nature reviews disease primers https://doi.org/10.

1038/s41572-023-00424-7

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Intracerebral haemorrhage
Laurent Puy1, Adrian R. Parry-Jones    2,3,4, Else Charlotte Sandset5,6, Dar Dowlatshahi7, Wendy Ziai8,9
& Charlotte Cordonnier1 
Abstract Sections

Intracerebral haemorrhage (ICH) is a dramatic condition caused by Introduction

the rupture of a cerebral vessel and the entry of blood into the brain Epidemiology
parenchyma. ICH is a major contributor to stroke-related mortality Mechanisms/pathophysiology
and dependency: only half of patients survive for 1 year after ICH, and
Diagnosis, screening and
patients who survive have sequelae that affect their quality of life. prevention
The incidence of ICH has increased in the past few decades with shifts
Management
in the underlying vessel disease over time as vascular prevention
Quality of life
has improved and use of antithrombotic agents has increased. The
pathophysiology of ICH is complex and encompasses mechanical Outlook

mass effect, haematoma expansion and secondary injury. Identifying

the causes of ICH and predicting the vital and functional outcome of
patients and their long-term vascular risk have improved in the past
decade; however, no specific treatment is available for ICH. ICH remains
a medical emergency, with prevention of haematoma expansion as
the key therapeutic target. After discharge, secondary prevention and
management of vascular risk factors in patients remains challenging
and is based on an individual benefit–risk balance evaluation.

1
Lille Neuroscience & Cognition (LilNCog) - U1172, University of Lille, Inserm, CHU Lille, Lille, France. 2Geoffrey
Jefferson Brain Research Centre, Manchester Academic Health Science Centre, Northern Care Alliance NHS
Foundation Trust & University of Manchester, Manchester, UK. 3Division of Cardiovascular Sciences, Faculty
of Biology, Medicine and Health, University of Manchester, Manchester, UK. 4Manchester Centre for Clinical
Neurosciences, Northern Care Alliance NHS Foundation Trust, Salford, UK. 5Department of Neurology, Stroke Unit,
Oslo University Hospital, Oslo, Norway. 6The Norwegian Air Ambulance Foundation, Oslo, Norway. 7Department
of Medicine (Neurology), University of Ottawa and Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
8
Division of Neurocritical Care, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins
University School of Medicine, Baltimore, MD, USA. 9Department of Neurology, Johns Hopkins University School
of Medicine, Baltimore, MD, USA.  e-mail: charlotte.cordonnier@univ-lille.fr

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Introduction
Intracerebral haemorrhage (ICH) is defined by the rupture of a cerebral
blood vessel and the entry of blood into the brain parenchyma. The
most common cause of non-traumatic (also called spontaneous) ICH
is cerebral small-vessel disease (SVD; a group of diseases that affect
the small arteries, arterioles, venules and capillaries of the brain;
namely cerebral amyloid angiopathy (CAA) and arteriolosclerosis).
The pathophysiology of ICH is complex and encompasses mechanical
haematoma expansion, mass effect (local pressure from the bleeding
core on adjacent structures of the brain) and secondary injury (mainly
driven by toxicity of blood compounds).
The concept of ‘time is brain’ is relevant for the management of
ICH. Even in the absence of specific treatment, ICH is a neurological
emergency. No clinical scale is accurate enough to distinguish ischae-
mic stroke from bleeding; therefore, emergency brain and vascular
imaging is mandatory to diagnose ICH, elucidate its cause and identify
patients who may need surgical interventions (such as those with
intraventricular extension with hydrocephalus or brainstem compres-
sion). Prompt treatments that target haematoma expansion (such as
intensive blood pressure (BP) lowering or correction of haemostatic
disorders) should be implemented immediately. Long-term BP control
is probably the most important intervention in terms of secondary
prevention.
Although ICH represents 20–30% of all acute strokes, the disability-
adjusted life years (DALYs) lost for ICH is greater than that for ischaemic
stroke1–3. Mortality is >50% 1 year after ICH onset, and survivors can
have functional and cognitive impairment4–6. In addition, survivors
of ICH are at high risk of future vascular events (both ischaemic and
haemorrhagic, cerebral and extracerebral), adding to the complexity
of the management of the disease.
This Primer focuses on non-traumatic spontaneous ICH and sum-
marizes the pathophysiology, diagnosis and treatment of this condition,
in addition to the effects of ICH on patient quality of life (QoL).
Epidemiology
In the Global Burden of Disease Study 2019, ICH constituted 27.9% of all
new strokes in 2019 (ref. 3). The worldwide global incidence of ICH was
~3.5 million (42 cases per 100,000 person-years), with a particularly high
incidence in low-income countries and parts of Oceania and Southeast
Asia3 (Fig. 1). People living in low-income countries or regions have an
almost twofold greater proportion of ICH compared with those living
in higher-income countries or regions (29.5% compared with 15.8% of all
stroke cases in 2019)2,3. The global prevalence of ICH almost doubled from
~1.9 million in 1990 to ~3.7 million in 2013 in people aged 20–64 years7.
Improved access to imaging, as well as an ageing population with more
antithrombotic agent use may explain this increase.
Between 1990 and 2019, ICH rose from the ninth to the fourth
leading cause of premature death, with an estimated 3 million indi-
viduals dying from ICH in 2019 (ref. 3). The case fatality rate was high-
est in Oceania, Central Asia, Southeast Asia and parts of sub-Saharan
Africa. The higher prevalence and mortality of ICH in low-income and
middle-income countries might be due to a lack of public awareness of
preventive measures (such as diagnosis and treatment of arterial hyper-
tension) and access to health care. In 2019, an estimated ~70 million
DALYs lost (combination of years of life lost owing to premature mortal-
ity and years lived with disability) were due to ICH, whereas an estimated
~65 million DALYs were lost owing to ischaemic stroke3 (Fig. 1).
Risk of ICH increases with age, although ICH can still affect young
individuals8. In people <50 years old, the annual incidence of ICH varied
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from 2 to 5 per 100,000 individuals and was most common in men9.
Moreover, the incidence of ICH in Asian individuals is around double
that in Black or white people1,10. Furthermore, in a US study, Black and
Hispanic people had ICH 10 years earlier than white individuals11. ICH
might be more prevalent in men than in women, possibly owing to a
complex sex-based interaction between age, ethnicity and underlying
risk factors12,13.
Mechanisms/pathophysiology
Causes of ICH
Non-traumatic ICH is a heterogeneous condition, with several potential
causes that share distinct acute management and outcome14. There-
fore, identification of the underlying mechanisms of ICH should be as
prompt as possible. Attempts have been made to produce a classifica-
tion system for ICH subtypes. ICH can be classified either according to
anatomical location (using the CHARTS instrument to classify haemor-
rhage as lobar (haemorrhage located in one of the cerebral lobes) versus
non-lobar (haemorrhage located in the deep structures of the brain),
supratentorial (in regions of the brain located above the tentorium
cerebelli) versus infratentorial (in regions of the brain located under the
tentorium cerebelli)) or according to presumed mechanisms (using
the H-ATOMIC, SMASH-U and CLASICH instruments)15–19. In ~80% of
cases20, ICH involves a small arteriole that is affected by chronic cer-
ebral SVD of one of two main origins: deep perforating vasculopathy
(also termed hypertensive arteriopathy or arteriolosclerosis) or CAA.
ICH caused by SVD is usually termed ‘spontaneous’ ICH whereas other
causes of ICH that have macrovascular aetiology (such as arteriovenous
malformation, cavernoma or cerebral sinus venous thrombosis) or neo-
plastic aetiology are usually referred to as secondary ICH. ICH has been
considered as a single entity for many years, and, although these condi-
tions share distinct risk factors, pathophysiology and prognosis, their
exact prevalence and distribution across the globe remain unknown.
Deep perforating vasculopathy or arteriolosclerosis. Deep per-
forating vasculopathy (also termed hypertensive arteriopathy or
arteriolosclerosis) is the main cause of ICH (Fig. 2). This condition
is characterized by lipohyalinosis, arteriolosclerosis and fibrinoid
necrosis, and it predominantly affects deep perforating arteries that
become prone to both rupture and occlusive events21. Bleeding gener-
ally occurs in deep structures (including the basal ganglia, thalamus,
deep white matter and pons) but can also arise from lobar regions22,23.
The main vascular risk factors for ICH caused by deep perforating vas-
culopathy are age, hypertension and excessive alcohol consumption8.
The prevalence of deep ICH is higher in Black and Hispanic individuals
than in white individuals and is higher in low-income countries than in
high-income countries (mediated by poorly controlled hypertension
in low-income countries)11,24.
Cerebral amyloid angiopathy. CAA is caused by vascular deposits of
Aβ-amyloid peptide (mostly comprising Aβ40) in the wall of cortical
and leptomeningeal vessels and is responsible for lobar ICH (Fig. 2).
Although hereditary forms of CAA exist, most cases are sporadic25. CAA
occurs frequently in elderly individuals; two-thirds of spontaneous
ICH in patients >70 years is related to CAA, with no reported sex differ-
ence26. Other clinical manifestations of CAA are cognitive impairment
and transient focal neurological episodes but it can be asymptomatic
for years27. Three main factors increase risk of ICH in patients with
CAA: untreated hypertension, a genetic predisposition (especially
apolipoprotein-ε2/4 status) and use of antithrombotic agents25.
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Incidence
(per 100,000 people)
<15.0
15.0–<21.4
21.4–<31.5
31.5–<39.7
39.7–<48.6
48.6–<57.4
57.4–<68.8
68.8–<80.4
80.4–<97.1
≥97.1
No data

DALYs
(per 100,000 people)
<136.8
136.8–<170.5
170.5–<223.2
223.2–<347.5
347.5–<533.3
533.3–<692.1
692.1–<959.9
959.9–<1,217.3
1,217.3–<1,507.4
≥1,507.4
No data

Fig. 1 | Epidemiology of intracerebral haemorrhage. The global distribution of age-standardized stroke incidence per 100,000 people (panel a) and related
disability-adjusted life years (DALYs) (panel b) by country or region for both sexes. Adapted with permission from ref. 3, CC BY 4.0 (https://creativecommons.org/
licenses/by/4.0/).

Other causes. Non-traumatic ICH is heterogeneous and can be caused cerebral infarction, severe clotting factor deficiency such as haemo-
by chronic cerebral SVD, brain arteriovenous malformation, intracra- philia, brain tumour (both primary or metastasis), vasculitis, infective
nial aneurysm, dural arteriovenous fistula, cavernous malformation, endocarditis or posterior reversible encephalopathy syndrome. Few
intracranial venous thrombosis, haemorrhagic transformation of data are available regarding sex specificities or other epidemiological

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a b
c d e
Fig. 2 | Examples of intracerebral haemorrhage associated with deep
perforating vasculopathy and probable cerebral amyloid angiopathy.
a, Deep intracerebral haemorrhage with deep cerebral microbleeds (arrow)
suggesting deep perforating vasculopathy in a 56-year-old man with chronic
hypertension. b, Lobar intracerebral haemorrhage with lobar cerebral
microbleeds (arrows) in a patient with cerebral amyloid angiopathy. c–e, Other
biomarkers frequently observed in cerebral amyloid angiopathy and used in the
Boston criteria version 2.0: cortical superficial siderosis (panel c), white-matter
hyperintensities with multispot pattern (panel d) and perivascular enlarged
spaces in centrum semi-ovale (panel e).
characteristics of these rare causes. Although 80% of non-traumatic
ICH is due to SVD, clinicians should keep the other causes in mind
when evaluating patients. Some of these causes of ICH require urgent
treatment (Fig. 3).
ICH pathophysiology
Vessel rupture. Regardless of the underlying cause, ICH begins with
blood vessel rupture and extravasation of blood into the brain paren-
chyma. In deep perforating vasculopathy-related ICH, vessel wall
fragility is related to hyaline changes and subsequent arteriolone-
crosis, which often occurs at bifurcation points in the lenticulostriate
arterioles28. In patients with CAA, a similar weakening of cortical and
leptomeningeal vessel walls by the deposition of β-amyloid leads to
lobar haemorrhage. In chronic SVD, the precipitant for vessel rupture
is unknown, but in one population-based study, systolic BP rose steeply
in the days to weeks preceding ICH and may have an important role29.
Haematoma expansion. One out of five patients with ICH experience
subsequent haematoma expansion, which is associated with poor
outcomes30. Indeed, the odds of death and disability triple with as
little as 3 ml of haematoma expansion31. Risk of expansion is highest
during the first 3 h and reaches a plateau after 6 h (ref.  30). The two
main predictors of haematoma expansion are the delay between ICH
onset and first brain imaging and the use of antithrombotic drugs30.
Early clinicopathological studies and modelling studies lend support
to the hypothesis that bleeding from a primary vessel rupture applies
shear forces (the force that the blood flow exerts on the vessel wall that
can deform endothelial cells) to adjacent vessels, precipitating further
bleeding and haematoma expansion32,33.
Perihaematomal area. The perihaematomal area is a strategic inter-
face for both deleterious and beneficial effects and as a result, the
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influence of this area on the prognosis of ICH is unclear34 (Figs. 4 and 5).
Immediate physical tissue injury occurs in the perihaematomal
brain owing to the space-occupying effect of the expanding haema-
toma. Larger haematomas will lead to raised intracranial pressure
(ICP; the pressure exerted by fluids such as cerebrospinal fluid
(CSF) inside the skull and on the brain tissue within the craniospinal
compartment) and herniation, which have implications for brain tissue
distant from the haematoma via compression and reduced cerebral
perfusion pressure (the net pressure gradient between mean arterial
pressure and ICP that drives oxygen delivery to cerebral tissue).
Secondary injury begins within hours of the ICH and progresses,
contributing to tissue damage over the subsequent days to weeks35.
Secondary injury is initiated and propagated by multiple cellular and
molecular events, including factors released by primary physical
injury, components of extravasated serum and lysis of erythrocytes36.
Factors released from damaged tissue and extravasated blood (such as
nucleic acids, ATP, thrombin and extracellular matrix components) are
detected by pattern recognition receptors on the surface of microglia37,
which become activated and initiate a damaging pro-inflammatory
response. Activated microglia cannot fully clear the haematoma;
therefore, they signal to endothelial cells to trigger the recruitment of
circulating macrophages and neutrophils38,39. Neutrophils are the first
leukocytes to infiltrate the brain tissue after initial injury40. Neutrophils
have a role in inflammation and can engage a specific suicidal death
mode (netosis), which has been observed after ICH in a human
post-mortem study41. Neutrophil extracellular traps (NETs) exert
pro-inflammatory and pro-haemostatic effects42.
Erythrocyte lysis begins ~24 h after ICH with release of haemo-
globin, haem and iron, which are all toxic to the surrounding tissue
through oxidative damage to proteins, nucleic acids, carbohydrates
and lipids37. Collectively, these processes (mass effect, thrombin,
microglial activation, recruitment of pro-inflammatory cells and blood
product toxicity) are toxic for the brain and precipitate cell death
through various mechanisms and timing (excitotoxicity mediated by
glutamate release, necrosis, apoptosis, pyroptosis and ferroptosis)43,44.
These processes also contribute to cerebral oedema, which occurs
progressively over 3 days and increases up to 1–2 weeks after ICH
onset45,46.
This perihaematomal area (brain parenchyma at the immediate
border of the haematoma core) is also a strategic interface for adaptive
response to ICH, including endogenous blood clearance process, and
tissue remodelling and repair47. These beneficial effects are mainly
driven by the changing nature of the inflammatory response over
time, switching form a pro-inflammatory to an anti-inflammatory
status48. Although the precise time frame remains unknown, this shift
is suggested to start in the first week after ICH47. This change is driven
by the release of cytokines, chemokines and enzymes by leukocytes
recruited to the site of injury and glial cells. Anti-inflammatory macro­
phages and microglia develop their haemoglobin-scavenger abilities
to enhance haematoma resorption47 and to limit the injury caused by
blood breakdown products. After erythrolysis, haptoglobin binds to
free haemoglobin, and this complex binds to CD163, a scavenger recep-
tor expressed by microglia and macrophages; however, haptoglobin
is rapidly depleted in ICH, meaning that not all free haemoglobin is
effectively scavenged, and haem can be released from haemoglobin49.
Haemopexin is a haem scavenger, neutralizing its toxicity and trans-
porting it to the liver for catabolism and excretion50. Regulators of
this scavenging system include the transcription factor NRF2 and the
receptor PPARγ50.
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Hydrocephalus. Patients with ICH are at risk of hydrocephalus
(dilatation of the ventricular system)51. The risk is higher (50–70%)
in patients with intraventricular haemorrhage (IVH)52. Two forms of
hydrocephalus exist: obstructive (blood clot blockage), which requires
urgent drainage, and non-obstructive, which can be a delayed compli-
cation. The latter may also require a chronic external drainage system
(shunt) depending on the clinical severity. Several factors are involved
in hydrocephalus including blood clot blockage, ependymal cell dam-
age, blood–brain barrier impairment, inflammation and the presence
of blood components (such as thrombin and iron) in CSF52.
Diagnosis, screening and prevention
Diagnosis
Although acute stroke must always be considered in patients with acute
onset focal neurological deficits owing to its relatively high pre-test
probability across all age groups in those presenting with these deficits,
medical history or clinical examination cannot reliably distinguish an
ischaemic stroke from ICH without neuroimaging. Some clinical fea-
tures such as headache at onset, severe hypertension, rapid progression
of symptoms and altered level of consciousness are anecdotally more
common in patients with ICH than in those with ischaemic stroke. How-
ever, clinical prediction rules incorporating these features and others
overlap with findings in ischaemic stroke from large vessel occlusions53.
Accordingly, immediate neuroimaging (CT scan or MRI) is a crucial first
step to differentiate ICH from ischaemic stroke54,55.
Given that early haematoma expansion and neurological deterio-
ration are common in those with ICH56, the clinical course of patients
in the acute setting can be highly dynamic and requires close and
frequent monitoring.
Recent advances in neuroimaging
Neuroimaging to guide acute care. CT or MRI of the brain should
be performed as soon as possible in those with suspected ICH. Owing
to its wide availability, non-contrast CT is the reference imaging
type worldwide for the positive diagnosis of ICH (visible as a spon-
taneous hyperdensity). Although with sensitivity equal to that of
CT scan, brain MRI is less often used in the acute setting55. As mentioned
earlier, individuals in low-income and middle-income countries have
a higher risk of ICH than those in high-income countries; however,
fewer than one CT scanner per million inhabitants is available in these
countries compared with ~40 scanners per million inhabitants in high-
income countries57. To reduce the mortality and morbidity due to ICH,
international public health policy should promote access to brain
CT scanners in low-income and middle-income countries. In addition
to the identification of ICH, the brain imaging performed at admis-
sion is also useful to assess the severity of the bleeding (for example,

Arteriovenous malformation Cavernous malformation

• Extension to other brain compartments • Small, homogeneous ICH with no
(subarachnoid haemorrhage) extension to other brain compartments
• Flow voids • ‘Popcorn’ appearance on MRI
• Calcification
• Nidus with abnormal dilated vessels
• Arteriovenous shunt
Cerebral venous thrombosis
• Area of venous infarct
• ICH close to sinuses or veins
Micro-aneurysm (infective endocarditis) • High relative oedema volume
• Acute and multiple ischaemic lesons
• Small irregular arterial aneurysms
• Diffuse brain microbleeds
Brain tumour (primary and/or metastasis)
• Large perihaematomal oedema

Haemorrhagic transformation
of cerebral infarction Vasculitis
• Substantial areas of acute ischaemic • Small multiple acute ischaemic lesions
lesions adjacent to the ICH • Segmentary diffuse arterial stenosis

Moya Moya disease Posterior reversible encephalopathy

• Stenosis and/or occlusion of the syndrome
terminal portion of the internal • Parietal and occipital asymmetrical
carotid arteries oedematous lesions
• Presence of dilated collateral vessels

Dural arteriovenous fistula

• Subarachnoid or subdural extension
Aneurysm • Abnormal dilated cortical veins and
• Disproportionate subarachnoid extension extracranial arteries without nidus
of the blood, abnormal focal dilatation of an artery • Arteriovenous shunt

Fig. 3 | Clues for underlying treatable causes of intracerebral haemorrhage. Non-traumatic cerebral haemorrhage can be caused by several macrovascular
disorders, each of which have key features that can be observed via brain MRI and CT. ICH, intracerebral haemorrhage.

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• Blood pressure lowering • Decompressive craniotomy Suggestion for therapeutic

• Haematoma evacuation • Boost the switch from pro-inflammatory intervention
• Haemostatic drugs to anti-inflammatory status • Iron chelators
Deleterious effects
Beneficial effects
• Mass effect • Excessive pro-inflammatory response • Toxicity of blood lysate
• Tissue necrosis • Oedema-related mass effect • Oxidative stress
• Microvascular collapse or rupture • Apoptosis/ferroptosis (cell death)

Minutes Hours Days Weeks Months

• Paracrine effect of inflammatory • Anti-inflammatory • Blood • Tissue remodelling

cells (encirclement of the lesion) status clearance and repair

• Boost the switch from pro-inflammatory • Enhance haemoglobin-

to anti-inflammatory status scavenging activity

Fig. 4 | Putative secondary injury and adaptive process following intracerebral haemorrhage and potential therapeutic targets. The upper part (red) of the
figure describes the secondary brain injuries that occur in the perihaematomal area, and the lower part (blue) describes the adaptive and repair processes. Grey boxes
indicate current or putative therapeutic interventions to limit deleterious effects and promote beneficial ones.

volume, proximity to the brainstem and the presence of blood in
the ventricles).
The most important imaging biomarker for risk of haematoma
expansion is ICH volume at admission30. Baseline ICH volume can be
estimated in clinical practice using the ellipsoid volume formula58
(Supplementary Fig. 1), although semi-automated software based
on intensity and planimetric volume measurement is under develop-
ment59. A more detailed analysis allows the identification of patients
with active bleeding, as these patients have a higher risk of haematoma
expansion.
The CT-angiography (CTA) spot sign is a radiological finding of
contrast extravasation from a ruptured vessel, representing active
haemorrhage into the parenchymal or ventricular space (Fig. 6). The
presence of CTA in the first few hours of ICH onset is predictive of both
haematoma expansion and functional outcome60. However, the clini-
cal use of the CTA spot sign is dependent on the timing of the imaging
relative to symptom onset; the presence of the spot sign within 2 h of
ICH onset represents active extravasation, whereas its presence 6 h
after ICH onset is more likely to reflect pseudo-aneurysmal fibrin globe
formation where the bleeding has stopped61. Several non-contrast CT
predictive biomarkers for haematoma expansion are being evaluated62
(Fig. 6), including blend signs, swirl signs, fluid–fluid levels, hypodensi-
ties and black hole signs as well as irregular morphologies and small
satellite haematomas; however, these markers are not validated for
clinical use.
Establishing aetiology
Identifying the cause of ICH is crucial for both acute management
and secondary prevention. Secondary causes of non-traumatic ICH
that may require urgent therapy should be ruled out after diagnosis of
ICH. In a prospective evaluation of CTA and MRI in patients with ICH,
20% of patients <70 years old had a secondary vascular cause such as
arteriovenous malformations, fistula or cavernous malformations20.
CT or MR venography may be indicated to exclude cerebral venous
thrombosis as the underlying cause of ICH, depending on the history
and radiological appearance. Other imaging sequences, such as arterial
spin-labelling MRI, can be useful to screen for an arteriovenous shunt
in arteriovenous malformations (Fig. 7). A catheter digital subtraction
angiogram is indicated in a subgroup of patients with ICH with a high
probability of an underlying vascular secondary cause and in whom
the benefit–risk balance of the procedure is deemed reasonable: those
with lobar spontaneous ICH and age <70 years, deep/posterior fossa
ICH and age <45 years, or deep/posterior fossa and age 45–70 years
without history of hypertension and negative non-invasive imaging63.
After ruling out these secondary causes of ICH, a detailed evaluation of
the brain parenchyma using MRI is necessary to assess for biomarkers
of deep perforating vasculopathy and CAA (Fig. 2).
The traditional sequence to detect haemorrhagic biomarkers is
T2*-weighted gradient Echo, in which the local magnetic field inho-
mogeneities caused by paramagnetic iron in ICH, microbleeds and
siderosis, result in signal loss (also called susceptibility effect). Of note,

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several parameters can influence the detection rate of these haemor-
rhagic biomarkers. For instance, a higher magnetic field (1.5 T com-
pared with 3 T), low flip angle, long echo time and long repetition
time increase the sensitivity to susceptibility effects64. Susceptibility-
weighted imaging (SWI) is another key sequence to improve the
detection of such lesions65.
For deep perforating vasculopathy, clinicians should search for
related haemorrhagic (deep cerebral microbleeds and/or old silent
deep ICH) and ischaemic (cerebral white-matter hyperintensities
of presumed vascular origin and/or lacunes) biomarkers. Impor-
tantly, deep perforating vasculopathy is likely to be part of a dynamic
multisystemic disorder affecting the small vessels outside the brain;
therefore, the detection of typical end-organ damage related to arte-
rial hypertension (retinopathy, coronary heart disease or myocardial
infarction and heart failure, proteinuria and renal impairment, and
vasculature atherosclerotic changes (stenosis and aneurysms)) is
important66.
By contrast, the definitive diagnosis of CAA requires neuro-
pathological examination. Hence, in vivo indirect biomarkers — lobar
cerebral microbleeds, cortical superficial siderosis, white-matter
hyperintensities, subcortical dilated perivascular spaces and cortical
microinfarcts — that reflect various aspects of CAA pathophysiol-
ogy are used. The most commonly used criteria for CAA diagnosis
are the Boston criteria 2.0; these criteria provide various degrees of
diagnostic certainty for CAA (possible, probable or definite)67. The
most clinically relevant category is the probable category, defined
as: a patient older than 50 years old who experienced a lobar ICH and
showing either multiple strictly lobar haemorrhagic lesions (old lobar
ICH or lobar cerebral microbleeds or cortical superficial siderosis)
or one lobar haemorrhagic lesion with white-matter feature (visible
severe perivascular space in the centrum semi-ovale or white-matter
hyperintensities in a multisport pattern). In patients who cannot
undergo brain MRI, the Edinburgh CT scan-based criteria can predict
underlying moderate or severe CAA22 (Supplementary Box 1).
Although the anatomical location of ICH in the lobar versus deep
brain regions has traditionally been used to indicate different underly-
ing causes of ICH, this approach is probably too reductionist. In older
patients with lobar ICH, it is likely that a certain degree of both CAA
and deep perforating vasculopathy exist22,68.
In young patients with ICH who have biomarkers of SVD and
familial history, hereditary SVD due to COL4A1, COL4A2, HTRA1 or
APP mutations should be discussed69–71. In patients with no identifiable
cause of ICH, a repeat brain MRI, and/or catheter digital subtraction
angiogram in selected patients, can be repeated in 3–6 months, as
identifying the cause of the bleeding is important to inform prognosis
and tailor secondary prevention.
Prevention
The Interstroke study identified several modifiable risk factors
that can be targeted for the prevention of ICH72. In this study, the
greatest population attributable risk for ICH was from untreated
hypertension (73.6%), followed by lack of exercise (27.6%), waist-
to-hip ratio (26.1%), poor diet (24.1%), excessive alcohol intake
(14.6%), current smoking (9.5%) and psychosocial stress (3.5%). This
study highlights the importance of lifestyle management for the
prevention of ICH, particularly for the treatment of hypertension.
Tight control of hypertension is associated with a significant reduc-
tion in ICH occurrence in both the primary and secondary prevention
setting73,74.
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Management
Stroke unit care
A stroke unit is a 24/7 specialized ward dedicated to the care of patients
with acute stroke by a multidisciplinary team that includes specialist
nursing staff, physiotherapists and speech therapists. A meta-analysis of
eight trials involving 2,657 patients showed that stroke unit care benefits
patients with ICH at least as much as patients with ischaemic stroke75.
Targeting haematoma expansion
Treatments targeted at limiting haematoma expansion should
be initiated as quickly as possible in all patients with ICH. As for
ischaemic stroke, monitoring door-to-treatment times may improve
the in-hospital workflow and potentially affect short-term mortality76.
Blood pressure management. Both high and low BP after ICH are asso-
ciated with poor outcomes (death and dependency)77. Multiple trials
have been conducted aiming to lower BP in acute ICH with diverging
results. Many trials were carried out >24 h after ICH, which may be too
late to affect haematoma expansion. Indeed, one meta-analysis found no
effect of BP lowering on functional outcome assessed using the modified
Rankin Scale (mRS); however, BP lowering was associated with reduced
haematoma expansion in those recruited within 6 h of symptoms78.
Current international guidelines from the European Stroke Organ­
isation, the American Heart Association (AHA)/American Stroke Associa-
tion and the Canadian Stroke Best Practice Recommendations endorse
systolic BP lowering to 140 mmHg as soon as possible after symp-
tom onset, with the goal of maintaining systolic BP between 130 and
150 mmHg (refs. 63,79,80). However, a more individualized approach is
warranted for some patients, such as those with a very high BP after ICH
(systolic BP >220 mmHg). Indeed, patients with very high BP (systolic
BP >220 mmHg) were not included in the trials, and lowering systolic BP
to 140 mmHg in this population might be harmful, with a higher rate of
neurological deterioration and kidney adverse events; therefore, BP
lowering should be more cautious81. In these patients, the target systolic
BP or the rate of BP reduction remains unknown. Recent data suggest that
the magnitude of systolic BP reductions in 1 h is associated with outcome,
with larger drops in BP (>70 mmHg) being potentially deleterious82.
Acute aggressive BP management can successfully limit haema-
toma expansion but has failed to demonstrate a benefit on functional
recovery. To bridge this gap, other approaches should be considered,
including ultra-early intervention (<2 h)83, defining an individualized
BP target that takes into account ethnicity84, the nature and severity of
the underlying vessel disease, the magnitude of BP reduction and pre-
existing conditions such as renal impairment. Limiting BP variability
might also contribute to a better outcome85.
Anticoagulation reversal. Nearly 15% of patients with ICH were using
oral anticoagulants at the time of stroke6. Patients with anticoagulation-
associated ICH have larger baseline haematomas, higher risk of hae-
matoma expansion and higher mortality than those not receiving
anticoagulants86–88. Stopping ongoing anticoagulation followed by
reversal of the anticoagulation effect may reduce the risk of haema-
toma expansion and improve vital and functional outcome89–91. As with
BP lowering, reversal of anticoagulation should be started as soon as
possible after onset of symptoms63. Prothrombin complex concen-
trates and vitamin K should be administered to target an international
normalized ratio (INR) to normal value (<1.3) in patients treated with
vitamin K antagonists. By contrast, specific reversal agents should
be used in patients treated with direct oral anticoagulants. When no
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1 Vessel rupture and

massive entry of blood

2 Mass effect —
excitotoxicity
necrosis
10 Ferroptosis
ROS
Macrophage
Free
Microglia iron

Neuron ICH

8
Blood
Thrombin clearance
process
5 9

Neutrophil
7

NETs
AQP4
6
Apoptosis

• NF-κB Astrocyte
• IL-1β
• Chemokines
• MMPs Inflammatory cell
recruitment
Plasma
extravasation 4 Extravasation

PAR1 VCAM1, ICAM1

and E-selectin

Blood
Red blood cell
vessel
3 ↑ BBB
permeability Endothelial cell

Pro-inflammatory
cytokines and Brain tissue Mass effect Haemoglobin
interleukins compression Haptoglobin

ATP depletion and CD163

neuronal depolarization

Amoeboid microglia Glutamate Haem Biliverdin

release oxygenase reductase
Haemoglobin Biliverdin Bilirubin
Microglial Neuronal
DAMPs
activation damage CO Fe 2+
Fe 3+

and/or death
MRC
Glutamate O2 O2 •–
H2O2 HO• +OH−
channel Fenton
Ca2+-activated Hydroxyl radical
pathways

Oxidative stress

Neuron
Resting microglia Macrophage or microglia

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Fig. 5 | Mechanisms involved in the pathophysiology of intracerebral
haemorrhage. (1) Intracranial pressure increases in the minutes after blood
vessel rupture and blood effraction within the brain parenchyma. (2) This
increase in pressure results in mechanical compression of brain tissue,
leading to necrosis and reduced perfusion, which precipitate cell death by
excitotoxicity owing to glutamate release. Necrotic cells release proteases
and damage-associated molecular patterns (DAMPs) that are detected by
microglia. (3) Microglia engage their amoeboid active form and release pro-
inflammatory cytokines to trigger the recruitment of circulating inflammatory
cells (neutrophils and macrophages). To allow this recruitment, endothelial cells
increase their capillary permeability. (4) Plasma and its constituents also
infiltrate the parenchyma through the vascular walls. This fluid, termed exudate,
contains numerous enzymes, antibodies and other molecules that disrupt
ionic homeostasis and local cellular function, also amplifying the inflammatory
response. (5) Thrombin from circulating blood also amplifies inflammation
and blood–brain barrier (BBB) disruption, as thrombin promotes the release of
various inflammatory mediators (nuclear factor-κB (NF-κB), tumour necrosis
factor, IL-1β, chemokines) and various proteolytic enzymes that degrade the
interstitium and the extracellular matrix (such as matrix metalloproteinases
(MMPs)). Thrombin also activates PAR1 receptors on endothelial cells, resulting
in a disruption of the BBB and exacerbated inflammatory response. (6) In
the parenchyma, leukocytes move towards and circumscribe the site of the
specific reversal agent is available, prothrombin complex concentrates
should be considered63.
Other haemostatic therapies. Tranexamic acid is an antifibrinolytic
drug that reduces bleeding by inhibiting the enzymatic breakdown of
fibrin blood clots. Tranexamic acid can reduce mortality due to bleeding
after trauma, post-partum haemorrhage92 and traumatic brain injury93.
Treatment is most effective when given early, and the effect is greatest on
early mortality93. Several differences in patient populations, pathophysi-
ology and natural history mean that these results cannot be translated
to ICH but this therapy holds promise for this indication94. In patients
with ICH, recent trials (Table 1) showed that tranexamic acid treatment
can reduce haematoma expansion, without a significant benefit on
90-day functional outcome. Several other trials using tranexamic acid
in ICH with early intervention (<2 to 4.5 h after stroke onset) are ongo-
ing (ISRCTN97695350, NCT03385928 and CHICTR1900027065)95–97.
No proven benefit has been seen with other haemostatic therapies
such as desmopressin for antiplatelet-associated ICH or recombinant
factor VIIa98,99. Platelet transfusion may be harmful in patients with ICH
associated with antiplatelet use, and should not be used100.
Interestingly, intensive BP management and haemostatic drugs
reduce haematoma expansion without a clear benefit on functional
outcome. The reasons for this discrepancy remain unclear but some
hypotheses can be discussed. The time to intervention is crucial, and
ongoing trials are focusing on a shorter time window (NCT03385928)96.
Moreover, patient characteristics (namely, ethnicity, medical history
and ICH aetiology) may also be important in terms of addressing hae-
matoma expansion. Eventually, haematoma expansion may be one
factor that mainly influences mortality, then to improve functional
outcome a different target should be defined such as peri-haematoma
oedema or secondary brain injuries.
Neurocritical care and surgical options
ICH is a neurological emergency, and 70% of patients are at risk of
early neurological deterioration within the first 24 h (ref. 101). Patients
at risk of clinical worsening are those with moderate to severe ICH
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bleeding. (7) First, neutrophils phagocytose apoptotic cells and their debris
to stop the spread of necrosis and engage a suicidal mode of death (netosis),
which exacerbates inflammation. (8) Subsequently, macrophages try to manage
the toxicity of blood degradation products. Between 3 and 7 days after ICH
erythrocyte haemolysis, the ICH core releases free haemoglobin (Hb) and iron
compounds that can form reactive oxygen species (ROS). In the extracellular
space, Hb is taken up by haptoglobin and the free haem by haemopexin.
Recruited macrophages and active microglia can uptake the Hb–haptoglobin
complex through the CD163–haem oxygenase 1 (HO-1) system. However, severe
haemolysis overwhelms these elimination capabilities, therefore, these toxic
blood products accumulate. (9) ROS also contribute to BBB disruption and the
development of peri-haemorrhagic oedema. In addition, free haem stimulates
endothelial expression of the adhesion molecules ICAM1, VCAM1 and E-selectin,
which allow leukocyte extravasation. Moreover, iron deposits exacerbate
the expression of AQP4 by astrocytes, which is highly involved in brain tissue
water homeostasis. Iron deposits also activate microglia through the TLR4
pathway. (10) ROS trigger a form of oxidative stress responsible for a specific
iron-mediated cell death called ferroptosis. Of note, although all these steps
are supported by experimental data, the precise roles and timing of each step
remain to be determined. ICH, intracerebral haemorrhage; MRC, mitochondrial
respiratory chain; NETs, neutrophil extracellular traps.
(identified in most studies by volume ≥30 ml), IVH, hydrocephalus
or infratentorial location102. Patients with higher clinical severity and
respiratory compromise can benefit from care in a neurointensive
care unit103–107.
External ventricular drainage (EVD; temporary drainage of CSF and
blood from the ventricles) as a treatment for obstructive hydrocepha-
lus secondary to IVH (presence of blood in the ventricles of the brain)
or external compression or obstruction of the ventricular system is
reasonable, especially in patients with decreased level of consciousness
in whom EVD is associated with reduced 30-day mortality108,109. IVH is
an independent risk factor of poor functional outcome in patients with
ICH and increases mortality at 90 days from 21% in patients without
IVH to 50% in those with IVH110,111. The mechanism of IVH-related injury
includes acute obstructive hydrocephalus, mass effect caused by the
haematoma, toxic blood breakdown products resulting in local tissue
ischaemia, and chronic hydrocephalus112. The benefit of EVD use on
functional outcomes in patients with IVH is less clear, with only data
with a high risk of bias available from observational studies and post-
hoc analyses112. One of the reasons is that the use of EVD alone is limited
by slow flow of CSF and catheter obstruction by blood clots. This led
to consideration of the association of drainage with intraventricular
thrombolysis (IVT). The CLEAR III trial is the largest randomized con-
trolled trial (RCT) of IVT for IVH. This trial compared EVD plus IVT (using
alteplase) with EVD plus intraventricular saline (placebo) in patients
with obstructive IVH secondary to ICH (volume <30 ml)113. Although
the study did not meet the primary outcome (mRS 0–3 at 180 days),
it suggested that good outcomes could be achieved in patients with
>80% IVH clot removal. A recent meta-analysis showed that a higher
treatment effect occurs when the combined EVD plus IVT approach
is initiated within the first 48 h after ICH onset114. Other interventions
for IVH suggest that endoscopic surgery with or without fibrinolysis
might be a good alternative to EVD; however, high-quality large RCTs
have not been performed115–117.
The frequency of elevated ICP and indications for use of ICP moni-
toring in ICH are not well established, although observational data
suggest that ICP monitoring might reduce mortality and improve
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a Baseline b c +24 h
d craniectomy with or without evacuation.
2 Surgical evacuation of supratentorial ICH is of uncertain
1
3
Regularity marker examples
e especially for young, comatose patients with midline shift (a shift of
5 and with refractory elevated ICP126.
4 2
1
Homogeneity marker examples
Fig. 6 | Imaging markers of haematoma expansion. Non-contrast CT scan in
the axial plane showing a right deep intracerebral haemorrhage (panel a). The
spot sign CT-angiography scan (panel b; arrow) at admission suggests a risk of
haematoma expansion as illustrated by the plain CT scan performed 24 h after
admission (panel c). Representative examples of non-contrast CT markers of
haemorrhage expansion (panels b and e). Illustration of margin irregularity
features associated with higher risk of haemorrhage expansion. (1) Satellite
sign. (2) Island sign. (3) Margin irregularity within the Barras scale (panel d).
Illustration of haemorrhage’s density features. (4) Hypodensity. (5) Hypodensity
also qualifying for a swirl sign owing to the greater density difference with the
adjacent clot (panel e).
outcomes63. One meta-analysis reported a pooled prevalence of 67%
for any episode of intracranial hypertension and a pooled mortality of
50% associated with intracranial hypertension118. ICP is not frequently
elevated after obstructive IVH treated with EVD monitoring and drain-
age, although increased ICP and duration, are associated with poor
outcome and mortality119,120. In the absence of clinical trials, thresholds
to indicate the need for ICP monitoring are typically borrowed from the
traumatic brain injury literature and are considered for patients with
ICH who have a reduced level of consciousness (for example, Glasgow
Coma Scale (GCS) score ≤8, indicating severe injury). However, the
data are conflicting121,122.
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Prophylactic administration of hyperosmolar agents has been
studied predominantly for mannitol; the ERICH study found no asso-
ciation of prophylactic use of mannitol with clinical benefit123. There is
no evidence-based role for corticosteroids in the treatment of elevated
ICP in patients with ICH.
Surgical considerations. Surgical evacuation in patients with ICH may
seem intuitive owing to the deleterious effect of massive blood entry
into the brain; however, the reality is more complex as no study has
demonstrated a compelling functional outcome benefit from surgery.
Various surgical techniques exist for ICH: craniotomy with evacuation,
drainage using minimally invasive techniques and decompressive
benefit. Two large RCTs (STICH I and STICH II) showed no benefit
with craniotomy compared with standard care in terms of mortality
or functional outcomes assessed with the extended Glasgow Out-
come Scale124,125; however, these trials suggested a potential benefit
for mortality in lobar ICH. The STICH I and STICH II trials had high
medical-to-surgical crossover rates and promoted the policy that
early haematoma evacuation is not clearly beneficial compared with
haematoma evacuation when patients deteriorate. Craniotomy for
supratentorial ICH is therefore considered as a life-saving measure,
the brain past its centre line), deep or lobar haemorrhages with IVH,
Owing to the results of the STICH trials, there was a paradigm shift
towards less-invasive approaches for ICH evacuation to mitigate dam-
age to surrounding healthy brain. Multiple less-invasive techniques and
devices have been developed, including stereotaxic and endoscopic
approaches. The minimally invasive surgery approaches have shown
potential for improved outcomes compared with conventional crani-
otomy127–134. Of these approaches, MISTIE (minimally invasive surgery
with thrombolysis in intracerebral haemorrhage evacuation) emerged
as one of the most gentle and promising strategies. The MISTIE
III trial showed that minimally invasive surgery followed by thrombo-
lytic irrigation of the catheterized ICH with alteplase in patients with
supratentorial ICH135 was safe and resulted in survival benefit compared
with standard management; however, the primary outcome (functional
improvement based on mRS score 0–3 at 1 year) was not met. However,
the MISTIE III trial also demonstrated that a threshold of ICH evacua-
tion of ≥70% haematoma reduction or end-of-treatment volume to
≤15 ml conferred a significantly higher probability of a good outcome
compared with medical management alone in a post-hoc exploratory
analysis. These data suggest that with improved evacuation, minimally
invasive surgery could be the game changer of ICH management.
For cerebellar ICH, surgical haematoma evacuation is generally
recommended to avoid brainstem compression in patients with large
ICH volumes (>3 cm in diameter), IVH extension and/or hydrocepha-
lus and with neurological deterioration. Because cerebellar ICH is a
rare and potentially dramatic event, RCTs are not likely to be performed
for this condition. One large individual participant data meta-analysis
that included patients with spontaneous cerebellar haemorrhage
without brainstem extension, found that haematoma evacuation was
associated with a survival benefit at 1 year for larger haematoma vol-
umes (>15 ml), although no improvement in functional outcomes at
3 months was reported136.
Decompressive hemicraniectomy (DC) either alone or combined
with clot evacuation can alleviate elevated ICP, midline shift caused
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by mass effect and associated perihaematomal oedema, although
evidence is dominated by case series and small RCTs. These series and
small trials also demonstrated that DC is safe and improves survival,
although the effect on functional outcomes was inconclusive137–140.
Results are awaited for the SWITCH trial, which is a RCT designed to
determine whether decompressive surgery improves outcomes com-
pared with best medical treatment in patients with supratentorial ICH
(NCT02258919)141.
The optimal timing for surgery after ICH is uncertain given the
variability of RCT design (up to 96 h from onset for STICH trials and
within 72 h after the first CT imaging for the MISTIE III trial) and as no
large RCTs have evaluated surgery within the first 12–24 h. Several RCTs
are underway to better understand whether earlier surgical interven-
tion with advanced techniques can mitigate risk of rebleeding while
reducing secondary brain injury and improving outcomes.
Secondary prevention
Secondary prevention aims to prevent the recurrence of ICH and
prevent other ischaemic events, owing to the associated high risk
in survivors of ICH. Indeed, the risk of recurrent ICH is 1.3–7.4% per
year depending on bleeding location (thus to the underlying vessel
disease), with higher rates in patients with lobar ICH or probable
CAA compared with those with deep ICH or deep perforating vascu-
lopathy4. Of note, clinicians cannot precisely quantify the individual
risk of future haemorrhagic events. Some radiological biomarkers
(such as cerebral microbleeds, cortical superficial siderosis or severe
white-matter lesions) may be useful to improve the prognostication
of future ICH142,143.
Patients with ICH also have increased risk of ischaemic stroke and
other extracerebral vaso-occlusive events6. The nature of incident
events differs according to ICH location and can guide the second-
ary preventive strategy. Risk of ischaemic events is higher after deep
ICH, whereas risk of haemorrhagic events is higher after lobar ICH144.
Patients with ICH or ischaemic stroke share multiple vascular risk
factors, including atrial fibrillation (which is present in one in five sur-
vivors of ICH)6. Accordingly, survivors of ICH have an annual 5% risk of
serious vascular events, but risk increases to 12% per year in those with
concomitant atrial fibrillation145,146.
In the absence of clear consensus, secondary prevention after ICH
should be individualized, and multidisciplinary discussion is strongly
encouraged.
Blood pressure control. Irrespective of ICH location and aetiology,
long-term BP control is the most important action to prevent ICH recur-
rence147. In survivors of ICH, it is reasonable to lower systolic BP below
130 mmHg and diastolic below 80 mmHg (ref. 63).
Antithrombotic agents. Fifty per cent of patients in high-income
countries are treated with antithrombotic agents (including oral anti-
coagulants for 15% of them) at the time of their ICH6. The discussion
of antithrombotic resumption at discharge or later during follow-up
is difficult as evidence-based data are scarce63,80.
The RESTART trial148 found no significant difference in ICH recur-
rence and major haemorrhagic event occurrence (recurrent sympto-
matic ICH, other intracranial haemorrhages and symptomatic major
extracranial haemorrhage) at any site in patients who restarted anti-
platelet therapy compared with those who did not restart antiplatelet
therapy. Moreover, this trial found no difference in the rate of major
occlusive vascular events (ischaemic stroke, myocardial infarction,
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a b c
Fig. 7 | Representative example of advanced imaging to determine the cause
of intracerebral haemorrhage. MRI of a lobar intracerebral haemorrhage.
The susceptibility-weighted imaging (SWI) sequence (panel a) shows the
haemorrhage in the left frontal lobe delimited by a hyposignal rim. The angioMRI
sequence (panel b) shows an abnormal, dilated vessel in the upper part of the
haemorrhage (arrows). The red signal in arterial spin-labelling MR imaging
(panel c) within the vessel indicates an arteriovenous shunt, suggesting the
diagnosis of an arteriovenous malformation.
peripheral arterial occlusion, mesenteric ischaemia, pulmonary
embolism, deep vein thrombosis and revascularization procedures)
in patients who restarted antiplatelet therapy compared with those
who did not restart antiplatelet therapy. On the basis of this RCT, it
seems safe to start or restart, antiplatelet agents in survivors of ICH
when they have a clear indication for secondary prevention.
The benefit of anticoagulation to prevent future ischaemic events
in those with atrial fibrillation is less clear. The SoSTART and APACHE-
AF trials were the first two RCTs to investigate the safety and efficacy
of oral anticoagulation (OAC) in patients with ICH and atrial fibrilla-
tion146,149. SoSTART found non-inferiority of OAC resumption compared
with avoidance of OAC use. However, symptomatic major vascular
events were numerically higher in patients without OAC149. Similarly, the
APACHE-AF trial found a 12% annual risk of non-fatal stroke or vascular
death in patients with ICH and atrial fibrillation who either received or
did not receive apixaban146. Of note, some ethnicities (Black, Hispanic
and Asian individuals), women and patients with presumed CAA were
under-represented in these trials. Other RCTs evaluating the risk–
benefit balance of resuming anticoagulant drugs after ICH are ongoing
with a planned individual patient data meta-analysis (COCROACH:
PROSPERO CRD42021246133).
When the decision to start anticoagulation has been made, there is
no consensus regarding the timing of introduction or re-introduction150.
The best choice of OAC has also yet to be established. Direct OACs
are the preferred therapy as they are at least as effective as vitamin K
antagonists in preventing future ischaemic events and are associated
with significantly less bleeding, including ICH151. The availability of
rapid reversal agents is also a consideration when using these drugs152.
In patients at high risk of ICH recurrence (such as those with severe CAA
or recurrent ICH), the AHA guidelines suggest that non-pharmacological
approaches (such as transcatheter left atrial appendage closure) could
be an alternative to OACs63. This suggestion is being evaluated in one
ongoing RCT (NCT03243175)153.
Statins. The use of statins after ICH is controversial as they may increase
the risk of recurrent bleeding154,155. The SATURN trial (NCT03936361)156,
a phase III RCT, is investigating the benefit of continuation versus dis-
continuation of statins after spontaneous lobar ICH. To date, in patients
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Table 1 | Main randomized clinical trials targeting haematoma expansion in patients with intracerebral haemorrhage

Trial name, Design and size Main inclusion criteria Time Main characteristics Intervention in Main findings
year window treatment group
(h)

Blood pressure lowering

INTERACT 2, Randomized, open- Spontaneous ICH, <6 Mean age 64 years; men Target systolic BP <140 Intensive lowering of BP
2013 (ref. 186) label, phase III trial BP >150 mmHg and 63%; lobar ICH 16%; versus <180 mmHg did not reduce death
(n = 2,839) <220 mmHg and GSC >5 median baseline ICH during 1 day or major disability but
volume 11 ml may improve functional
outcomes in ordinal
analysis of the mRS
ATACH-II, 2016 Randomized, open- Supratentorial <4.5 Mean age 62 years; men Target systolic BP Intensive lowering of BP
(ref. 187) label, phase III trial spontaneous ICH, BP 62%; lobar ICH 10%; 110–139 versus did not reduce death or
(n = 1,000) >180 mmHg, ICH volume median baseline ICH 140–179 mmHg major disability
<60 ml and GSC >4 volume 10 ml during 1 day
Haemostatic agent administration
TICH-2, 2018 Randomized, Spontaneous ICH, and <8 Mean age 69 years; men TXA: 1 g in 100 ml 0.9% No significant difference
(ref. 94) placebo-controlled, GSC >4 56%; lobar ICH 32%; NaCl over 10 min followed in functional outcome;
phase III trial median baseline ICH by 1 g in 250 ml 0.9% NaCl significant but modest
(n = 2,325) volume 14 ml infusion over 8 h versus reduction in HE and early
placebo (saline) death (within 7 days)
STOP-AUST, Randomized, Spontaneous ICH, <4.5 Median age 71 years; TXA: 1 g in 100 ml 0.9% No significant difference
2020 (ref. 188) placebo-controlled, presence of active men 62%; lobar ICH 30%; NaCl over 10 min followed in HE or functional
phase II trial (n = 100) bleeding (spot sign), median baseline ICH by 1 g in 500 ml 0.9% NaCl outcome at 3 months
ICH volume <70 ml and volume 15 ml infusion over 8 h versus
GSC >7 placebo (saline)
TRAIGE, 2021 Randomized, Spontaneous ICH, <6 Mean age 56 years; men TXA: 1 g in 100 ml 0.9% No significant difference
(ref. 189) placebo-controlled, presence of active 73%; lobar ICH 26%; NaCl over 10 min followed in HE or functional
phase II trial (n = 171) bleeding (spot sign or median baseline ICH by 1 g in 250 ml 0.9% NaCl outcome at 3 months
spot-like appearance), volume 20 ml infusion over 8 h versus
ICH volume <70 ml, and placebo (saline)
GSC >7
BP, blood pressure; GCS, Glasgow Coma Scale; HE, haematoma expansion; ICH, intracerebral haemorrhage; mRS, modified Rankin Scale; TXA, tranexamic acid.

at risk of vascular ischaemic events, there is no evidence to withhold
statins in general for survivors of ICH.
Quality of life
ICH-related mortality has not decreased over the past decade owing to
the lack of specific treatment for this condition157. Most deaths occur
within the first 30 days of ICH, but the cumulative survival rate at 10 years
is 40%158. Long-term mortality is also high in young patients (18–55 years)
with ICH, reaching 35% after a median follow-up of 8 years159.
QoL is a major issue among stroke survivors. The assessment of
QoL is complex and highly dependent on individual preference. To help
clinicians in their evaluation of QoL, the two most used validated scales
are the SS-QOL and the EQ-5D-5L160,161. However, these instruments were
not specifically designed for ICH and are mainly used in patients with
ischaemic stroke. In the ensuing months to years after a bleeding event,
ICH survivors may face complications that affect their QoL.
Almost one-quarter of ICH survivors have progressive functional
decline over time162. Elderly patients with diabetes mellitus, a large ICH
at baseline and strictly lobar or mixed cerebral microbleeds are at high
risk of future decline and should be regularly followed up to improve
secondary prevention162. In addition to functional dependency (usually
measured with the mRS163), patients with ICH also have increased risk of
cognitive impairment of various severity (from mild cognitive impair-
ment to dementia). Indeed, during a median follow-up of 4 years, 28%
of patients with ICH will develop new-onset post-ICH dementia5. Elderly
patients with more than five cerebral microbleeds, cortical superficial
siderosis or cerebral atrophy at ICH onset (that is, those with markers of
ongoing SVD) are more likely to develop dementia5. As the occurrence
of new strokes also contributes to future cognitive decline, secondary
prevention should be carefully monitored in those high-risk patients.
Neuropsychiatric symptoms evaluated using the Neuropsychi-
atric Inventory Questionnaire164 are observed in more than half of
ICH survivors 6 months after ICH165. Patients with post-ICH dementia
have a three times higher risk of neuropsychiatric symptoms com-
pared with those without post-ICH dementia. Affective symptoms are
the most prevalent neuropsychiatric symptoms. Hyperactivity and
apathy are more frequent in those with post-ICH dementia, whereas
affective symptoms (such as anxiety and depression) are more fre-
quent in patients without post-ICH dementia165. Although data on
neuropsychiatric symptoms in patients with ICH are scarce, the existing
data suggest that timely recognition of neuropsychiatric symptoms
could improve care planning and have a clinically meaningful effect
for long-term ICH management63.
Patients with ICH also have an increased risk of post-ICH epilepsy.
The frequency of post-ICH epilepsy varies across studies from 8% to
13% 2 years after ICH166–168. Patients with ICH can develop partial or
secondary generalized seizures, and seizures are more likely to occur in
those <65 years of age with cortical involvement of the ICH166–168. Some
prognostic scores (such as the CAVE score) have been developed166,
but these scores fail to identify patients at such a high risk of post-ICH
epilepsy that it would outweigh the adverse effects caused by long-term
preventive anti-epileptic treatments63.

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During the clinical follow-up, clinicians should screen for all these
complications to improve the global care and QoL of survivors of
ICH. Special attention should also be given to family caregivers as
they have a key role in the recovery process of patients. Accordingly, they
need to be involved in the care plan as well as knowledgeable about
the disease63.
Early prediction of outcome in patients with ICH is challenging.
To avoid the self-fulfilling prophecy of poor outcome during a time
period in which prognostic uncertainty is present169, initial care for
every patient with ICH is recommended unless patients have previously
documented a desire for these treatment limitations before the onset
of their ICH. ICH is usually considered a more severe condition than
ischaemic stroke. In terms of long-term functional outcome among
Box 1
Knowledge gaps and future directions for intracerebral
haemorrhage research
Reduce the incidence of ICH
Challenges
•• Raise public awareness of intracerebral haemorrhage (ICH)
Suggestions
•• Promote blood pressure control
•• Promote reduction of salt and alcohol consumption
•• Public health campaigns on awareness and education on stroke
Improve understanding of the disease
Challenges
•• Heterogeneity of the disease
•• Complex natural history
Suggestions
•• Develop ICH preclinical models that mimic human disease
•• Disentangle the causes of ICH
•• Develop radiological, genetic and biological biomarkers to
improve classification
Develop new treatment strategies
Challenges
•• Failure of the translational pipeline
•• Different targets associated with different outcomes
-- Haematoma expansion and mortality
-- Secondary brain injuries and functional recovery
•• Define the expected treatment effect
Suggestions
•• Optimization of the translational pipeline
-- Implementation of modifiable and non-modifiable (genetic)
risk factors
-- Widespread use of female animals
-- Use of different methods to generate the bleeding
-- Use of different species
-- Compare animal data with human post-mortem data
-- Multidisciplinary approach including clinicians and basic
scientists when designing new therapeutic avenues for ICH
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survivors, this belief is debatable. One post-hoc analysis of two inter-
ventional RCTs found that more than 40% of patients with severe ICH
with IVH who initially had a poor functional outcome recovered to good
outcome by 1 year170. Clinicians should therefore avoid early pessimistic
prognostication. Different prognostic models demonstrated valuable
outcome prediction after ICH, but the inclusion of patients with early
care limitations induces a negative bias that results in an overestima-
tion of poor outcome. In this view, the max-ICH score was developed to
prevent patients with ICH from experiencing unwarranted limitations
of care171,172.
Outlook
There are several future research avenues for ICH (Box 1).
•• More inclusive trials including the whole range of patients with
ICH (large ICH, lobar ICH, women and individuals of different
ethnicities)
Redefine the different temporalities in ICH management
Challenges
•• ‘Time is brain’ in ICH
•• Adjust the best time window of interventions according to the
treatment target
•• Define the best timing for outcome measures
Suggestions
•• Improve pre-hospital care with mobile stroke unit equipped with
on-board brain imaging and artificial intelligence
•• Improve diagnostic and treatment workflow to save time
•• Implement the use of a bundle of care — combined interventions
at various timepoints
-- Limit haematoma expansion in the first hours after stroke, as it
can be life saving
-- Improve blood evacuation in the first hours to days after stroke
as it can be life saving and can improve functional outcome
-- Limit secondary brain injuries in the first days to weeks after
stroke to improve functional outcome
•• Refine the optimal timing to assess functional outcome (180 days
and 360 days instead of 90 days as in ischaemic stroke)
Improve the outcome of patients with ICH
Challenges
•• Improve prognostic tools
•• Tailor secondary prevention
Suggestions
•• Develop radiological, genetic and biological biomarkers to
improve prognostication
•• Promote research calls dedicated to support international studies
on ICH
13
Primer
Prevention clinics
Prevention should be promoted in people who have already had an ICH
or for those with high haemorrhagic risk (such as patients with CAA).
Home-based monitoring of BP and prognostic blood biomarkers may
help better identify very high-risk patients.
Precision and personalized diagnosis
Mobile stroke units permit pre-hospital stroke assessment and early
treatment (FASTEST trial; NCT03496883)173. In a mobile environment,
automated evaluations of the bleeding (as a prognostic factor) will
be available. Of note, automated haematoma assessment tools have
already been developed that can automatically detect ICH, perform
volumetric assessments and calculate the rate of haematoma expan-
sion174. A better definition of chronic SVD (outside the bleeding) with
approaches such as texture analysis will also contribute to an early and
personalized assessment175. Furthermore, rapid on-site characterization
of blood components (for example, its content of pro-inflammatory
and haemostatic markers) will contribute to definition of the ICH sig-
nature, and eventually therapeutic strategies will be tailored to these
signatures.
New therapeutic approaches
The time window to prevent haematoma expansion after ICH is
extremely short, and patients are often admitted to hospital when
this therapeutic opportunity has elapsed. Haemostatic and haemody-
namic therapies designed to stabilize haematomas and limit expansion
have proved challenging: patients at high risk of expansion cannot be
clearly identified. Therefore, there is considerable interest in discover-
ing neuroimaging biomarkers that can identify patients who are best
suited for these therapies.
Two types of trial are ongoing: those that focus on specific
subgroups of patients at very high risk of haematoma expansion
that evaluate agents such as recombinant factor VII (FASTEST trial;
NCT03496883)173, and others that evaluate tranexamic acid in all types of
ICH (TICH-3 trial; ISRCTN97695350)95. Endovascular techniques are also
in development and present a potential new mechanical paradigm for
acute ICH therapy. For example, flow diversion used in aneurysmal repair
or balloon tamponade techniques already used to control haemorrhage
extracranially could be applied to hyperacute ICH management.
During the evaluation of treatments that target secondary injury,
it will be vital to heed the lessons from ischaemic stroke, in which many
promising therapies from preclinical research failed to translate to ben-
efit in clinical trials. Coordinating the efforts of research and industry
ICH investigators are likely to be beneficial in this regard176.
As previously mentioned, blood toxicity is a key driver of sec-
ondary injuries including post-ICH cognitive decline and dementia.
Although surgery may be life saving by preventing fatal mass effect
and herniation syndromes (which occur when increased ICP causes
the abnormal protrusion of brain tissue through openings in rigid
intracranial barriers), its benefit in improving functional outcome
has not been proved. The development of mini-invasive approaches
for ICH is promising135. These approaches could be combined with
pharmacomodulation targeting secondary injury (Fig. 4).
Several strategies targeting secondary injury in ICH have been
evaluated. For example, one phase II randomized, placebo-controlled
trial of deferoxamine (an iron chelator) found no improvement in clini-
cal outcome at day 90 (ref. 177). However, a new look at all those interven-
tional studies suggests that the evaluation of functional dependency
should be performed later than 90 days. A first evaluation at 180 days
Nature Reviews Disease Primers | (2023) 9:14
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and a second one at 1 year seem more adapted to the trajectory of
patients with ICH compared with patients with ischaemic stroke102.
Another therapeutic approach is to target neuroinflammation. Early-
phase trials of targeting inflammation have been completed and further
studies are ongoing. Two small studies evaluating minocycline (which
has multiple potentially beneficial actions including modulation of
inflammation and reduction in glutamate toxicity) reported no safety
concerns in 36 patients178,179. However, larger trials are not planned.
A small trial of fingolimod (a sphingosine 1-phosphate receptor modu-
lator that sequesters lymphocytes in lymph nodes) found a reduction of
oedema and an improvement in recovery180, and a further small study is
underway (NCT04088630)181. The naturally occurring inhibitor of IL-1,
IL-1 receptor antagonist (IL-1Ra) is an approved treatment for rheuma-
toid arthritis and has been evaluated in phase II studies in ischaemic
stroke and subarachnoid haemorrhage, with a demonstrated reduc-
tion in markers of peripheral and central inflammation (neutrophil
leucocytosis, plasma C-reactive protein and IL-6)182. IL-1Ra is being
evaluated in two phase II trials with oedema as the primary outcome
(NCT03737344 and NCT04834388)183,184.
Global societal efforts for worldwide challenges
Until now, most research and funding efforts for stroke have focused
on acute ischaemic stroke treatments, which led to the development
of thrombolysis and mechanical thrombectomy185. Research on ICH
(both experimental and clinical) remains rare. To reduce mortality
and improve functional and cognitive outcome for patients with ICH,
more collaborative research programmes are needed that are specific
for ICH. Patient participation in studies worldwide and data sharing are
important steps to achieve this goal.
Moreover, ICH disproportionately affects low-income countries.
In those countries, access to primary prevention, especially to improve
BP management, should be reinforced. It concerns treatment of arterial
hypertension and also public health measures to reduce salt and alco-
hol consumption. Such actions could have an effect on the incidence
and severity of ICH in the most vulnerable populations.
Recovery approaches specific to ICH
Stroke rehabilitation efforts for ICH are largely based on those devel-
oped for ischaemic stroke. However, the recognition that ICH follows a
very different time course102 opens the possibility for a novel recovery
paradigm of more aggressive therapy in a later time window, perhaps
once the mass effect from ICH has resolved. Moreover, emerging thera-
peutic modalities such as magnetic brain stimulation may need to
target different recovery windows in patients with ICH compared with
those with ischaemic stroke. Moreover, the minimally invasive surgical
approaches used for acute ICH evacuation can also represent a unique
method by which to deliver regenerative therapeutics directly into the
injured parenchyma.
Published online: xx xx xxxx
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Acknowledgements
The authors thank G. Boulouis for his assistance for Fig. 6.
Author contributions
Introduction (L.P. and C.C.); Epidemiology (L.P.); Mechanisms/pathophysiology (A.R.P.-J. and L.P.);
Diagnosis, screening and prevention (D.D. and L.P.); Management (E.C.S., W.Z., A.RP.-J., L.P.
and C.C.); Quality of life (L.P. and D.D.); Outlook (D.D. and C.C.); Overview of Primer (C.C.).
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Competing interests
L.P. received speaker fees from Daichi–Sankyo. A.R.P.-J. participated in advisory boards for
and received speaker’s fees from Alexion Pharmaceuticals, Inc. E.C.S. is on the steering
committee of ANNEXAi. D.D. holds a patent for the CARL software to automatically detect
contrast extravasation, has received honoraria from AstraZeneca Canada, is on the
steering committee of the FASTEST and ENRICH-AF trials. W.Z. is supported by the NIH
(1U01NS080824, R01NS102583, U01NS106513 and 1R01NS120557). C.C. received speaker fees
from BMS and Pfizer.
Additional information
Supplementary information The online version contains supplementary material available at
https://doi.org/10.1038/s41572-023-00424-7.
Peer review information Nature Reviews Disease Primers thanks G. Donnan, J. Kuramatsu,
L. P. Liu and the other, anonymous, reviewer(s) for their contribution to the peer review of
this work.
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