physicians recommend that patients taking a NOAC (novel oral anticoagulant) should be excluded from receiving alteplase [1].

The only exception is for patients on dabigatran (Pradaxa Ò). The RCP suggest that if the prothrombin time and activated partial thromboplastin time are both normal, thrombolysis can be considered for these patients. You should discuss this with your local clinical lead for stroke.

The use of reversal agents (idarucizumab or andexanet alfa) in order to then administer alteplase for an ischaemic stroke that has occurred during NOAC treatment is not recommended.

Time Benchmarks for Potential Thrombolysis

Current US guidelines recommend the following ambitious time benchmarks [19]:

Antiplatelets

Aspirin

“The pooled results of 2 large trials in 1997 established the efficacy of aspirin in acute ischaemic stroke [32, 33]. The authors found 9 fewer deaths or non-fatal strokes per 1000 in the first few weeks, and 13 fewer dead or dependent patients per 1000 after follow-up.

Aspirin should be withheld for 24 hours in patients treated with tPA [1, 19].

Otherwise, it should be given (300mg) as soon as haemorrhage has been excluded, i.e. post-CT scan. It can be given orally if the patient’s swallow is unaffected; otherwise it can be given rectally or by enteral tube.

If the patient previously had dyspepsia with aspirin, a proton pump inhibitor should be co-administered.

If the patient is allergic to or intolerant of aspirin, they should be given an alternative antiplatelet agent (e.g. clopidogrel) [1].

Other antiplatelets

Some studies have suggested benefit from dual antiplatelet therapy [34]. This is not yet recommended by national stroke guidelines.

Anticoagulation

A recently updated systematic review found no benefit from any currently available anticoagulant in acute ischaemic stroke [35]. They included standard unfractionated heparin, low-molecular-weight heparins, heparinoids, oral anticoagulants, and thrombin inhibitors in their analysis.

They are not recommended in the treatment of acute ischaemic stroke at present.

Endovascular therapy

Stroke patients who receive organised inpatient care in a stroke unit are more likely to be alive, independent, and living at home one year after the stroke [39]. The benefits are most apparent in units based in a discrete ward.

Service reconfiguration in the UK means that patients may be treated first at a regional stroke centre/hyperacute stroke unit, then transferred back to their local hospital after 72 hours for further rehabilitation [21].

In 2015/16, 59% of stroke patients in England, Wales and Northern Ireland were admitted to a stroke unit within the 4 hour target [22]. 84% of all patients spent a least a portion of their inpatient stay in a stroke unit.

Close co-operation between the ambulance service, ED, stroke team and stroke unit should ensure patients receive optimum treatment.

Malignant Middle Cerebral Artery Infarct

Large space-occupying middle cerebral artery or hemispheric ischaemic brain infarcts are associated with the development of massive brain oedema, which may lead to herniation and early death. This condition, which has been described as malignant middle cerebral artery infarction, is associated with 80% mortality due to herniation during the first week [40, 41].

About 5% of strokes result in this complication, and almost all are caused by embolic occlusion of the proximal middle cerebral artery. The patient’s condition usually deteriorates on the third to fifth day, despite maximal conservative ICU treatment [42].

Young patients are particularly at risk because they have little cerebral atrophy and, therefore, little spare space for any brain swelling to occur without significant symptoms.

Hemicraniectomy relieves mechanical compression of the brain, and may improve cerebral perfusion and prevent further ischaemia. Evidence suggests if indicated, it should be performed within 48 hours of stroke onset [41].

A section of skull is removed to allow the brain to swell. The bone is stored, and can be replaced at a later date.

UK National Guidelines [1]

Patients with middle cerebral artery (MCA) infarction who meet all the criteria below should be considered for decompressive hemicraniectomy:

• Pre-stroke modified Rankin Scale score of less than 2;
• Clinical deficits indicating infarction in the territory of the MCA;
• NIHSS score of more than 15;
• A decrease in the level of consciousness to a score of 1 or more on item 1a of the NIHSS (i.e no longer alert);
• Signs on CT of an infarct of at least 50% of the MCA territory with or without additional infarction in the territory of the anterior or posterior cerebral artery on the same side, or infarct volume greater than 145 cubic centimetres on diffusion-weighted MRI.

Patients should be referred to neurosurgery within 24 hours of stroke onset and treated within 48 hours of stroke onset.

A previous upper age limit of 60 years was withdrawn on the basis of the DESTINY-II trial [40]. It is recommended that decisions to undertake major life-saving surgery need to be carefully considered on an individual basis, but patients should not be excluded from this treatment by age alone.

ED physicians should be aware of this likely fatal complication, and of the treatment options.

Neurosurgical centres may not have much experience of the procedure, and senior decision makers may need to be involved to get the patient appropriate treatment.

Learning Bite

Decompressive hemicraniectomy can be lifesaving in malignant MCA stroke.

Basilar Artery Stroke

Basilar artery occlusion is a rare, but under-recognised, cause of stroke. This condition has a high mortality and morbidity rate. The basilar artery is formed by the union of the two vertebral arteries and terminates as the posterior cerebral arteries (PCAs). Signs and symptoms will depend on where the occlusion is. Patients frequently will have had preceding posterior circulation TIA symptoms.

There may be:

• Basilar artery occlusion that can cause severe quadriplegia, coma and the locked-in syndrome
• A stuttering course of posterior circulation symptoms that finally become progressively disabling. The most characteristic motor manifestation is an asymmetric quadriparesis

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2. Department of Health, National Stroke Strategy. 2007, Department of Health: London.
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26. I. S. T. collaborative group, et al., The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet, 2012. 379(9834): p. 2352-63.
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