Stroke

Seminar
Stroke
Nina A Hilkens, Barbara Casolla, Thomas W Leung, Frank-Erik de Leeuw
Stroke affects up to one in five people during their lifetime in some high-income countries, and up to almost one Published Online
in two in low-income countries. Globally, it is the second leading cause of death. Clinically, the disease is May 14, 2024
https://doi.org/10.1016/
characterised by sudden neurological deficits. Vascular aetiologies contribute to the most common causes of S0140-6736(24)00642-1
ischaemic stroke, including large artery disease, cardioembolism, and small vessel disease. Small vessel disease is
Department of Neurology,
also the most frequent cause of intracerebral haemorrhage, followed by macrovascular causes. For acute ischaemic Radboud University Nijmegen
stroke, multimodal CT or MRI reveal infarct core, ischaemic penumbra, and site of vascular occlusion. For Medical Center, Nijmegen,
intracerebral haemorrhage, neuroimaging identifies early radiological markers of haematoma expansion and Netherlands (N A Hilkens MD,
Prof F-E de Leeuw MD); Donders
probable underlying cause. For intravenous thrombolysis in ischaemic stroke, tenecteplase is now a safe and
Institute for Brain, Cognition
effective alternative to alteplase. In patients with strokes caused by large vessel occlusion, the indications for and Behaviour, Radboud
endovascular thrombectomy have been extended to include larger core infarcts and basilar artery occlusion, and University, Nijmegen,
the treatment time window has increased to up to 24 h from stroke onset. Regarding intracerebral haemorrhage, Netherlands (N A Hilkens,
Prof F-E de Leeuw); Université
prompt delivery of bundled care consisting of immediate anticoagulation reversal, simultaneous blood pressure Nice Cote d’Azur UR2CA-URRIS,
lowering, and prespecified stroke unit protocols can improve clinical outcomes. Guided by underlying stroke Stroke Unit, CHU Pasteur 2,
mechanisms, secondary prevention encompasses pharmacological, vascular, or endovascular interventions and Nice, France (B Casolla MD);
lifestyle modifications. Division of Neurology,
Department of Medicine and
Therapeutics, The Prince of
Introduction not be discussed separately in this Seminar. Cerebral Wales Hospital, The Chinese
Stroke is an acute, focal neurological deficit with no venous thrombosis that constitutes less than 2% of all University of Hong Kong,
other explanation than a cerebrovascular cause. ischaemic strokes is beyond the scope of this Seminar Shatin, Hong Kong Special
Administrative Region, China
Common symptoms include hemiparesis, dysarthria, given its distinct pathophysiology and treatment. (Prof T W Leung MD)
sensory deficits, aphasia, and visual deficits. Globally, Intracerebral haemorrhages are due to acute vessel
Correspondence to:
with only little variation, ischaemic strokes constitute rupture, most often within the brain parenchyma. Globally Prof Frank-Erik de Leeuw,
between 60–70% of all strokes and result from an acute there are marked differences in distribution of stroke Department of Neurology,
arterial occlusion. Historically, transient ischaemic subtypes. In high income countries (HICs) 15% of all Radboud University Nijmegen
Medical Center, PO Box 9101,
attack (TIA) was diagnosed when complete resolution of strokes are intracerebral haemorrhages, whereas in low- Nijmegen 6500 HB, Netherlands
symptoms happened within 24 h, although nowadays income and middle-income countries (LMICs) intra FrankErik.deLeeuw@
the presence of a restricted diffusion lesion on MRI cerebral haemorrhage accounts for almost 30% of all radboudumc.nl
despite clinical recovery qualifies for a diagnosis of
ischaemic stroke (irrespective of the duration of
symptoms).1 This qualification implies that a TIA is in Search strategy and selection criteria
fact a minor ischaemic stroke, which is also in line with We searched the Cochrane Library, MEDLINE, and Embase for
advances in neuroimaging (eg, higher field strength) articles published in English between Jan 1, 2019, and
showing tissue loss in areas with only transient Jan 31, 2024. When relevant we included older publications
interruption of cerebral blood flow.2,3 It is therefore and papers that we deemed relevant from reference lists of
doubtful if the term TIA is tenable—in fact it could papers identified. Review articles are cited to provide readers
distract from the immediate medical attention it with more details and references. For the sections on acute
deserves. treatment and secondary prevention we performed
Lesions observable on diffusion-weighted imaging a systematic search by using the following search terms: “acute
(DWI) can appear minutes after symptom onset and stroke treatment”, “ischaemic stroke”, “intravenous
disappear within weeks contingent upon symptom thrombolysis”, “endovascular thrombectomy”, “secondary
duration and infarction volume.4 However, without prevention”, “antiplatelet therapy”, and “clinical trial” or
imaging confirmation of ischaemia, transient focal “meta-analysis”. For the section on intracerebral haemorrhage,
neurological episodes, hypoglycaemia, a postictal state, we used the following search terms: “brain haemorrhage”,
metabolic disturbances, or migraine with aura are “brain hemorrhage”, “cerebral haemorrhage”, “cerebral
potential stroke mimics. Postictal state, metabolic hemorrhage”, “intracerebral haemorrhage”, “intracerebral
disturbances, or migraine with aura can also lead to DWI- hemorrhage”, “brain bleeding”, “cerebral bleeding”,
positive lesions, mimicking acute ischaemic stroke.5 “intracerebral bleeding”, “cerebral haematoma”, “brain
Occasionally, functional disorders might also present haematoma”, “intracerebral haematoma”, “ICH”, and “clinical
with focal neurological deficits. Therefore, history taking, trial” or “meta-analysis”. For the other sections, we selected
neurological examination, and relevant investigations are studies with a substantial sample size (>100 people) that were
crucial steps to reach the definitive diagnosis. As the published in high-impact, peer reviewed journals to provide
pathogenesis and secondary prevention mechanisms the most recent and relevant advances.
of TIA overlap with those of ischaemic strokes, TIA will
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Seminar
strokes. Less frequently, acute arterial rupture can also been discussed in previous research.6 This Seminar covers
occur in the subarachnoid space, resulting in a the diagnosis, acute management, and secondary preven
subarachnoid haemorrhage. Both subarachnoid and pure tion of ischaemic stroke and intracerebral haemorrhage,
intraventricular haemorrhages are beyond the scope of with a focus on recent developments and future
this Seminar, and subarachnoid haemorrhage has also perspectives.
Clinical Diagnostic
Ischaemic stroke
Arteriopathy
Large artery disease History of cardiovascular disease; presence of traditional vascular Duplex, CT, or magnetic resonance angiography: stenosis of large vessels (cervical, intracranial) at
or atherosclerosis risk factors; often older than 50 years typical sites
Cervical artery Often younger (18–50 years); cervical pain and headache; head CT or magnetic resonance angiography: long, irregular stenosis (so-called mouse tail appearance;
dissection trauma, cervical trauma, or both (often minor); tinnitus; Horner starting >2 cm above the bifurcation for carotid cervical artery dissection); occlusion or a dissecting
syndrome and cranial nerve palsy aneurysm, intramural hematoma; less often a double lumen or intimal flap
Sporadic small vessel disease
Deep perforating Traditional vascular risk factors (eg, hypertension); preceding Recent subcortical infarction; MRI markers of small vessel disease
vasculopathy cognitive decline
Cardioembolism
Atrial fibrillation Often older than 60 years; history of palpitations; multifocal ECG: atrial fibrillation; CT or MRI: multiple infarctions in different arterial territories
neurological symptoms
Infective Fever (fluctuating); cardiac murmur at auscultation; splinter Echocardiography: abscess, dehiscence of prosthetic valve; valvular regurgitation; valve vegetation
endocarditis haemorrhage; spondylodiscitis
Other causes
Vasculitis Headache; behavioural and cognitive symptoms; other organ Raised erythrocyte sedimentation rate, C-reactive protein, or both; cerebrospinal fluid: mild
involvement (lungs, skin, joints, kidney, eye) pleocytosis, usually with protein elevation; contrast enhanced CT or MRI: multiple infarctions, at
various stages, usually affecting different vascular territories, meningeal enhancement;
intracerebral haemorrhage might be present; CT or magnetic resonance angiography: focal or
multifocal segmental narrowing of branches of cerebral (or extracranial) arteries or occlusions with
or without vessel wall enhancement
Antiphospholipid History of arterial or venous thrombosis; history of pregnancy Positive antiphospholipid antibodies† at two different time points with at least a 12-week interval
syndrome complications*
Intracerebral haemorrhage
Sporadic small vessel disease
Deep perforating Traditional vascular risk factors (eg, hypertension); preceding Deep intracerebral haemorrhage (basal nuclei, thalamus, cerebellum, internal capsule); lobar
vasculopathy cognitive decline intracerebral haemorrhage; deep microbleeds, lobar microbleeds, or both; no superficial siderosis
Cerebral amyloid Older than 55 years; transient focal neurological episodes; Haemorrhagic spectrum: lobar intracerebral haemorrhage; strictly lobar microbleeds; superficial
angiopathy preceding cognitive decline siderosis. Ischaemic spectrum: covert MRI markers of small vessel disease
Macrovascular causes
Cerebral Absence of traditional vascular risk factors; often younger than Flow voids in abnormal regions; calcifications in the arteriovenous malformation
arteriovenous 70 years
malformation
Dural arteriovenous Absence of traditional vascular risk factors; often younger than Flow voids in abnormal regions; often abnormal, dilated cortical veins
fistula 70 years
Cerebral cavernous Absence of traditional vascular risk factors; often younger than Small intracerebral haemorrhage; so-called popcorn appearance on MRI; other cerebral cavernous
malformation 70 years malformations that have not bled might be present
Other causes
Cerebral venous Absence of traditional risk factors; headaches preceding Haemorrhage location close to sinuses or veins; perihaematomal oedema; associated convexity
thrombosis intracerebral haemorrhage onset; onset in pregnancy and subarachnoid haemorrhage (cortical vein thrombosis)
postpartum; subacute presentation of neurological signs, epileptic
seizures
Reversible cerebral Absence of traditional risk factors; headaches preceding Multiple intracerebral haemorrhages; lobar intracerebral haemorrhage location; associated
vasoconstriction intracerebral haemorrhage onset (typically thunderclap); onset in convexity subarachnoid haemorrhage; arterial constriction
syndrome pregnancy and postpartum; use of vasoactive medication or illicit
drugs; subacute presentation of neurological signs, epileptic
seizures
Tumour (primary or Absence of traditional risk factors; headaches preceding Nodular aspect of the haemorrhage; disproportionate perihaemorrhagic oedema
metastasis) intracerebral haemorrhage onset; subacute presentation of
neurological signs, epileptic crises
*Three or more miscarriages, intrauterine death, prematurity due to high blood pressure, pre-eclampsia, haemolysis, elevated liver enzymes, and low platelets (HELLP)-syndrome, or placenta failure. †Lupus
anticoagulant, anti-beta-2 glycoprotein, and anticardiolipin antibodies.
Table: Clinical, radiological, and diagnostic clues to the underlying causes of ischaemic stroke and intracerebral haemorrhage
2 www.thelancet.com Published online May 14, 2024 https://doi.org/10.1016/S0140-6736(24)00642-1

Seminar
Epidemiology—global burden of stroke Pathophysiology and diagnostic workup of

Stroke poses an enormous challenge to health-care ischaemic stroke
systems worldwide, but especially in LMICs (where Identification of the cause of stroke is central to secondary
90% of all stroke-related deaths and disability occur, prevention (table). Investigations should identify indivi
coupled with a surge in stroke incidence) compared with dual stroke mechanisms. TOAST is one of the ischaemic
high-income countries.7 Stroke is the second leading stroke classification schemes13 and the four major
cause of death globally, with almost 7 million deaths categories are: large artery atherosclerosis (artery-to-
worldwide, and is the third leading cause of disability. artery thromboembolism from atherosclerotic lesions of
In 2019, there were over 100 million patients who had a internal carotid artery or intracranial major arteries);
stroke and 12 million new stroke cases globally. Both the embolism from the heart; small vessel disease (occlusion
incidence (6·4 million vs 5·8 million) and prevalence of lenticulostriate arteries or vertebrobasilar perforators);
(56·4 million vs 45·0 million) of all strokes was higher in and other causes, including arterial dissection, prothrom
women than men.7 There are reports that this worrisome botic states, paraneoplastic conditions, infections
sex difference becomes even more pronounced as women (including infective endocarditis, neuro syphilis, and
might have poorer access to endovascular therapy and also tuberculous meningitis), autoimmune vasculitis, here
have lower poststroke functional outcomes;8 however, ditary causes, and hormonal treatment, including oral
there are still many knowledge gaps on the causes and contraception. In young people, there is a substantial
interpretation of these sex differences. The global absolute proportion of patients who have a stroke of an
incidence of stroke increased by 70% and the prevalence undetermined cause (cryptogenic strokes).
by 85% between 1990 and 2019.7 This increase was partly Infarct topography could provide clues to the underlying
due to population growth and ageing.7 However, there is a pathophysiology of ischaemic stroke (figure 1). Acute
concern over the increasing age standardised incidence of infarcts present concomitantly in bilateral hemispheres, or
ischaemic stroke in people between 18 and 50 years, which in both anterior and posterior circulations (without fetal
increased by 50% over the last decade.9 posterior cerebral artery), are highly suggestive of
Possible explanations for the increased incidence cardioembolism (atrial fibrillation or infective or marantic
in stroke in young patients are two-fold. First, endocarditis). A wedge-shaped territorial infarct points to a
advanced neuroimaging techniques, particularly proximal vascular occlusion (commonly at distal internal
diffusion-weighted MRI, might simply result in better carotid artery or a main trunk of a cerebral artery) and
stroke detection and more sensitive diagnosis, reducing warrants cardiac monitoring for atrial fibrillation and
the risk of misclassification. Second, there is an imaging investigation for ipsilateral carotid artery disease.
increased prevalence of modifiable traditional vascular Border zone infarction can appear as single or multiple
risk factors among young people, such as obesity, ischaemic lesions in the watershed region between two
diabetes, and increased use of illicit and recreational major cerebral arteries where the perfusion is the lowest,
drugs worldwide, which is a known cause of stroke.10 commonly due to hypotensive episodes (eg, hypovolaemic
The yearly incidence of ischaemic stroke varies between shock, septic shock, or both, or during general anaesthesia)
less than 41 per 100 000 people in HICs to more than or large artery steno-occlusive disease (high-grade carotid
150 per 100 000 in LMICs; for intracerebral haemorrhage artery disease, intracranial atherosclerotic disease, or
these figures are less than 15 per 100 000 people in HICs and Moyamoya syndrome or disease). In cases of Moyamoya
over 97 per 100 000 people in LMICs.7 Major contributors disease there is no underlying cause; in cases of Moyamoya
to stroke in LMICs are the high prevalence of vascular syndrome, there is an underlying cause (eg, neuro
risk factors such as (uncontrolled) hypertension, fibromatosis, trisomy 21, irradiation). Subcortical infarcts
diabetes, obesity, smoking, poor diet, and lack of physical due to occlusion of a single penetrating arterial branch are
exercise as well as poor access to primary care facilities typically small (2–15 mm) and present in the basal ganglia
or general practitioners. However, reliable data on the and brainstem. These infarcts are most often caused by
epidemiology of stroke in LMICs are scarce. As most small vessel disease, although small emboli could
strokes occur in these countries, investigating causes potentially also occlude these perforators.
and both short-term and long-term consequences of
stroke should be a priority for future research. Over Diagnostic investigations
90% of all ischaemic strokes are attributed to these Investigations into the cause of ischaemic stroke should
treatable and preventable risk factors.11 Apart from these include blood tests for lipid profile and glycaemic control,
conventional vascular risks, it has become increasingly blood pressure assessment, imaging of the brain (CT
clear that environmental factors such as lead exposure, or MRI), ultrasonography of intracranial and cervical
ambient air pollution (more serious in LMICs than in arteries, CT angiography, or magnetic resonance
the HICs), and extremes of atmospheric temperature7 angiography, and Holter monitor examination or
are also important risks for stroke. Evidence suggests an telemetry for at least 48 h to detect possible atrial
escalated risk for stroke after short-term (days) and fibrillation and concurrent cardiovascular morbidities. In
long-term (years) exposure to air pollution.12 young patients without conventional cardiovascular

Seminar
Ischaemic stroke Intracerebral haemorrhage

Territorial infarction Cerebral amyloid angiopathy
DWI ADC FLAIR T2 CT SWI SWI
A E F G
Recent small subcortical infarction Deep perforating artery vasculopathy

DWI ADC FLAIR SWI CT SWI FLAIR
B H I J
#
* *
* #
#
Arterial borderzone infarction Arteriovenous malformation

DWI ADC T2 MRA CT SWI DSA
C K L M
Infarctions in multiple territories

DWI T2 DWI T2
Figure 1: Patterns of ischaemic stroke and intracerebral haemorrhage

Arrows in panels A–D indicate areas of cerebral ischaemia. (A) Territorial infarction caused by posterior artery occlusion. (B) Recent small subcortical infarction
(lacunar stroke) due to small vessel disease based on MRI markers of SVD (*WMH; #microbleed). (C) Borderzone infarction due to high grade stenosis of the distal
internal carotid artery caused by Moyamoya disease (MRA scan). (D) Territorial infarctions in multiple arterial territories (left and right middle cerebral artery [anterior
circulation] and left posterior inferior cerebellar artery [posterior circulation]), highly suggestive of cardioembolism. (E) Lobar left temporoparietal intracerebral
haemorrhage (red arrow), in a patient with cerebral amyloid angiopathy with finger-like projections (asterisk) on brain CT scan according to Edinburgh diagnostic
criteria. These features are associated with MRI markers including lobar brain microbleeds (F, red arrow) and cortical superficial siderosis, appearing as hypointensities
on the superficial cortex, involving adjacent sulci, according to Boston diagnostic criteria (G, red arrow). Intracerebral haemorrhage (H, red arrow) in the left thalamus
with internal capsule involvement, most likely resulting from a deep perforating artery vasculopathy, a common form of small vessel disease. MRI markers of SVD
include cerebral microbleeds in the basal ganglia (deep location), appearing as a small area of signal void on SWI shown in panel I (red arrow) and white matter
hyperintensities of presumed vascular origin on MRI FLAIR images (panel J, blue arrow). Lobar right frontal intracerebral haemorrhage can be seen in panel K
(red arrow), visualised in the hyperacute acute phase (<4 h), with peripheral hypointense signal on SWI sequences (L, red arrow) and a nidus of an underlying left
frontal arteriovenous malformation on digital subtraction angiography (M, DSA, red arrow), draining into the superior saggital sinus via
cortical veins (M, blue arrow). ADC=apparent diffusion coefficient. DWI=diffusion-weighted imaging. FLAIR=fluid-attenuated inversion recovery. SVD=small vessel
disease. SWI=susceptibility weighted image. WMH=white matter hyperintensities.
risks, ischaemic stroke can be precipitated by anti- with subcortical infarcts and leukoencephalopathy,
phospholipid syndrome, autoimmune disease, use of cerebral autosomal recessive arteriopathy with
oral contraceptives, or illicit drugs (amphetamine, subcortical infarcts and leukoencephalo pathy, Fabry
cocaine, and cough-mixture abuse).10 Hereditary stroke disease, mitochondrial disease, etc) should be considered
disorders (cerebral autosomal dominant arteriopathy when ischaemic stroke runs within families.14 Genome-

Seminar
wide association studies have identified some common Diagnostic investigations

genetic variants associated with different ischaemic Intracerebral haemorrhage can occur as the consequence of
stroke subtypes (eg, large artery or cardio embolic different, sometimes overlapping, vascular and brain
stroke).15,16 pathologies, but a validated unifying causal classification
system is still missing.24 A standard diagnostic investigation
Pathophysiology and diagnosis of intracerebral should, apart from history taking and evaluation of vascular
haemorrhage risk factors, include brain imaging (preferably with MRI)
Spontaneous (non-traumatic) intracerebral haemorrhage for every patient with an intra cerebral haemorrhage.
is a multifactorial disease, with diverse underlying causes Macrovascular causes underlying intracerebral
(table, figure 1). The rupture of small arteries initially haemorrhage should be excluded in patients aged under
results in brain damage due to the haematoma mass 70 years with either CT angiography, magnetic resonance
effect.17,18 During the first hours, one in three patients angiography, or digital subtraction angiography, especially
have haematoma expansion, sometimes leading to in the absence of arterial hypertension and radiological
hydrocephalus, raised intracranial pressure, or both, that markers of small vessel disease. Underlying small vessel
can result in brain herniation.19 Bleeding triggers delayed disease as the cause of intracerebral haemorrhage can be
molecular mechanisms (including microglia activation, investigated by identifying MRI markers of small vessel
influx of inflammatory cells, thrombin-induced toxicity, disease, as the pathology of small cerebral arteries cannot be
and iron-induced toxicity20) that promote blood–brain visualised with neuroimaging. Despite high costs and
barrier breakdown and contribute to vasogenic and limited accessibility, brain MRI allows more accurate
cytotoxic perihaematomal oedema development that can identification of the underlying causes of intracerebral
present from a few days to a few weeks after intracerebral haemorrhage. Updates to the diagnostic criteria for cerebral
haemorrhage.21,22 amyloid angiopathy and small vessel disease biomarkers
In approximately 80% of non-traumatic intracerebral have been published.28–30
haemorrhage, vessel rupture is caused by sporadic CT angiography and magnetic resonance angiography
cerebral small vessel disease. There are two main forms showed greater than 90% sensitivity and specificity for
of sporadic small vessel disease: deep perforating artery detecting macrovascular causes of intracerebral
vasculopathy and cerebral amyloid angiopathy.23 haemorrhage.27 Diagnostic digital subtraction angio
Small (50–400 µm) perforating arteries are vulnerable graphy remains the gold standard in patients younger
to the effects of vascular risk factors, especially than 45 years with any intracerebral haemorr hage
hypertension. The resultant progressive deposition of location and in patients younger than 70 years with lobar
fibrinoid material in the vessel wall (ie, arteriolosclerosis) intracerebral haemorrhage, without any vascular risk
weakens the vessel wall with a consequent increased factors or signs of cerebral small vessel disease.25–27,31,32
risk of rupture. In cerebral amyloid angiopathy, According to clinical and radiological presentation (table),
deposition of amyloid β (Aβ) protein affects small and other intracerebral haemorrhage causes should be ruled
medium sized arterioles; the Aβ protein perforates the out as they require urgent therapeutic management.
cerebral and cerebellar cortex and leptomeninges, with These include reversible cerebral vasoconstriction
consequent arterial wall thickening, vasoreactivity loss, syndrome and cerebral venous thrombosis, which
and focal fragmentation. Cerebral amyloid angiopathy requires CT angiography, magnetic resonance angio
typically causes only lobar (or superficial cerebellar) graphy, digital subtraction angiography, or
haemorrhages; deep perforating artery vasculopathy can CT venography or magnetic resonance venography.25,33
cause both deep and lobar haemorrhages. Sometimes, Repeating contrast CT or MRI and vascular imaging
different small vessel disease subtypes might overlap.24 3 months after intracerebral haemorr hage helps to
Other causes of intracerebral haemorrhage include exclude a mass, lesion, or vascular malformation that
macrovascular malformation (arteriovenous malfor was initially compressed by the intracerebral
mations, aneurysms, dural arteriovenous fistula, cerebral haemorrhage, and to verify intracerebral haemorrhage
cavernous malformation), cerebral venous thrombosis, resorption.
and reversible vasoconstriction syndrome.25–27 Underlying
primary brain or metastatic tumours can cause intra Acute treatment for ischaemic stroke
cerebral haemorrhage and should be suspected in case of The goal of acute ischaemic stroke management is to
extensive perihaematomal oedema. A differential diag restore cerebral perfusion as soon as possible with
nosis is haemorrhagic transformation of ischaemic intravenous thrombolysis, endovascular thrombectomy,
lesions, mainly in patients with infective endocarditis, or both, followed by admission to a dedicated stroke care
vasculitis, or posterior reversible encephalopathy syn facility (figure 2).
drome. Clotting factor deficiency (eg, haemophilia) can
also precipitate brain bleeding, but like oral anticoagulants Prehospital stroke management
should not be considered as a direct cause of intracerebral As substantial delays occur in the pre-hospital phase, the
haemorrhage.28 primary objective of prehospital stroke management is to

Seminar
suspected large vessel occlusion from emergency sites

Acute focal neurological deficit could be burdened by an increased number of
hemorrhagic strokes.
Diagnosis
Individuals with suspected large vessel occlusion strokes
or contraindications to intravenous thrombolysis might
CT and CT angiography
benefit from direct transfer to thrombectomy-capable
centres, bypassing the nearest primary stroke centre
(ie, the mothership model), even if this causes some
Ischaemic stroke Intracerebral haemorrhage transport delays.37 However, randomised clinical trials
investigating transport strategy models in patients with
suspected acute large vessel occlusion stroke were either
prematurely halted before full recruitment38 or did not
Large vessel occlusion No large vessel occlusion
report a significant difference in 90-day neurological
outcomes between direct transportation to thrombectomy-
Acute capable centre or local stroke centre in non-urban areas of
management Spain.39 The optimal referral strategy likely depends on
<4·5 h Intravenous <4·5 h Intravenous • Immediate anticoagulant
the regional organisation of health care, the probability of
thrombolysis thrombolysis reversal large vessel occlusion, and interhospital transport delays.
and endovascular • Treatment of high blood
thrombectomy*
Mobile stroke units have been established to shorten
4·5–9 h Late intravenous pressure ideally within 1 h
thrombolyis based on • Neurosurgery when the time between an emergency call and beginning
4·5–6 h Endovascular perfusion imaging† indicated intravenous thrombolysis. A mobile stroke unit is an
thrombectomy
>9 h No proven reperfusion
ambulance with a CT scanner, a telemedicine system,
6–24 h Endovascular therapy and a point of care laboratory system, staffed with a
thrombectomy based on
perfusion imaging†
nurse and a paramedic, with or without an onboard
physician. The mobile stroke unit can deliver intravenous
>24 h No proven reperfusion thrombolysis at the emergency site, reducing the time
therapy
between stroke onset and intravenous thrombolysis.
Moreover, patients diagnosed with large vessel occlusion
by onboard CT angiography can be directly transferred
Subacute to a thrombectomy-capable centre. Compared with usual
management care, use of a mobile stroke unit was associated with an
• Admission to stroke unit • Admission to stroke unit approximately 65% increase in the chance of an excellent
• Start antithrombotic therapy, • Investigate underlying outcome and a 30 min reduction in stroke onset to
cholesterol lowering drugs, macrovascular cause <70 years
antihypertensive treatment
intravenous thrombolysis times without safety
• Identify aetiology to guide concerns.40 Nevertheless, a mobile stroke unit requires
additional secondary substantial financial investment, with its effectiveness
prevention strategies
depending on local geography. Overall, prehospital
stroke management should be organised based on a
Figure 2: Stroke management flowchart
FLAIR=fluid-attenuated inversion recovery. *In case of contraindications to intravenous thrombolysis, only
regional hub and spoke network basis, considering
endovascular thrombectomy should be performed. †Diffuse-weighted imaging–FLAIR mismatch or CT–perfusion interhospital distances, geographical barriers, and the
mismatch. There is a shift towards selection of patients for endovascular thrombectomy between 6 to 24 h based cost-effectiveness of triage and patient diversion
on non-contrast CT alone, however this is not incorporated into guidelines yet. systems.
expedite reperfusion therapies. The BE FAST test Intravenous thrombolysis with alteplase or tenecteplase
(balance, eyes, face, arm, speech, time) helps to quickly Alteplase is currently the only thrombolytic agent
recognise the symptoms of a stroke34—and in the era of approved by all regulatory agencies for acute ischaemic
endovascular thrombectomy, field assessments strokes.41,42 Upon exclusion of intracerebral haemorrhage
like the Field Assessment Stroke Triage for Emergency by non-contrast brain CT, alteplase at 0·9 mg per kg
Destination (FAST-ED) that incorporates cortical signs (10% bolus followed by 90% infused in 1 h; maximum
(eg, aphasia, eye deviation, and denial or neglect) is 90 mg) reduced stroke-related disability.43 Current
crucial to identify possible large vessel occlusion guidelines recommend intravenous thrombolysis within
strokes.35 Yet administration of the National Institutes of 4·5 h after stroke onset, and the number needed to treat
Health Stroke Scale (NIHSS) prehospitally by paramedics for intravenous thrombolysis to achieve one additional
did not improve triage further.36 Of note, these screening patient with excellent functional outcome (modified
tools discriminate poorly between ischaemic strokes and Rankin Scale [mRS] 0–1) is time-dependent; 10 within
intracerebral haemorrhage. As a result, thrombectomy- 3 h after stoke onset, and 19 from 3–4·5 h.44,45 The absolute
capable hospitals that directly admit patients with risk of fatal intracerebral haemorrhage was

Seminar
approximately 2%.46 The benefit of alteplase was less of patients needed to treat to reduce disability by at least
clear in patients with non-disabling stroke symptoms.47,48 one level on the mRS for one patient was 2·6; patients
Tenecteplase is a genetically modified variant of younger than 80 years and those not qualifying for
alteplase that allows intravenous thrombolysis in a single intravenous thrombolysis also benefit from endovascular
bolus in seconds without subsequent infusion. Although thrombectomy.68
tenecteplase is currently only approved for acute The treatment window of endovascular thrombectomy
myocardial infarction by the US Food and Drug has been extended to 24 h from symptom onset on the
Administration (FDA), it has been frequently used off- basis of imaging evidence of salvageable brain tissue69,70 or
label in acute ischaemic strokes.41 For patients who have collateral flow.71,72 In a meta-analysis of endovascular
had an ischaemic stroke with a duration of less than 4·5 h thrombectomy trials using a 6–24 h window, endovascular
who are eligible for intravenous thrombolysis, thrombectomy was associated with higher rates of
tenecteplase 0·25 mg per kg (maximum 25 mg) is now independent daily living (mRS 0–2) without increasing
considered as a safe and effective alternative to alteplase intracerebral haemorrhage or mortality compared to
0·9 mg per kg.49–55 The rate of symptomatic intracerebral medical treatment, and while there was no heterogeneity
haemorrhage of tenecteplase at 0·25 mg per kg was of treatment effect noted across subgroups defined by age,
comparable to alteplase 0·9 mg per kg. In prehospital gender, baseline stroke severity, vessel occlusion site,
thrombolysis by a mobile stroke unit, tenecteplase baseline Alberta Stroke Program Early CT Score, or mode
0·25 mg per kg for patients with ischaemic stroke with a of presentation, treatment effect was stronger in patients
duration of less than 4·5 h enhanced early reperfusion randomly assigned within 12–24 h than those randomly
rate.56 assigned within 6–12 h.72
For patients with acute large vessel occlusion stroke of Although patients with large vessel occlusion and large
with a duration of less than 4·5 h who are eligible for core infarcts were excluded in early trials, randomised
both intravenous thrombolysis and endovascular studies have found meaningful clinical benefits of
thrombectomy, tenecteplase 0·25 mg per kg (maximum endovascular thrombectomy in this subgroup of
25 mg) enhanced recanalisation rates before and at the patients.73–76 A pooled analysis showed that compared
end of the endovascular thrombectomy.49,50,57,58 However, it with medical therapy alone, endovascular thrombectomy
was not associated with better functional outcome at for patients with extensive ischaemic injury selected
90 days in patients with wake-up stroke selected by on non-contrast CT, CT perfusion, or MRI was
non-contrast CT.59 associated with a higher likelihood of reduced disability,
independent ambulation, and good functional
Intravenous thrombolysis in extended time-window outcome at 3 months.77 In practice, treatment decisions
In general, infarct core progresses with time from stroke for patients with large core infarcts need to be
onset, but the pace of progression varies among patients. individualised and consider patients’ comorbidities.
Therefore, ideally an individual tissue clock rather than a Figure 3 depicts large vessel occlusion, salvageable brain
fixed time window should determine eligibility of tissue, and restoration of cerebral blood flow after
reperfusion therapies. Advanced imaging (CT or MRI endovascular thrombectomy.
perfusion) could act as such a clock and was used to For posterior circulation large vessel occlusion, two
identify patients with salvageable brain tissue 9 h from studies have shown improved functional outcomes at
symptom recognition.60,61 This subset of patients had as 90 days in patients with basilar artery occlusion with
much benefit from intravenous thrombolysis, with endovascular thrombectomy compared with medical
similar risk of fatal intracerebral haemorrhage, as did treatment, although endovascular thrombectomy was
those treated within 3 h from stroke onset. Alternatively, associated with procedural complications and intracerebral
if patients with unknown stroke onset time (or wake-up haemorrhage.78,79 A meta-analysis suggested the overall
stroke) had diffuse-weighted imaging-positive lesions benefit of endovascular thrombectomy in acute basilar
indicative of acute ischaemia that were not yet hyper artery occlusion up to 24 h.80 However, the treatment
intense on fluid-attenuated inversion recovery (FLAIR) benefit in individuals with basilar artery occlusion with
sequence (eg, diffuse-weighted imaging–FLAIR milder deficits (NIHSS <10) remained uncertain.
mismatch), the stroke onset was likely to be within 4·5 h, Although stroke guidelines emphasise that intravenous
and they might benefit from alteplase.62 However, the thrombolysis should not delay endovascular throm
constrained MRI service in many regions might reduce bectomy, there is no strong evidence that intrave nous
the applicability of this technique. thrombolysis should be skipped in patients with large
vessel occlusion.81–86 Therefore, for stroke patients with
Endovascular thrombectomy and acute stroke anterior circulation large vessel occlusion who are
treatment admitted directly to a centre capable of endovascular
In 2015, endovascular thrombectomy was shown to thrombectomy within 4·5 h of symptom onset and who
reduce disability and mortality for ischaemic strokes are eligible for both treatments, current guidelines
attributed to acute large vessel occlusion.63–68 The number recommend both intravenous thrombolysis and

Seminar
Acute treatment for intracerebral haemorrhage

A B C In the early hours after intracerebral haemorrhage onset,
therapeutic options aim to limit haematoma expansion in
an attempt to prevent complications and poor clinical
outcomes.19 Although studies on single interventions
during the acute phase of intracerebral haemorrhage did
not show benefit on functional outcomes, the
implementation of a bundle of care (consisting of
immediate simultaneous anticoagulation reversal, blood
pressure management, and prespecified stroke unit
protocols [including glucose control and antipyretics])
within 6 h after intracerebral haemorrhage onset
improved both survival rates and functional outcome at
D CBF Tmax 6 months.89,90 Accordingly, implementation of an acute
bundle of care concept, combining a rapid anticoagulation
reversal, intensive blood pressure reduction, surgery, and
easy access to critical care, was significantly associated
with lower mortality rates 30 days after intracerebral
haemorrhage.91
The immediate reversal of anticoagulation improves
survival after intracerebral haemorrhage, yet its benefit
on functional outcomes is uncertain. The recommended
pharmacological anticoagulation reversal strategy
includes 4-factor prothrombin complex concentrate (in
CBF <30%: 46 ml Mismatch volume: 177 ml preference to fresh frozen plasma) and intravenous
Tmax >6·0s: 223 ml Mismatch ratio: 4·8 vitamin K for vitamin K antagonist-associated intra
cerebral haemorrhage; protamine for unfractionated and
E F G low molecular weight heparin reversal; andexanet alfa to
antagonise factor Xa inhibitors; and idarucizumab to
reverse the effects of dabigatran.92–102 When specific
medications to manage anticoagulation reversal are not
available, prothrombin complex concentrate can improve
haemostasis. For patients taking antiplatelets without the
need for neurosurgery, platelet transfusion is potentially
harmful.103 Other haemostatic therapies, including
recombinant activated factor VII104,105 and tranexamic
Figure 3: Ischaemic stroke due to large vessel occlusion acid,106–111 have not shown benefit on functional outcome.
CT performed 43 min after stroke onset showed no haemorrhage or early infarct changes, but a dense middle
Current recommendations advocate for blood pressure
cerebral artery sign on the right (arrow) and an electrocardiogram revealed atrial fibrillation (A). CT angiography
showed an occluded right middle cerebral artery (arrows in coronal and axial views; B and C). CT perfusion revealed reduction as soon as possible to a systolic target of
imaging evidence of salvageable brain tissue with a mismatch ratio of 4·8 between ischaemic penumbra volume approximately 140 mm Hg, with titration for a smooth
(223 mL, the region in green where Tmax delay > 6 s) and infarct core volume (46 mL, the region in purple where and sustained control ideally within 1 h.25,112 Reducing
cerebral blood flow <30%) in right middle cerebral artery territory (D). After intravenous tenecteplase (0·25 mg/kg)
systolic blood pressure to less than 130 mm Hg is
and endovascular thrombectomy, the occluded right middle cerebral artery (E, arrow) was recanalised (F) and the
neurological deficits largely resolved. The door-to-reperfusion time was 60 min. Subsequent diffuse-weighted MRI potentially harmful and should be avoided.113,114
showed residual infarction over the right insular region (G, arrow). The patient resumed full independence in daily Intravenous antihypertensive drugs with rapid action and
activities in a week and was discharged home with oral anticoagulants. Tmax=time-to-maximum. short half-life, such as nicardipine or labetalol, facilitate
blood pressure titration—but venous vasodilators like
endovascular throm bectomy. In stroke patients with transdermal glyceryl nitrate might be harmful.115 Despite
anterior circulation large vessel occlusion guideline recommendations, the benefit of intensive
admitted to a primary stroke centre and eligible for blood pressure reduction on functional outcomes after
intravenous thrombolysis (symptom onset ≤4·5 h) and acute intracerebral haemorrhage has been inconsistent
endovascular thrombectomy, guidelines recommend across randomised controlled trials, posthoc analyses,
intravenous thrombolysis followed by rapid transfer to and meta-analyses.113,116–123
endovascular thrombectomy-capable centres. During In patients with infratentorial intracerebral haemorrhage
postendovascular thrombectomy care, intensive control of who deteriorate clinically from hydrocephalus or
systolic blood pressure to lower than 120 mm Hg should brainstem compression, external ventricular drainage and
be avoided to prevent compromising the patients’ neurosurgical removal of large (>3 cm) cerebellar
functional recovery.87,88 haematomas reduces mortality compared with medical

Seminar
treatment alone.25 For supratentorial intracerebral Antithrombotic therapy after ischaemic stroke
haemorrhage, studies on craniotomy with surgical Antithrombotic therapy is indicated for almost all patients
evacuation have not shown clinical benefit.124–129 Current after an ischaemic stroke, either with oral anticoagulants
recommendations suggest that minimally invasive for patients with atrial fibrillation, or antiplatelet agents
surgery, with or without thrombolytic use, can reduce after non-cardioembolic causes of stroke. For minor
mortality for patients with a Glasgow coma scale between 5 strokes, initiation of antiplatelet therapy as early as
and 12 due to large supratentorial intracerebral possible after the first day of symptom onset reduces
haemorrhage (>20–30 mL), compared with conservative 90 day stroke recurrence.142 In case of a non-cardioembolic
management, although its benefit on functional outcomes minor stroke, a short course of dual antiplatelet therapy
is uncertain.130–136 Minimally invasive surgery compared to (clopidogrel and aspirin) initiated within 24 hours and
conventional craniotomy could improve functional lasting between 21 and 90 days is more effective in
outcomes but the benefit on mortality reduction is reducing recurrent vascular events than aspirin alone.143–145
similarly uncertain. The optimal timing for surgery The benefit in preventing early relapse is still evident
remains controversial because early intervention when dual antiplatelet agents were commenced within
(<12–24 h) can increase the risk of rebleeding despite the 72 h.146 Likewise, the combination of ticagrelor and aspirin
objective to reduce secondary brain injury and for 30 days provides benefit over aspirin monotherapy for
perihematomal oedema.137 Randomised controlled trials prevention of stroke.147 Approximately a quarter of White
addressing these questions are underway and extend to patients and 60% of Asian patients have a genetic variant
other techniques such as decompressive hemicraniectomy. in CYP2C19, resulting in reduced conversion of
clopidogrel into its active metabolite.148,149 It is unclear
Stroke unit whether this reduced platelet inhibition by clopidogrel is
In a stroke unit, patients are treated by an integrated, synonymous with higher stroke recurrence. In Chinese
multidisciplinary team of medical, nursing, and allied patients with CYP2C19 loss of function, the combination
health stroke experts. Stroke unit care has clearly shown of ticagrelor with aspirin was more effective in reducing
to improve survival and diminish stroke-related disability recurrent stroke within the first 90 days than clopidogrel
for patients of all ages, severities, and stroke subtypes.138 with aspirin.150,151 For long-term secondary prevention,
Crucial components of stroke unit care include clopidogrel, aspirin, or aspirin-dipyridamole are
swallowing assessment and training to minimise recommended as first-line agents. The addition of
aspiration pneumonia; timely management of fever, cilostazol to clopidogrel or aspirin after atherothrombotic
sepsis (if present), and glucose; early mobilisation and stroke showed promising results among Japanese
rehabilitation; pressure sore prevention; deep venous patients,152 and warranted further study in other
thromboembolism prophylaxis; and targeted secondary populations.153 There is no indication for direct oral
stroke prevention.139 Admission to a stroke unit also anticoagulants in patients with embolic stroke of
warrants the early detection and management of undetermined source (ESUS, defined as non-lacunar
neurological complications such as haemorrhagic ischaemic stroke without an obvious cause after standard
transformation of an ischaemic stroke, early seizures, evaluation).154,155
delirium, early recurrent stroke, or the development of Oral anticoagulants are indicated for patients with non-
cerebral oedema (including a space occupying middle valvular atrial fibrillation, with direct oral anticoagulants
cerebral artery infarction). Surgical decompression preferred over vitamin K antagonists due to a two-fold
performed within 48 h of stroke onset could reduce the lower risk of intracranial haemorrhage.156 The optimal
risks of death or a poor outcome in patients 60 years or time to start oral anticoagulation after ischaemic stroke
younger.140 With the exception of surgical decompression, has been addressed in randomised clinical trials, which
other treatments of early poststroke complications are reported that oral anticoagulation started 48 h after a
only based on empirical recommendations and this is an minor to moderate ischaemic stroke or on day 6 or 7 after
area requiring future research.141 a major ischaemic stroke appears safe without
exacerbating haemorrhagic transformation, although
Secondary prevention these results are yet to be stipulated in published
Secondary prevention demands prompt diagnostic guidelines.157,158
workup for the underlying stroke cause, early
identification of modifiable risk factors, and life-long Management of vascular risk factors
compliance to treatment. The strategy encompasses Hypertension is a major modifiable risk factor for both
antiplatelet therapy for non-cardioembolic ischaemic ischaemic stroke and intracerebral haemorrhage. Blood
strokes, oral anticoagulation for cardioembolic strokes, pressure control after ischaemic stroke to less than
treatment of hypertension, diabetes, and hyperlipidaemia, 130/80 mm Hg reduces risk of recurrent stroke by
as well as lifestyle adjustments, including smoking about 20% compared to less strict targets
cessation, promotion of physical activity, a healthy diet, (140–150/80 mm Hg) and prevents 17 cases of stroke
and weight management for obesity. per 1000 patients treated.159 Greater reductions in systolic

Seminar
and diastolic blood pressure appear to be linearly related combined.172 Stringent risk factor control and dual
to lower risk of recurrent stroke,160 although it is unclear antiplatelet therapy for 90 days could be considered.173
whether there is an optimal lower limit.161 The magnitude There is no benefit of intracranial angioplasty or stenting
of blood pressure reduction appears more important adjunctive to optimal medical management.174,175 The
than the class of antihypertensive medication used.162 The effect of ischaemic preconditioning in patients with
optimal timing of treatment initiation is uncertain; early intracranial atherosclerosis has been investigated in
blood pressure reduction within 7 days of an ischaemic a randomised trial and showed no effect on risk of
stroke was not superior to deferred blood pressure recurrent ischaemic stroke.176
control in terms of death or dependency.163 Closure of patent foramen ovale with a transcatheter
LDL cholesterol reduction lowers overall recurrent risk. device could be considered in patients up to 60 years with
A target of less than 1·8 mmol per L provides additional non-lacunar cryptogenic stroke who have a patent foramen
benefit over a less stringent target of 2·3–2·8 mmol per L ovale with a large shunt, atrial septum aneurysm, or both.
among patients with evidence of atherosclerosis.164 The high number needed to treat (131 to prevent
Adjunctive use of ezetimibe, PCSK9 inhibitors, or both is one recurrent stroke for 1 person-year) and the
recommended if the LDL target cannot be achieved with approximately 5% risk of periprocedural complications
statins alone. including atrial fibrillation should be taken into
For patients with diabetes, a glycated haemoglobin account.177,178 Patient selection in these trials was usually
level (HbA1C) of less than 53 mmol per mol (or <7%) done with the Risk of Paradoxal Embolism score, however
resulted in a reduced risk of microvascular and that does not include (high risk) characteristics of the
macrovascular complications,165 although an patent foramen ovale. The patent foramen ovale associated
individualised target is indicated if the risk and Stroke Causal Likelihood classification scheme does
inconvenience of a strict control outweigh potential include this by acknowledging the presence of an atrial
benefits. Whether more intensive control of HbA1C is septum aneurysm and the size of the shunt and shows
beneficial remains uncertain.166–168 GLP-1 receptor potential to guide personalised patent foramen ovale
agonists are new antihyperglycaemic drugs that have closure based on individual patient data meta-analysis.178
been shown to improve control of vascular risk factors
(HbA1C levels, blood pressure, body weight) in patients Resumption of antithrombotic therapy after
with diabetes, and reduce risk of stroke by 15%.169 To date, intracerebral haemorrhage
the benefit of GLP-1 receptor agonists has only been Risk of intracerebral haemorrhage recurrence varies
established in patients with diabetes or impaired glucose according to the underlying intracerebral haemorrhage
metabolism, of whom only a minority had a history of cause, reaching 15–20% per year in patients with cerebral
stroke; as such, GLP-1 receptor agonists have no role in amyloid angiopathy with multifocal cortical superficial
secondary stroke prevention yet. Various support siderosis and multiple microbleeds.179,180 However,
programmes aimed at improving adherence to secondary intracerebral haemorrhage is increasingly recognised as
prevention strategies resulted in improved control of a marker for ischaemic events.181–184 In patients who have
vascular risk factors but did not translate into a reduction had an intracerebral haemorrhage who also have clinical
of major vascular events.170,171 Anti-hypertensive treatment indications for antiplatelet therapy, resumption of aspirin
and lifestyle modification are indicated as secondary within 30 days after intracerebral haemorrhage was safe
prevention measures after intracerebral haemorrhage.25 in the RESTART trial.185–188 Other randomised controlled
The ideal target blood pressure is unknown, but a target trials are ongoing to investigate the effect of antiplatelet
of 130/80 mm Hg is recommended. resumption after intracerebral haemorrhage on safety,
reduction of major ischaemic events, overall long-term
Cause specific management of ischaemic stroke functional outcome, and optimal timing of resumption.
Carotid endarterectomy is recommended for patients In patients who have had an intracerebral haemorrhage
with ipsilateral severe (50–99%) carotid artery stenosis who also have atrial fibrillation, observational data showed
and surgery should be done within two weeks of the index that anticoagulation restarted 4–8 weeks after the
stroke. Among patients with 50–69% stenosis, the benefit intracerebral haemorrhage improved survival and
of carotid endarterectomy is dependent on patient functional outcome, even in patients with cerebral amyloid
characteristics, carotid endarterectomy symptom interval, angiopathy.189–193 Results of two randomised controlled
comorbidities, and plaque characteristics. Carotid trials confirmed the safety of restarting oral anticoagulation
endarterectomy is the preferred type of carotid after intracerebral haemorrhage,194,195 and several studies
revascularisation, however after restenosis, previous are still ongoing.192,193 Compared with oral anticoagulation,
irradiation or high perioperative risk carotid artery percutaneous left atrial appendage occlusion is an
stenting is an alternative. Intracranial atherosclerosis is a interventional approach that might reduce recurrent
frequent cause of stroke among Asian people and is intracerebral haemorrhage risk. The overall clinical benefit
associated with a high risk of early recurrence if the stroke of left atrial appendage occlusion, including reduction of
mechanism is thromboembolism and hypoperfusion ischaemic and haemorrhagic risk compared to oral

Seminar
anticoagulation, is tested in several randomised controlled intensive rehabilitation and vagal nerve stimulation
trials.196 In patients with mechanical heart valves, early showed promising results on recovery of arm function.204
anticoagulant resumption (eg, 1–2 weeks following Aphasia is among the most debilitating poststroke
intracerebral haemorrhage) is recommended, despite sequalae, without any proven intervention that resulted in
limited data from randomised controlled trials, due to the meaningful improvement in conversation.205 Due to the
excessive risk of major ischaemic events.197 revolution in the acute treatment of ischaemic
stroke many more people survive their stroke,
Life after ischaemic stroke and intracerebral resulting in increasing numbers of patients with
haemorrhage accompanying poststroke motor and cognitive disabilities.
Cognitive impairment, often resulting in poststroke WHO operationalised intervention packages in specific
dementia, mood disorders, and fatigue affects almost domains (eg, cognitive function, vision, language, pain,
every stroke survivor. The tragedy is that these symptoms bowel and bladder management, among others) for
are often unrecognised and only rarely investigated in which targeted interventions exist and should be
clinical trials despite being associated with mortality and developed. However, despite these recommendations
poor functional outcome.198 Trials that have been done there currently is a scarcity of evidence-based guidelines
are often aimed at improving poststroke functional (often in this area.206 Rigorous research with sound
motor) outcomes. The administration of fluoxetine in methodological approaches is therefore key to ultimately
randomised clinical trials among almost 6000 patients ameliorate this and ranks high among research priorities
with either ischaemic stroke or intracerebral of patients.207
haemorrhage showed no clinical meaningful effect on
functional outcome.199–201 Conclusion
Although a review of 45 trials including over There have been major advances in all areas of stroke
1600 patients with stroke (not otherwise specified) showed since the publication of the previous Seminar on stroke
that electromechanical arm training and robot-assisted in The Lancet, with many alluring future perspectives
arm training improved arm function, the clinical (panel). The acute treatment of ischaemic stroke has
importance remained uncertain.202 The effect of device- revolutionised over the past years, particularly with the
assisted arm training on functional arm performance advent of imaging-based late intravenous thrombolysis
could not be confirmed in a subsequent trial.203 Combined and endovascular thrombectomy. Recent advances again
Panel: Recent advancements and future perspectives

Major progress since last seminar Future perspectives
Treatment of acute ischaemic stroke Treatment of acute ischaemic stroke
• Imaging triage and intravenous thrombolysis by mobile • Endovascular thrombectomy for medium-sized vessel
stroke units. occlusions.
• Treatment time window for endovascular thrombectomy • Immediate transfer to angiosuite of patients with a high
extended up to 24 h in patients with large infarct core likelihood of large vessel occlusion, with direct endovascular
based on non-contrast CT without penumbra thrombectomy after exclusion of intracerebral
demonstration by CT perfusion. haemorrhage on non-contrast CT at angiosuite.
• Endovascular thrombectomy for basilar artery occlusion up Treatment of intracerebral haemorrhage
to 24 h. • Tailored (minimally invasive) surgical approach in the acute
Treatment of intracerebral haemorrhage phase of intracerebral haemorrhage.
• Early bundled interventions in the hyperacute phase, • New strategies to improve haemostasis, limit
including immediate (<1 h from admission) anticoagulant inflammation, and reduce perihematomal oedema.
reversal, blood pressure management, and stroke unit Secondary prevention
admission. • New targets for secondary prevention including
Secondary prevention inflammation and raised lipoprotein levels.
• Early initiation of oral anticoagulants after ischaemic • Antithrombotic treatment with factor XIa inhibitors, which
stroke, ranging from within 2 days in mild–moderate could inhibit thrombus formation more selectively than
stroke to 1 week in severe stroke in patients with atrial conventional oral anticoagulants without compromising
fibrillation. haemostasis.
• Growing body of evidence on safety of resumption of • Optimised medical management according to current
antithrombotic therapy (antiplatelet therapy and oral standards and refrain from carotid revascularisation in
anticoagulants) in patients who have an indication after patients with an estimated 5-year risk of below 20% of
intracerebral haemorrhage. recurrent stroke.

Seminar
move away from selection of patients for endovascular 4 Moseley ME, Kucharczyk J, Mintorovitch J, et al. Diffusion-weighted
thrombectomy based on perfusion imaging, given the MR imaging of acute stroke: correlation with T2-weighted and
magnetic susceptibility-enhanced MR imaging in cats.
beneficial effects of endovascular thrombectomy in AJNR Am J Neuroradiol 1990; 11: 423–29.
virtually every patient within 24 h of symptom onset. 5 Vilela P. Acute stroke differential diagnosis: stroke mimics.
Acute treatment of intracerebral haemorrhage is the next Eur J Radiol 2017; 96: 133–44.
6 Claassen J, Park S. Spontaneous subarachnoid haemorrhage. Lancet
frontier with acute, minimally invasive surgical 2022; 400: 846–62.
techniques as promising options, and the future 7 Feigin VL, Stark BA, Johnson CO, et al. Global, regional, and
perspective of additional anti-inflammatory treatment. national burden of stroke and its risk factors, 1990–2019:
a systematic analysis for the Global Burden of Disease study 2019.
Although the recurrent risk in some stroke subtypes Lancet Neurol 2021; 20: 795–820.
remains high, the challenge of secondary prevention also 8 Ospel JM, Schaafsma JD, Leslie-Mazwi TM, et al. Toward a better
lies in long-term treatment adherence. Putting the four understanding of sex- and gender-related differences in
important pillars of monitoring and prevention of endovascular stroke treatment: a scientific statement from the
American Heart Association/American Stroke Association. Stroke
modifiable risk factors, access to acute stroke treatment, 2022; 53: e396–406.
access to stroke units, as well as secondary prevention 9 Ekker MS, Verhoeven JI, Vaartjes I, van Nieuwenhuizen KM,
and rehabilitation on the political and public health-care Klijn CJM, de Leeuw FE. Stroke incidence in young adults
according to age, subtype, sex, and time trends. Neurology 2019;
agenda is key to tackling the global burden of stroke and 92: e2444–54.
reducing its immense personal and societal strain, 10 Ekker MS, Boot EM, Singhal AB, et al. Epidemiology, aetiology, and
particularly in LMICs.208 management of ischaemic stroke in young adults. Lancet Neurol
2018; 17: 790–801.
Contributors 11 O’Donnell MJ, Chin SL, Rangarajan S, et al. Global and regional
All authors contributed equally to the literature search, data collection effects of potentially modifiable risk factors associated with acute
and their interpretation, writing of the manuscript (original drafts, stroke in 32 countries (INTERSTROKE): a case-control study. Lancet
reviewing and editing each other sections), and visualisation (ie, tables 2016; 388: 761–75.
and figures). All authors verified and approved the final version of the 12 Verhoeven JI, Allach Y, Vaartjes ICH, Klijn CJM, de Leeuw FE.
manuscript. Ambient air pollution and the risk of ischaemic and haemorrhagic
stroke. Lancet Plan Health 2021; 5: e542–552.
Declaration of interests
13 Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of
NAH receives research support from the Dutch Heart Foundation subtype of acute ischemic stroke. Definitions for use in a
(03–005–2022–0031). BC has received research grants from Regional multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke
GIRCI Méditerranée, Nice University Hospital, Acticor Biotech, and Treatment. Stroke 1993; 24: 35–41.
Bayer; support for attending meetings from the European Stroke 14 Dichgans M, Pulit SL, Rosand J. Stroke genetics: discovery, biology,
Organisation, French Neurovascular Society, Belgium Stroke Council, and clinical applications. Lancet Neurol 2019; 18: 587–99.
and French Neurology Society; and is an editorial board member of the 15 Mishra A, Malik R, Hachiya T, et al. Stroke genetics informs drug
European Stroke Journal, chair of the European Stroke Organisation discovery and risk prediction across ancestries. Nature 2022;
(ESO) Simulation Committee, and chair of the Education and 611: 115–23.
Communication committee within StrokeLink (all unpaid). TWL has 16 Traylor M, Persyn E, Tomppo L, et al. Genetic basis of lacunar
received support for the present manuscript from the Kwok Tak Seng stroke: a pooled analysis of individual patient data and genome-
Centre for Stroke Research and Intervention and the SHKP Kwok Brain wide association studies. Lancet Neurol 2021; 20: 351–61.
Health Research Centre; an educational grant from Boehringer 17 Keep RF, Hua Y, Xi G. Intracerebral haemorrhage: mechanisms of
Ingelheim; consulting fees from Shionogi & Co and Janssen Research & injury and therapeutic targets. Lancet Neurol 2012; 11: 720–31.
Development; honoraria from Daiichi-Sankyo and Argenica 18 Shao Z, Tu S, Shao A. Pathophysiological mechanisms and
Therapeutics; payment for expert testimony; travel expenses from potential therapeutic targets in intracerebral hemorrhage.
Pfizer, Daiichi-Sankyo, and Boehringer Ingelheim; was a member of the Front Pharmacol 2019; 10: 1079.
data safety monitoring board for the ENCHANTED2/MT study at The 19 Morotti A, Boulouis G, Dowlatshahi D, et al. Intracerebral
George Institute for Global Health; and is chairman of the exemptions haemorrhage expansion: definitions, predictors, and prevention.
sub-committee, and member of the licentiate committee for The Lancet Neurol 2023; 22: 159–71.
Medical Council of Hong Kong, co-chair of the co-chairs committee for 20 Wilkinson DA, Pandey AS, Thompson BG, Keep RF, Hua Y, Xi G.
Mission Thrombectomy 2020+ as part of The Society of Vascular Injury mechanisms in acute intracerebral hemorrhage.
Interventional Neurology, associate editor for the International Journal of Neuropharmacology 2018; 134: 240–48.
Stroke, assistant editor for the journal Stroke, and board member of the 21 Chen Y, Chen S, Chang J, Wei J, Feng M, Wang R. Perihematomal
specialty board in neurology at Hong Kong College of Physicians (all edema after intracerebral hemorrhage: an update on pathogenesis,
unpaid). F-EdL received funding from the Dutch Heart Foundation, risk factors, and therapeutic advances. Front Immunol 2021;
12: 740632.
Abbott, and ZonMW; serves as a member of the scientific advisory
board of the Dutch Heart Foundation and is associate editor for the 22 Cliteur MP, Sondag L, Cunningham L, et al. The association
between perihaematomal oedema and functional outcome after
International Journal of Stroke (unpaid); and has received registration
spontaneous intracerebral haemorrhage: a systematic review and
fees from ESO for the ESO Conference. None of these parties or meta-analysis. Eur Stroke J 2023; 8: 423–33.
funders had any influence in any part of the preparation of this
23 Cordonnier C, Demchuk A, Ziai W, Anderson CS. Intracerebral
Seminar. haemorrhage: current approaches to acute management. Lancet
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2 www.thelancet.com Published online May 14, 2024 https://doi.org/10.1016/S0140-6736(24)00642-1

Epidemiology—global burden of stroke Pathophysiology and diagnostic workup of

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Ischaemic stroke Intracerebral haemorrhage

Recent small subcortical infarction Deep perforating artery vasculopathy

Arterial borderzone infarction Arteriovenous malformation

Infarctions in multiple territories

Figure 1: Patterns of ischaemic stroke and intracerebral haemorrhage

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wide association studies have identified some common Diagnostic investigations

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suspected large vessel occlusion from emergency sites

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Acute treatment for intracerebral haemorrhage

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Panel: Recent advancements and future perspectives

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