REVIEWS

Nontraumatic intracerebral
haemorrhage in young adults
Turgut Tatlisumak1,2*, Brett Cucchiara3, Satoshi Kuroda4, Scott E. Kasner3
and Jukka Putaala2
Abstract | Nontraumatic intracerebral haemorrhage (ICH) is a common subtype of stroke with a
poor prognosis, high mortality and long-term morbidity. The incidence of ICH increases with age.
ICH has not been widely investigated in young adults (herein defined as aged ~18–50 years)
despite an annual incidence of ~5 per 100,000 individuals. Furthermore, ICH characteristics differ
between young and elderly patients. Risk factors for ICH are surprisingly common in young
adults, in whom ICH is often caused by structural lesions or hypertension, and only rarely by
anticoagulation therapy and cerebral amyloid angiopathy (which are common predisposing
factors in elderly patients). High short-term mortality (17% at 3 months) and long-term mortality
(>25% at 10 years) persist even in contemporary series from high-income countries, and
long-term disability is very common. Thus, an aggressive approach to identifying treatable
underlying conditions and preventing ICH recurrence is indicated in young patients, although
treatment strategies have generally not been investigated specifically in this age group. This
narrative Review summarizes existing knowledge on the epidemiology, risk factors, causes,
diagnosis, treatment and outcomes of ICH in young adults. We provide comparisons with the
population of elderly patients with ICH and discuss challenges for future research.

1
Department of Clinical
Neuroscience and Neurology,
Institute of Neuroscience and
Physiology, The Sahlgrenska
Academy at University of
Gothenburg and Sahlgrenska
University Hospital,
Gothenburg, Sweden.
2
Department of Neurology,
Helsinki University Central
Hospital, Helsinki, Finland.
3
Comprehensive Stroke
Center, Department of
Neurology, University of
Pennsylvania and University
of Pennsylvania Medical
Center, Philadelphia, PA, USA.
4
Department of
Neurosurgery, Graduate
School of Medicine and
Pharmaceutical Science,
University of Toyama,
Toyama Prefecture, Japan.
*e-mail: turgut.tatlisumak@
neuro.gu.se
doi:10.1038/nrneurol.2018.17
Published online 9 Mar 2018
Nontraumatic intracerebral haemorrhage (ICH) in
young adults is an uncommon but dreaded disease.
A young adult patient with ICH is usually defined as
aged between 18 years and 50 years, although the pre‑
cise age range differs between studies and experts. ICH
in young adults differs from that in older individuals in
several respects, including the spectrum of risk factors,
triggers and underlying causes. Furthermore, death or
permanent disability is surprising and highly devastat‑
ing in young and otherwise healthy individuals — who
are often building a career and establishing a family,
might have small children to look after or might even be
pregnant at the time of ICH. Even among patients with
fair recovery, many will not be able to return to work.
Apart from the economic and social consequences for
the patient, ICH in young adults can also generate high
costs for society associated with either early retirement
from work owing to illness or disability or the need for
permanent institutional care.
Several excellent reviews have been published on
ICH in general populations of patients1–3. However,
nontraumatic ICH in young adults differs from that in
elderly individuals in several key respects, and in‑depth
guidance for physicians on the approach to diagnosis
and treatment of ICH in young adults is lacking. Such
guidance is long overdue as, to the best of our know­
ledge, this narrative Review is the first on this topic to
be published in the English language. Several excel‑
lent reviews are also available on individual diseases
associated with ICH in young adults, such as arterio‑
venous malformations4, cerebral venous thrombosis5,
moyamoya vasculopathy 6 and cerebral vasculitides7.
However, these articles lack a holistic focus on the
young adult who presents with ICH. This compre‑
hensive Review addresses several points where crucial
evidence-based data are missing; we hope that drawing
attention to these areas will help to stimulate future
research. Most novel data in the field of ICH in young
adults have come from genetic studies, which have found
numerous previously unknown genetic loci linked to
ICH-causing diseases. Large collaborative teams are also
conducting comprehensive genome-wide association
studies in patients with ICH. These studies are likely to
bring novel insights to disease mechanisms that could,
in the long run, change clinical practice.
In this narrative Review, we provide a comprehen‑
sive overview of reported studies that investigated the
epidemi­ology, risk factors, causes, diagnosis, manage‑
ment and outcomes of nontraumatic ICH in young
adults. Most data on this topic come from the 13 largest

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Key points
• The incidence of intracerebral haemorrhage (ICH) increases steeply with age and has
an annual incidence of ~5 per 100,000 individuals in young adults (<50 years of age).
• Classic risk factors for ICH are common even in young adults; drug abuse, pregnancy
and the postpartum period are additional important young-adult-specific risk factors.
• Hypertension is the predominant cause of ICH in young adult Indian and Asian
populations, whereas hypertension and vascular abnormalities are equally important
in white populations.
• Potential causes of ICH in young people are many and require systematic diagnostic
studies with imaging of the intracranial vasculature as the cornerstone of the
diagnostic work‑up.
• Observational evidence supports an aggressive approach to the management of ICH
in young patients, including lowering of elevated blood pressure, surgical haematoma
evacuation (in selected patients) and vigorous rehabilitation.
• ICH in young adults has a dismal prognosis: 3‑month mortality is 17%, 10‑year
mortality is >25% and long-term disability is common.
independent series of patients (summarized in TABLE 1),
which included a total of 2,121 individuals, 65% of
whom were men8–20. Further, we briefly discuss some
future challenges and perspectives. Haemorrhagic trans‑
formation of ischaemic stroke is not discussed, as it is
not classified as ICH according to the WHO definition
of stroke; ICH following thrombolysis or thrombectomy
is also not dealt with in this Review.
Incidence and prevalence
Haemorrhagic stroke, including ICH and subarachnoid
haemorrhage, accounts for ~10–27% of all strokes21.
In young adults, the distribution of the main stroke
subtypes differs from that in older patients in most
studies. Although two outlier studies reported nota‑
bly low proportions of ICH of 3.7%, 14 other studies
published since the 1980s have reported proportions
of ICH ranging from 10.0% to 38.5% and of sub­
arachnoid haemorrhage ranging from 9.6% to 55.4%
in patients with stroke aged <45 years22. In one of the
few population-based studies of haemorrhagic stroke
in young patients (aged <45 years), the proportion of
ICH was 20.2%, subarachnoid haemorrhage was 22.5%
and ischaemic stroke was 57.3%23. The ratio of ICH
to ischaemic stroke was 1:1.5–2.0 in young adults and
progressively decreased with advancing age to 1:5.4 in
individuals >75 years of age24.
The overall incidence of ICH is about 24.6 affected
individuals per 100,000 person-years, although this
value is influenced by age, sex and ethnic background25.
In a meta-analysis published in 2010, the incidence of
ICH in people aged <45 years was 1.9 per 100,000 indi‑
viduals (95% CI 1.6–2.2) but increased by tenfold for
those aged 45–54 years (19.1 per 100,000 individuals;
95% CI 13.4–27.4) and by nearly 20‑fold for those aged
55–64 years (36.5 per 100,000 individuals; 95% CI 28.4–
46.7)25. In an Italian study, the incidence of ICH in a
community-based cohort of people aged 0–44 years was
2.06 affected individuals per 100,000 person-years23.
Another Italian study reported a similar incidence of
ICH in people aged 15–44 years: 1.9 affected individu‑
als per 100,000 person-years26. A Finnish hospital-based
study with good capture of all ICH patients (exclud‑
ing those with subarachnoid haemorrhage) from a
defined catchment area suggested an incidence of 4.9
per 100,000 individuals (95% CI 4.5–5.3) in people aged
<50 years. This study also reported a higher incidence
of ICH in men (6.2 per 100,000 individuals; 95% CI
5.0–7.3) than in women (4.0 per 100,000 individuals;
95% CI 3.4–4.7)9.
The overall incidence of ICH has not declined glob‑
ally for all age groups combined during the past 3 dec‑
ades, in contrast to that of ischaemic stroke21. In fact, the
results of the 2010 Global Burden of Diseases, Injuries,
and Risk Factors study revealed a statistically signifi‑
cant increase in the incidence of haemorrhagic stroke
specifically in people aged 20–64 years in low-income
and middle-income countries between 1990 and 2013
(by contrast, the incidence of ICH declined across all
age groups in high-income countries)27. Furthermore,
the global prevalence of haemorrhagic stroke almost
doubled from 1990 to 2013 in people aged 20–64 years,
reaching ~3.7 million patients (95% CI 3.5–3.9 million
patients)28. Most of the global burden of stroke in this age
group affects developing countries, and haemorrhagic
stroke accounts for the greatest part of this increased
burden among young adults27.
Finally, the incidence of ICH in Asian individuals is
roughly double that in either black or white people25.
In studies focusing on young people, marked ethnic
variation is similarly evident in the main stroke sub‑
types. In the Northern Manhattan Study, the incidence
rates of ICH in young Hispanic and black individuals
were higher than those in young white individuals29.
Furthermore, in a Baltimore study, the incidence of ICH
was higher in black individuals than in white individu‑
als of both sexes30. However, these data are limited to
the US population, and further studies are warranted
to explore population and ethnic differences in ICH
incidence in the rest of the world.
Risk factors and causes
A large number of nonmodifiable and modifiable risk
factors have been associated with ICH31. Most of these
have not been explicitly studied in young patients. Only
a few case–control studies have investigated the risk
­factors for ICH specifically in young patients.
An early case–control study found that a high ethanol
intake was a prominent risk factor for ICH (OR 13.31)
in young and middle-aged individuals after accounting
for potential confounding variables32. Hypertension
(OR 5.71), diabetes (OR 2.40), menopause (OR 2.50),
current cigarette smoking (OR 1.58), a high alcohol
intake (≥2 drinks daily; OR 2.23), a high caffeinated
drink intake (≥5 drinks daily; OR 1.73) and caffeine
in drugs (OR 3.55) were associated with ICH in an
American population aged 18–49 years33. In a separate
study, cocaine use (OR 6.1), hypertension (OR 5.2) and
alcohol use (OR 1.9) were independent risk factors for
ICH in African-American people aged 18–45 years34.
In several series of consecutive patients, high frequen‑
cies of drug abuse were noted among young patients
with ICH11,14,18.

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Female-specific risk factors. Pregnancy and the post­
partum period are virtually the only ICH risk factors
exclusive to young individuals35–37. In the seminal study
on this topic, the adjusted relative risk of ICH was 2.5
during pregnancy and increased to 28.3 during the post‑
partum period35. As expected, pregnant women with ICH
tend to be younger and to have fewer risk factors than
nonpregnant women with ICH38. Advanced maternal
age, black ethnicity, pre-existing hypertension, gesta‑
tional hypertension, pre-eclampsia, eclampsia, coagulo­
pathy and tobacco use all independently increase the risk
of pregnancy-related ICH37. Pre-existing cerebrovascular
disease, eclampsia and HELLP syndrome (haemolysis,
elevated liver enzyme levels and low platelet count) seem
to be the leading causes of pregnancy-related ICH36,39.
Genetic risk factors. Early studies observed familial clus‑
tering of ICH, which was attributable in part to shared
genetics and in part to shared environmental factors
(such as living habits and nutrition, reviewed else‑
where40). Genetic factors might plausibly play a greater
part in ICH in young adults than in elderly patients.
Several genetic factors are increasingly recognized
to predispose individuals to ICH, including poly­
morphisms in the genes encoding apolipoprotein E
(APOE), collagen‑α1 (IV) chain (COL4A1), Krev inter‑
action trapped protein 1 (KRIT1), cerebral cavernous
malformations 2 protein (CCM2), programmed cell
death protein 10 (PDCD10) and amyloid precursor
protein (APP)40. Investigations in patients with auto‑
somal dominant familial cerebral cavernous angioma
found that variants in three genes (KRIT1, CCM2 and
PDCD10) account for 85–95% of all familial cases of
this disease41. The proteins produced by these genes
form junctions that connect neighbouring blood vessel
cells and interact with each other as part of a complex
that strengthens the interactions between cells and limits
leakage from blood vessels.
The genetic underpinnings of ICH could also include
alleles that increase the lifetime risk of developing ICH
(such as risk alleles for hypertension) and variants that
cause monogenic disorders that frequently manifest
with ICH: haemophilia, hereditary haemorrhagic tel‑
angiectasia, sickle cell anaemia, von Hippel–Lindau
disease, Ehlers–Danlos syndrome, Marfan syndrome,
von Willebrand disease, primary polycythaemia vera,
moyamoya vasculopathy and early-onset familial cere‑
bral amyloid angiopathy (which is caused by APP muta‑
tions). Multinational efforts to study the genetics of ICH
are ongoing and include individuals with primary and
secondary ICH from different ethnic and geographical
backgrounds. The largest active network in this field is
the International Stroke Genetics Consortium. Other
multinational networks such as the European Moyamoya
Research Network42 and the BEAST (Biorepository to
Establish the Aetiology of Sinovenous Thrombosis) con‑
sortium, which is investigating the genetic background
of cerebral venous thrombosis43, are deciphering the
genetic basis of ICH-related diseases.
Genetic studies of Asian patients with moyamoya
vasculopathy identified a single variant (c.14576G>A)
in the RNF213 gene that was present in 95% of
patients with familial forms of this disease and in 79%
of patients with the sporadic disease, in contrast to
only 1.8% of healthy control individuals44. Moreover,
50% of patients with autosomal dominant capillary
malformation–­a rteriovenous malformation syn‑
drome have RASA1 mutations45. RASA1 encodes Ras
GTPase-activating protein 1, an inhibitory regulator
of the RAS–mitogen-­activated protein kinase (MAPK)
signalling pathway. This pathway is involved in sev‑
eral important cell functions, including cell growth
and division (proliferation), and seems to be essential
for normal development of the vascular system. In a
subsequent study, the same researchers found that the
majority of their patients with capillary malformation–
arteriovenous malformation syndrome who did not
have RASA1 ­mutations had instead a ­mutation in the
EPHB4 gene46.
Hereditary haemorrhagic telangiectasia is an auto‑
somal dominant disease caused by at least five dif‑
ferent genetic defects; however, most patients have
causative mutations in either ENG (encoding endoglin)
or ACVRL1 (encoding serine/threonine-protein kinase
receptor R3), which both encode proteins linked to
transforming growth factor‑β signalling pathways47.
In 2017, eight genes (APP, ADA2, COL4A1, COL4A2,
GLA, HTRA1, NOTCH3 and TREX1) were reported
to be associated with Mendelian inheritance of small-­
vessel disease in a fairly large population of patients with
ICH or ischaemic stroke, who were compared with an
adequate control group. The findings suggested that
in the absence of syndromic features and a family his‑
tory of stroke, genetic screening for mutations linked
to Mendelian inheritance of small-vessel disease does
not have much diagnostic utility 48. Another genetic
study looked for COL4A1, COL4A2, NOTCH3, HTRA1,
TREX1 and ADA2 mutations in patients with either
ICH or ischaemic stroke who were compared with a
matched control group49. A single locus in COL4A2 was
associated both with deep ICH and lacunar ischaemic
stroke, pointing towards a shared pathology involving
the small-vessel vasculature of the brain49.
Increasing knowledge of the genetic basis of stroke
will improve our understanding of disease mechanisms
even if this information is not yet relevant to routine
clinical practice. The fascinating and quickly progress‑
ing field of stroke genetics is likely to have a substantial
effect on clinical practice in the near future. However,
only young patients with sporadic disease who carry
one or another of these mutations have been described
to date50, which suggests that the spectrum of genetic
factors predisposing to young-onset ICH remains poorly
understood. Thus, genetic testing is not routine in most
young patients with ICH.
Causes of ICH. Until recently, all studies used ­simple
location-based classification systems to describe dif‑
ferent subtypes of ICH, such as supratentorial ver‑
sus infratentorial, deep (nonlobar or basal ganglionic)
versus superficial (cortical or subcortical) and with
or without intraventricular haemorrhage. However,

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Table 1 | Key studies in consecutive unselected young patients with intracerebral haemorrhage
Country and Design Cohort Imaging Cause of ICHa Early Refs.
study period mortality
India Single-centre, • 404 patientsb aged NR HTN 79.2%, coagulopathy 4.0% (anticoagulants 1 month 8
2001–2010 retrospective 16–50 years (mean 3.5%), AVM 2.5%, CVT 2.2%, cavernoma 1.0%, 25.2%
41.6 years), 76.2% male mycotic aneurysm 0.7%, thrombocytopenia 0.7%,
• ICH: 16.6% lobar; vasculitis 0.5%, liver cirrhosis 0.5%, undetermined
NR mixed; 2.0% IVH 9.2%
Finland Single-centre, • 336 patientsc aged • Angiography HTN 25.0%, AVM 13.4%, cavernoma 10.7%, In hospital 9
2000–2010 retrospective 16–49 years (median 60.7% CVT 3.0%, drug abuse 3.0%, liver disease 2.1%, 14.9%,
42 years), 59.5% male • MRI 42.3% vasculitis 1.8%, tumour 1.8%, haematologic 1 month
• ICH: 20.9% lobar, 19.4% malignancy 1.5%, anticoagulants or thrombolytics 16.4%,
mixed, IVH 36.1% 1.5%, diabetic microangiopathy 1.2%, eclampsia 3 months
0.6%, essential thrombocythaemia or thrombocyte 17.0%
dysfunction 0.6%, moyamoya 0.3%, von Willebrand
disease 0.3%, HELLP 0.3%, RCVS 0.3%, epithelioid
haemangioendothelioma 0.3%, capillary
telangiectasia 0.3%, PRES 0.3%, undetermined
32.1%
Taiwan Single-centre, • 296 patientsc aged • Angiography HTN 46.7%, vascular malformations (not specified) In hospital 10
2000–2001 retrospective 15–45 years (mean 30.7% 16.9%, alcohol intoxication or smoking 8.8%, 24.0%
37 years), 75.7% male • MRI NR tumour 6.1%, coagulopathy 5.4%, other 1.7%,
• ICH: lobar 25.0%, undetermined 14.5%
mixed 2.0%, IVH 3.0%
Mexico Single-centre, • 200 patientsd aged NR AVM 33.5%, cavernoma 16.0%, HTN 11.0%, CVT In hospital 11
1986–1997 retrospective 15–40 years (mean 5.0%, drug abuse 3.5%, pre-eclampsia 3.5%, 12.5%
27 years), 53.5% male undetermined 20.5%
• ICH: lobar 55.0%,
mixed 1.5%, IVH 4.0%
Taiwan Single-centre, • 170 patientse aged • Angiography HTN 37.6%, AVM 20.0%, coagulopathy 7.5%, In hospital 12
1986–1992 retrospective 15–45 years (mean 42.9% aneurysm 1.8%, alcohol intoxication 1.8%, 34.1%
34.5 years), 65.3% male • MRI 0% drug abuse 1.8%, moyamoya 1.2%, infective
• ICH: lobar 41.8%, endocarditis 1.2%, pre-eclampsia or eclampsia
mixed 2.9%, IVH 5.3% 1.2%, tumour 0.6%, SLE 0.6%, undetermined 24.7%
Ecuador Single-centre, • 151 patientsb aged • Angiography HTN 39.7%, aneurysm 10.6%, AVM 9.9%, alcohol 1 month 13
1986–1996 retrospective 15–44 years (mean 41.1% intoxication 4%, pre-eclampsia or eclampsia 22.5%
and 33.4 years), 60.9% male • MRI 15.2% 3.3%, cavernoma 1.3%, anticoagulants 1.3%,
prospective • ICH: lobar 41.7%, endocarditis 0.7%, ITP 0.7%, drug abuse 0.7%,
mixed 2.6%, IVH 6.6% undetermined 27.8%
UK Single-centre, • 111 patients aged • Angiography AVM 10.8%, HTN 10.8%, aneurysm 9.0%, drug 1 month 14
2006–2010 prospective 18–40 years (mean 53.2% abuse 9.0%, cavernoma 7.2%, head trauma 7.2%, 8.1%
32.6 years), 58.6% male • MRI NR haemorrhagic infarction 5.4%, vasculitis 4.5%, CVT
• ICH: lobar 61.3%, 1.8%, pregnancy 3.6%, tumour 3.6%, coagulopathy
mixed 3.6%, IVH NR 2.7%, undetermined 27.0%
Saudi Arabia Multicentre, • 107 patientsf aged • Angiography AVM 23.4%, HTN 19.6%, coagulopathy 15.9%, In hospital 15
1981–1995 retrospective 0.5–45.0 years (mean 54.2% aneurysm 8.4%, haematologic malignancy 8.4%, 27.1%
28.6 years), 64.5% male • MRI 9.3% coagulation factor deficiency 2.8%, pregnancy or
• ICH: lobar 61.7%, delivery 2.8%, vasculitis 0.9%, liver disease 1.9%,
mixed 2.8%, IVH NR ITP 1.9%, disseminated intravascular coagulopathy
0.9%, endocarditis 0.9%, drug abuse 0.9%, tumour
0.9%, undetermined 26.2%
Netherlands Single-centre, • 98 patientsg aged NR HTN 26.8%, AVM 21.6%, cavernoma 5.2%, 1 month 16
1980–2010 prospective 18–50 years (mean medication 5.2%, coagulopathy 3.1%, drug abuse 20.4%
38 years), 50.0% male 2.1%, septic embolism 1.0%, multiple causes 3.1%,
• ICH: lobar 59.0%, undetermined 31.9%
IVH 37.2%, mixed NR
Taiwan Single-centre, • 91 patientsh aged • Angiography HTN 29.7%, AVM 22.0%, aneurysm 5.5%, tumour 1 month 17
1991–1994 retrospective 15–40 years (mean NR), 39.6% 3.3%, drug abuse 3.3%, uraemia 2.2%, liver 17.6%
63.7% male • MRI 0% cirrhosis 2.2%, endocarditis 1.1%, haemorrhagic
• ICH: lobar 37.4%, infarction 1.1%, SLE 1.1%, moyamoya 1.1%,
IVH 8.8%, mixed NR alcoholism 1.1%, leukaemia 1.1%, undetermined
25.3%
USA Single-centre, • 72 patientsh aged • Angiography AVM 29.1%, HTN 15.3%, aneurysm 9.7%, drug In hospital 18
1978–1985 retrospective 15–45 years (mean 84.7% abuse 6.9%, tumour 4.2%, pre-eclampsia 12.5%
30.5 years), 58.3% male • MRI 0% or eclampsia 2.8%, alcohol intoxication
• ICH: lobar 55.6%, 2.8%, CVT 1.4%, moyamoya 1.4%, SLE 1.4%,
IVH 5.6%, mixed NR cryoglobulinaemia 1.4%, undetermined 23.6%

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Table 1 (cont.) | Key studies in consecutive unselected young patients with intracerebral haemorrhage
Country and Design Cohort Imaging Cause of ICHa Early Refs.
study period mortality
USA Single-centre, • 46 patients aged • Angiography Aneurysm 45.6%, AVM 19.6%, HTN 15.2%, tumour 1 month 19
1982–1987 retrospective 15–45 years (mean NR 10.9%, coagulopathy 4.3%, moyamoya 2.2%, 26.1%
33.1 years), 54.3% male • MRI 0% eclampsia 2.2%
• ICH: lobar 63.0%,
mixed NR, IVH NR
Korea Single-centre, 39 patientsi aged • Angiography AVM 25.6%, HTN 23.1%, aneurysm 5.1%, venous NR 20
2001–2012 retrospective 15–40 years (mean NR angioma 5.1%, undetermined 41.0%
33.2 years), 71.8% male • MRI 0%
ICH: lobar 61.6%,
IVH 46.2%, mixed NR
Studies listed here represent 13 distinct cohorts, each including ≥20 consecutive young adults with intracerebral haemorrhage (ICH): a total of 2,121 patients, of
whom 65% were male. The largest series included 404, 336 and 296 patients. For studies with overlapping samples, only the largest and most recent study is
presented except when the overlap is partial or different parameters were assessed. Autopsy series are included. AVM, arteriovenous malformation; CVT, cerebral
vein thrombosis; HELLP, haemolysis, elevated liver enzyme levels and low platelet count; HTN, hypertension or hypertensive angiopathy; ITP, idiopathic
thrombocytopenic purpura; IVH, intraventricular haemorrhage; NR, not reported; PRES, posterior reversible encephalopathy syndrome; RCVS, reversible cerebral
vasoconstriction syndrome; SLE, systemic lupus erythematosus. aReported with accuracy enabled by the data presented. bPatients with primary subarachnoid
haemorrhage were excluded. cPatients with primary subarachnoid haemorrhage, head trauma and haemorrhagic transformation of brain infarction were excluded.
d
Patients with primary subarachnoid and traumatic haemorrhage, previously diagnosed vascular malformation, aneurysm or brain tumour were excluded. ePatients
with haemorrhagic infarction or a history of head trauma were excluded. fIncluded 12 children aged <10 years and 18 patients aged 10–19 years; haemorrhagic
arterial or venous infarctions were excluded. gPatients with subarachnoid and traumatic haemorrhage, haemorrhage in a brain tumour and ICH attributable to
ruptured aneurysm were excluded. hPatients with prior blood dyscrasias, primary subarachnoid haemorrhage or head trauma were excluded. iPatients with primary
subarachnoid haemorrhage, previously diagnosed brain tumour bleeding or vascular malformation were excluded.

correlations between ICH location and cause are impre‑
cise, and such systems have limited prognostic value.
The first cause-based classification system for ICH was
published in 2012 and includes six categories: struc‑
tural causes, medication, amyloid angiopathy, systemic
disease, hypertension and undetermined aetiology
(SMASH‑U)51 (BOX 1). In addition to helping to identify
the cause of ICH, the SMASH‑U categories are fairly
predictive of prognosis. Although the SMASH‑U classi‑
fication has not yet been specifically investigated or vali­
dated for use in young patients with ICH, the known
causes of ICH in young adults (TABLE 2) are grouped
according to the SMASH‑U classification system. A large
number of additional conditions have been associated
with ICH in single case reports or small series of young
patients with ICH for which causality cannot yet be con‑
clusively determined. Moreover, whether hypertension
is predominantly a risk factor for ICH or a cause of ICH
(or both) remains a matter of debate. Our own approach
is to classify hypertension as a risk factor when a clear
alternative cause of ICH is present; however, if appro‑
priate investigations reveal that hypertension (or hyper‑
tensive angiopathy) is the only potentially causative
mechanism present, hypertension can be considered
the presumptive cause of ICH.
Published series of young adult patients with ICH
show substantial methodological differences, which
hamper comparisons of the frequency of various ICH
aetiologies across different populations. However, hyper‑
tension seems to be the leading cause of ICH in India
and among Asian populations8,10, whereas structural
lesions such as arteriovenous malformations are either
the leading causes of ICH14,18,19 or share that position
with hypertension9,16 in populations of European ori‑
gin. Cavernous angioma was the most common cause
of brainstem ICH in one series11. Amphetamines and
cocaine were the most common drugs of abuse linked
to ICH in young patients9,13,14,17,19. Simultaneous, multiple
ICHs are found in ~6% of unselected patients with ICH52
but in only ~3% of young patients with ICH10,12,14,15.
Reduced anticoagulant use and the lack (or extreme
rarity) of cerebral amyloid angiopathy might largely
explain this difference; anticoagulation-associated ICH
is extremely rare in young adults, reflecting both the
infrequent use of anticoagulation therapy as well as
the low risk of haemorrhage in young adults receiving
anticoagulant drugs. Most anticoagulation treatment in
young patients was related to heart valve disease.
Reversible cerebral vasoconstriction syndrome
(RCVS) deserves attention, as it is an important and
under-recognized cause of ICH in young patients.
Angiography and even repeat angiography are a neces­
sary component of the work‑up of these patients when
clinical suspicion of RCVS is raised (FIG. 1). RCVS is
characterized by recurrent thunderclap headache
attacks of varying durations associated with transient,
non­athero­s clerotic and noninflammatory bilateral
segmental constriction of the cerebral arteries. RCVS
most commonly occurs in individuals aged 20–50 years
and shows a strong female bias53. Other clinical mani­
festations of RCVS are seizures and focal neurologi‑
cal deficits related to ischaemic and/or haemorrhagic
cerebrovascular events secondary to vasoconstriction.
Convexity sub­arachnoid haemorrhage and ICH mani­
fest mainly during the first week, whereas ischaemic
events usually occur during subsequent weeks. Catheter
angiography remains the gold standard for depicting
RCVS, which manifests as a bilateral ‘string-of‑beads’
pattern; CT angiography (CTA) and magnetic reso‑
nance angiography (MRA) have reduced sensitivity for
detecting RCVS. In approximately one-third of patients
with RCVS, angiography conducted during the first
week might not reveal the characteristic pathology, and
repeated investigations might, therefore, be required
for diagnosis (FIG. 1). The characteristic angiographic
findings typically disappear within 12 weeks of RCVS

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Box 1 | Causes of intracerebral haemorrhage in young adults Diagnosis

The criteria below are organized according to the SMASH‑U (structural lesion,
medication, amyloid angiopathy, systemic disease, hypertension, undetermined)
classification system for intracerebral haemorrhage (ICH)51.
Structural lesions
Arteriovenous malformation, aneurysm (and associated diseases such as fibromuscular
dysplasia, Marfan syndrome, Ehlers–Danlos syndrome and polycystic kidney disease),
cavernoma, venous angioma, dural arteriovenous fistula, capillary telangiectasia,
moyamoya vasculopathy, primary and secondary (metastatic) tumoursa of the CNS,
von Hippel–Lindau disease, developmental venous anomalies, dolichoectasia and
intracranial dissection
Medication
Anticoagulants, antiplatelet drugs, thrombolytics, selective serotonin reuptake
inhibitors, drug abuse (including of amphetamine, methamphetamine, cocaine,
crack, heroin, phencyclidine, methadone, ephedrine, pseudoephedrine,
phenylpropanolamine and pentazocine)
Amyloid angiopathy
Icelandic and Dutch forms of hereditary cerebral haemorrhage with amyloidosis
(cerebral amyloid angiopathy is extremely rare in patients with ICH <55 years of age)
Systemic disease
Severe liver disease, renal insufficiency, glomerulonephritis, HIV and/or AIDS,
endocarditis and/or septic embolism, pregnancy and the postpartum period, eclampsia,
vasculitides, haemolysis, elevated liver enzymes and low platelet count (HELLP),
reversible cerebral vasoconstriction syndrome, posterior reversible encephalopathy
syndromes, cerebral venous thrombosis, connective tissue disorders, hereditary
haemorrhagic telangiectasia (Osler–Weber–Rendu disease), lightning stroke, heat
stroke, haematological diseases and coagulopathies (severe anaemias, haemophilia,
leukaemia, lymphoma, von Willebrand disease, thrombocytopenias, polycythaemia
vera, sickle cell disease and disseminated intravascular coagulopathy)
Hypertension
Primary and secondary causes of hypertension (such as pheochromocytoma)
Undetermined
No clear cause of ICH could be detected after adequate investigations or the patient
could not be properly investigated
The SMASH‑U system omits tumours as a cause of ICH.
a
onset. Cerebrospinal fluid (CSF) samples from patients
with RCVS will show normal or near-normal leukocyte
and protein levels, which can help to distinguish RCVS
from vasculitis.
The proportion of young patients classified as having
no identifiable cause of their ICH ranges from 0% to
41% in the studies included in TABLE 1 (mean ~22%)8–20.
However, these studies often included patients who
died before the aetiology of their stroke could be fully
investigated. In general, the more extensive the diagnos‑
tic work‑up of young patients with ICH, the higher the
likelihood of identifying a definite structural or systemic
underlying cause9.
A few studies have provided comparisons of young
and old patients with ICH8–12,15,16,19. Their results show
that the likelihood of having hypertension as the aetiol‑
ogy of ICH increases with advancing age, whereas that of
having arteriovenous malformations, coagulopathies and
rare causes of ICH decreases with advancing age. An age
threshold of 35 years seems to represent a border zone;
individuals <35 years of age most commonly present with
a structural cause of ICH, whereas older individuals most
commonly have hypertension as the cause of ICH.
Clinical features. The clinical presentation of ICH in a
young patient reflects the underlying cause, location(s)
and volume of the bleeding, as it does for ICH in older
patients. However, some data suggest that the younger
the patient with ICH, the less severe their neuro­logical
symptoms. This situation might reflect the increased
proportion of structural causes of ICH and the improved
viability of cerebrovascular compensatory mechanisms
in these young patients9. Additional features of the
patient’s clinical presentation can provide important
clues to the underlying cause of ICH (TABLE 2). These
features are particularly important to consider in young
patients, as unusual causes of ICH are much more
­common in this population than in elderly individuals.
Laboratory tests. Routine laboratory testing in the
emergency room should include a complete blood
count (todetect anaemia, infection, thrombocytopenia
and thrombocytosis), measurement of serum glucose
levels (to detect stress hyperglycaemia or undiagnosed
diabetes), measurement of serum electrolyte levels, kid‑
ney and liver function tests, measurement of C‑reactive
protein levels (to detect infection) and assessments of
prothrombin time, international normalized ratio and
partial thromboplastin time (to detect coagulation
disorders and the effects of anticoagulation therapy).
Assessments of specific coagulation factor levels and
enzyme activities might be of interest if a coagulation
factor deficit is suspected. Toxicology studies should
be performed if drug abuse is suspected. However,
a ­positive toxicology result should not be considered a
definitive and exclusive explanation for ICH in young
adults, as a substantial percentage of patients with cur‑
rent drug abuse also harbour alternative causes for their
ICH, such as a vascular malformation54. Blood cultures
are indicated if the patient’s clinical features raise sus‑
picion of infectious endocarditis. An electrocardiogram
should be performed to screen for left ventricular hyper‑
trophy, which is an indicator of chronic hypertension-­
related end-organ damage, and to determine whether
other concomitant cardiac c­ omorbidities are present.
Imaging. As the diagnosis of acute ICH is easily con‑
firmed by noncontrast head CT or brain MRI, suspicion
for this condition should result in immediate neuro­
imaging. CT is preferable to MRI in the emergency set‑
ting, although MRI is preferred when time constraints
are less important. Once the diagnosis of ICH is con‑
firmed by brain CT or MRI, further neuroimaging
­studies are generally performed to determine the specific
mechanism underlying the ICH.
The choice of imaging methodology should be
guided by the anatomical location of the ICH and any
features of the clinical presentation that raise suspicion
of a particular cause. For example, very young patients,
those with lobar haemorrhage (particularly if associated
with intraventricular or subarachnoid haemorrhage) and
those without a history of hypertension or coagulopathy
are especially likely to have an underlying vascular cause,
such as an arteriovenous malformation55,56. Either CT or

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MRI can be used for further investigation of the mech‑
anisms underlying ICH (BOX 2). When hyperacute non‑
contrast head CT identifies the presence of ICH, many
centres proceed directly to CTA and/or CT venography
to detect potential underlying vascular abnormalities.
Alternatively, MRA and/or magnetic resonance venog‑
raphy can be combined with brain MRI. Susceptibility-
weighted or gradient-echo sequences should be included
for all patients with suspected ICH who are under­going
MRI-based evaluation to detect chronic haemorrhage57.
Contrast-enhanced images should generally also
be obtained.
‘Spot sign’, the presence of active extravasation of con‑
trast agent during CTA, which indicates active ongoing
bleeding from an arterial tear, is a potent predictor of
haematoma expansion and in‑hospital mortality in
patients with primary ICH1. Spot sign might, there‑
fore, represent an important target for acute treatments
that aim to halt ongoing bleeding into the brain paren‑
chyma. Nevertheless, spot sign has not yet been specif‑
ically investigated as a therapeutic target in young adult
patients with primary ICH. In a large series of young
adult patients with secondary causes of their ICH, spot
sign was present in 14.4% of the whole cohort and was a
predictor of in‑hospital mortality 58. Spot sign was most
common in patients with arteriovenous fistulas (42%)
and moyamoya vasculopathy (40%). As secondary
causes of ICH are more common in young patients than
in elderly individuals, this report of a high frequency
of spot sign in young patients with ICH during acute
imaging suggests that systematic studies are warranted
to investigate this phenomenon in populations of young
patients with ICH.
Both CTA and MRA have good sensitivity (~95%) for
the identification of arteriovenous malformations com‑
pared with the gold standard technique, catheter angi‑
ography 59. CTA and MRA are also both very sensitive
for identification of cerebral venous sinus thrombosis60.
However, noninvasive imaging studies are less reliable
than catheter angiography for identifying RCVS. Both
false negative and false positive results can be obtained
with CTA-based and MRA-based detection of RCVS61.
Dural arteriovenous fistulas are also frequently missed
on noninvasive vascular imaging 62. Most experts, includ‑
ing the authors of this Review, recommend catheter
angiography in young patients with unexplained ICH
and negative findings on noninvasive vascular imaging.
This group includes young patients with subcortical

Table 2 | Clinical features that suggest underlying causes of intracerebral haemorrhage

Feature
Drug abuse (of amphetamines, cocaine
or other stimulants)
Injectable drug abuse
Sickle cell disease
Headache for days to weeks preceding
the acute presentation
History of venous thromboembolism or
hypercoagulability
Current or former malignancy
Migraine with aura or stereotyped aura
localizing to the anatomical region
where ICH occurred
History of haemorrhage in same location Cavernoma
Fever at presentation or recent or
concurrent bacterial infection
Family history of ICH
Pulsatile tinnitus or bruit
Haemophilia or another inherited
coagulopathy
Anticoagulant use
APTT, activated partial thromboplastin time; factor Xa, the activated form of coagulation factor X; ICH, intracerebral haemorrhage;
INR, international normalized ratio; PT, prothrombin time.
Possible ICH mechanism Diagnostic testing
• Induced hypertensive ICH Urine toxicology screen
• Drug-associated toxic vasculopathy
or vasculitis
• Reversible cerebral vasoconstriction
syndrome
Infectious endocarditis • Urine toxicology screen
• Blood cultures
Moyamoya vasculopathy Haemoglobin electrophoresis
• Cerebral vein thrombosis Advanced imaging
• Haemorrhagic brain tumour or metastasis
• Reversible cerebral vasoconstriction
syndrome
Cerebral vein thrombosis Advanced imaging
Haemorrhagic brain tumour or metastasis Advanced imaging
Arteriovenous malformation Advanced imaging
Advanced imaging
Infectious endocarditis • Sedimentation rate
• Blood cultures
• Familial cavernoma syndrome Genetic testing and counselling
• Hereditary haemorrhagic telangiectasias
• COL4A1 mutations
• Arteriovenous fistula Advanced imaging
• Cerebral venous thrombosis
ICH associated with coagulopathy • PT and/or APTT
• Specialized coagulation testing
ICH owing to anticoagulation therapy PT and/or APTT, thrombin time,
or acquired coagulopathy INR, anti-factor Xa level, specific
concentration assays

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Intracerebral haemorrhage on non-contrast CT

Urgent CT angiography
and/or CT venography

Brain MRI NO Cause identified? YES Treat as appropriate

Multiple
microhaemorrhages NO Other cause identified? YES Treat as appropriate
YES and/or severe
microvascular disease?
NO

History of hypertension
with or without evidence NO
of hypertensive Catheter angiography
end-organ damage
AND
Index ICH is
subcortical?
Cause identified? YES Treat as appropriate

YES NO

High suspicion for RCVS? Consider repeat catheter

YES angiography in 3–7 days
ICH due to hypertension

NO

Repeat brain MRI in No diagnostic finding

4–8 weeks

Cause identified? YES Treat as appropriate

NO

Consider repeat
catheter angiography

Figure 1 | An approach to the diagnosis of intracerebral haemorrhage in young adults (aged 18–50 years). ICH,
intracerebral haemorrhage; RCVS, reversible cerebral vasoconstriction syndrome. Nature Reviews | Neurology

ICH, as this subgroup has a high rate of having a non‑
hypertensive cause of ICH. For instance, in one series of
200 young individuals with ICH, a specific nonhyper‑
tensive cause could be identified in 16 of the 43 patients
(37%) with subcortical basal ganglia haemorrhage11. The
exception might be young adults with ICH who have a
history of hypertension or evidence of end-organ hyper‑
tensive damage and MRI findings showing substantial
microvascular disease and/or multiple deep micro‑
haemorrhages, in which case the ICH can be ­confidently
ascribed to hypertension.
Whether (and in which patients) angiography should
be repeated is a common clinical dilemma when the find‑
ings of comprehensive initial imaging s­ tudies are non‑
diagnostic. Vascular malformations can be compressed
owing to mass effects caused by the acute haematoma,
such that they are not seen on initial angiography but
become apparent on repeat imaging 4–8 weeks later.
Patients with RCVS can also have initially normal angio­
graphic findings that become abnormal on repeat study
3–7 days later 61. A proposed diagnostic imaging strat‑
egy is shown in FIG. 1 and examples of typical imaging
findings in patients with various aetiologies of ICH are
presented in FIG. 2.
Treatment
Medical management. Medical management of ICH in
young adults is broadly similar to that in older patients,
although many treatment trials in ICH populations have
included relatively few young individuals, and their
results might not always be generalizable to this age
group63. Initial management should include appropriate

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supportive care and aggressive treatment of increased
intracranial pressure. Osmotic agents and hyperventi‑
lation can be used as a temporizing measure in patients
awaiting definitive therapy, such as surgical evacuation
of the haemorrhage or placement of a ventricular drain.
Corticosteroids are ineffective and should be avoided63.
Prophylactic antiepileptic medications, particularly
phenytoin, seem to have deleterious effects, although
patients who undergo clinical or electrographic seizures
should be treated63. Procoagulant medications should
be used in research settings only. Anticoagulation ther‑
apy in patients presenting with cerebral venous sinus
­thrombosis and coexisting ICH is an accepted practice60.
The role of aggressive acute blood pressure lowering
in young patients with ICH remains controversial. The
INTERACT‑2 trial randomly assigned 2,839 patients with
mostly typical hypertensive ICH to a target systolic blood
pressure (SBP) of either <140 mmHg or <180 mmHg.
The results suggested a small benefit for aggressive
blood pressure lowering to <140 mmHg, although this
differential treatment effect disappeared when young
individuals (<65 years old) were compared with older
patients64. The similar ATACH‑2 trial randomly allo‑
cated 1,000 patients, mostly with typical hypertensive
ICH, to either aggressive or conservative blood pressure
lowering. The results revealed no benefit for the aggres‑
sive target (SBP 110–139 mmHg) over the conservative
target (SBP 140–179 mmHg), and more renal adverse
events occurred in the group assigned to aggressive SBP
lowering 65. In reality, however, the conservative-target
group in the ATACH‑2 trial reached a mean SBP of
141.1 mmHg ± 14.8 mmHg, whereas the intensive-target
group achieved a mean SBP of 128.9 mmHg ± 16.0 mmHg
during the first 2 h of treatment, followed by good control
during the next 24 h65. Therefore, in practice, this trial
compared two different intensive blood pressure lower‑
ing approaches. On the basis of these data, we recom‑
mend a moderate target SBP of 140–160 mmHg in the
acute phase for most young patients with ICH who have
elevated blood pressure.
In many centres, patients with a severe clinical
presentation of ICH are initially treated in general or
Box 2 | MRI-based versus CT‑based investigation of intracerebral haemorrhage
CT and MRI have similar sensitivity for detecting acute intracerebral haemorrhage
(ICH). Compared with CT‑based imaging, however, MRI-based imaging offers several
advantages and disadvantages:
Advantages of MRI
• MRI can identify cavernomas and chronic microhaemorrhages
• MRI offers improved visualization of underlying mass lesions such as tumours
• MRI enables improved characterization of microvascular disease burden
• MRI has the ability to visualize thrombus directly in the venous sinuses or cortical veins
• Chronic haemorrhage can be identified only with MRI, specifically by use of
susceptibility-weighted or gradient-echo (T2‑weighted) sequences
Disadvantages of MRI
• MRI is logistically much more challenging to perform than CT at most centres
• MRI is more susceptible than CT to motion artefacts in uncooperative patients
• MRI is not feasible in patients with claustrophobia or with metals in their body
neuro­surgical intensive care units. Despite careful early
management, some patients with massive ICH will inevi­
tably progress to brain death; organ donation should be
considered if it is in accordance with the patient’s or their
family’s wishes. Except for those with a clearly hopeless
prognosis, young patients with ICH should be treated in a
dedicated stroke unit once their condition is stable, as care
in such units is associated with reduced mortality and
disability in all subtypes of stroke, independent of age66.
Surgical treatment. Interestingly, neither European
nor American guidelines on ICH provide specific rec‑
ommendations for the treatment of young patients63,67.
In contrast to medical treatment (which is similar in all
age groups), some surgical treatments might be particu‑
larly suitable for young patients with ICH. Two major
randomized studies that investigated the role of surgical
haematoma evacuation in patients with ICH showed no
benefit of this intervention68,69. However, these studies
included very few young patients with ICH. As inclu‑
sion was dependent on surgical equipoise, many young
patients (who were considered the most likely group
to benefit from this surgery) were not enrolled. In sub‑
group analyses comparing patients <65 years of age
with those at or above this threshold, no clear benefit of
surgery was apparent in either age group68,69. The small
numbers of young patients with ICH included in ran­
domized trials of surgical treatment make it impossible
to judge whether haematoma evacuation or similar sur‑
gical strategies are of benefit to young patients. However,
despite the lack of evidence from randomized trials,
young patients with ICH — especially those with large
haematomas and impaired consciousness — are often
treated surgically.
Two observational studies showed independent and
robust associations between surgical haematoma evacu‑
ation and decreased mortality, which suggested a consid‑
erable benefit of surgical treatment in reducing mortality
in young patients with ICH10,70. In one of these studies,
which included propensity-score matching, 3‑month
mortality was over three times higher in patients who
were treated conservatively than in those who were sur‑
gically treated70. Decompressive craniectomy is seldom
used in patients with ICH, and evidence of its safety
or efficacy is scarce. However, one nonrandomized
small study that compared 12 young adults (age range
38–58 years; median 48 years) with supratentorial ICH
treated with decompressive craniectomy to 15 matched
conservatively treated patients reported a substantial
benefit in favour of surgery 71.
Secondary prevention. Strategies to prevent recurrence
of ICH in young adults should target the underlying
mechanism of ICH and are generally similar to those
in older patients63. For those with hypertension-related
ICH, a target SBP of ≤130 mmHg and/or diastolic blood
pressure ≤80 mmHg might be associated with a reduced
risk of recurrent ICH and other vascular events72. The
benefits of blood pressure reduction seem to be particu‑
larly robust in younger patients73. In some series, almost
half of young patients with hypertension-related ICH

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a b c d e

f g h i

j k l m

n o p q

Surgical equipoise
A principle according to which
patients who are eligible for
enrolment in randomized
clinical trials of medical versus
surgical treatments are
excluded from randomization
if the clinician decides that
(despite a lack of scientific
evidence) surgical treatment
will be superior, or life-saving.
Such considerations often
result in the exclusion of young
patients from clinical trial
cohorts.
Figure 2 | Brain CT, MRI and angiography scans showing intracerebral haemorrhages of various aetiologies in young
adults. a | CT scan showing an acute deep left putaminal intracerebral haemorrhage (ICH) in aNature
43‑year-old man| Neurology
Reviews with
untreated hypertension and left ventricular hypertrophy but no other detectable ICH causes or risk factors. b,c | MRI scans
of the same patient showing a single solid haematoma with early development of oedema on (part b) fluid attenuation
inversion recovery (FLAIR); and (part c) T2‑weighted images. No other old or new haemorrhages were found. d | CT scan
showing massive right frontal ICH in a 25‑year-old man. e | Cerebral digital subtraction angiography in this patient
revealed a large vascular nidus in the same territory fed by middle cerebral and middle meningeal arteries.
f,g | T2‑weighted MRI scans showing a cavernoma causing ICH in the medulla oblongata in a 48‑year-old woman. h | CT
scan showing left putaminal ICH in a 28‑year-old woman. i | Magnetic resonance angiography in this patient revealed
unilateral (left-sided) moyamoya vasculopathy. j | CT scan of a 42‑year-old man with massive right temporo-occipital ICH.
k,l | Digital subtraction angiography in this same patient disclosed (part k) a dural arteriovenous fistula between the right
occipital artery and transverse-sigmoid sinus with (part l) aggressive retrograde drainage into the vein of Labbe and
superficial middle cerebral veins. m | Susceptibility-weighted MRI scan from a young woman, showing multiple bilateral
ICHs caused by biopsy-proven cerebral vasculitis. n | A CT scan showing two small ICHs in a 36‑year-old woman, taken at
her first presentation with severe headache and vomiting. o | An MRI scan of the same patient showed hundreds of
cavernomas resulting in the typical ‘moth-eaten’ brain appearance (her family history was negative for ICH). p | MRI scan
showing right parietal ICH in a young man with a history of intravenous drug abuse. q | Digital subtraction angiography in
the same patient showed that the lesion harboured a mycotic aneurysm (the underlying cause of ICH was endocarditis).
were unaware of their hypertension before their ICH11,13. serotonin reuptake inhibitors, statins and ω3‑fatty acid
For patients with inadequately controlled hyper­tension, supplements have also been associated with an increased
referral to an appropriate specialist is indicated to risk of ICH and should be avoided if possible, particu‑
investi­gate potential causes of secondary hypertension larly in individuals with ICH due to hypertension or
and to optimize blood pressure control. of undetermined cause. Cessation of smoking and
Antithrombotic medications should generally be drug abuse should be advised. In patients with cere‑
avoided in patients with ICH. Obvious culprits include bral venous sinus thrombosis, oral contraceptives and
antiplatelet and anticoagulant agents, but selective ­oestrogen compounds should be stopped.

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The risk of recurrence in patients with ICH due to
arteriovenous malformation is as high as 18% in the
first year 74, and recurrence of ICH in such patients
results in high mortality (26%) and a high depend‑
ency rate (39%)75. Interventional therapies for ruptured
arteriovenous malformations aim at reducing the risk
of ICH recurrence. Young patients with arteriovenous
malformation-­related ICH should undergo evaluation
by a multidisciplinary team to decide on the best treat‑
ment approach(es); endovascular embolization, neuro­
surgery and stereotactic radiotherapy all seem to be
appropriate treatments for these patients76.
In patients with ICH due to moyamoya vasculopathy,
the annual rebleeding rate is about 7%77. The Japan Adult
Moyamoya Trial Group showed that direct or combined
extracranial–intracranial bypass surgery might reduce
the risk of rebleeding in this population of patients78.
The benefit of this intervention seems to be increased
in those with posterior circulation haemorrhages com‑
pared to those with anterior circulation haemorrhages79.
A wide variety of operative techniques is available to
treat moyamoya vasculopathy; however, no study has yet
directly compared the safety or efficacy of the d ­ ifferent
techniques.
In patients with cavernoma-related ICH, a previous
haemorrhagic presentation, focal neurological deficit,
infratentorial and deep location, and a positive fam‑
ily history all increase the risk of recurrent ICH80. The
results of a large meta-analysis showed that cavernomas
located in the brainstem and presenting as either ICH
or a focal neurological deficit were associated with a
5‑year risk of haemorrhage of 31%80. No consensus has
been reached on the optimal treatment for cavernoma.
However, the results of a single-centre series with 8 years
of follow‑up show that neurosurgical e­ xcision — when
feasible — is preferred over stereotactic radio­surgery 81.
Therapeutic decisions should ideally be based on a
multidisciplinary discussion that takes into account
characteristics of both the cavernoma and the patient.
Dural arteriovenous fistula consists of a direct con‑
nection between the dural or pial arteries and dural
sinus, without intervening vasculature. These fistulae are
believed to be acquired secondary to trauma, surgery,
infection or cerebral venous thrombosis. The presence
of retrograde cortical venous reflux is an independent
predictor of ICH in patients with dural arteriovenous
fistula 82. Endovascular and/or surgical treatment
are safe and effective options for patients with dural
­arteriovenous fistula.
Outcomes
Early mortality. In‑hospital mortality ranged from
12.5% to 34.1% and 1‑month mortality (also termed
case fatality) from 8.1% to 26.1% in a large series of
consecutive young patients with ICH (TABLE 1). In 2015,
a Finnish study reported a 3‑month mortality of 17.0%9.
Independent factors associated with early mortality
include female sex, increasing NIH Stroke Scale score,
decreased level of consciousness, substantial bleeding,
infratentorial haematoma location, multiple haemor‑
rhages, high leukocyte count, hyperglycaemia, clustering
of medical complications (including infection, venous
thrombosis, arrhythmia, renal failure, hyper­glycaemia
and electrolyte imbalances) and structural causes
of ICH8–10,70,83.
Some ethnic groups show increased ICH mortality,
which has been attributed to low socioeconomic status,
comorbid vascular conditions and an altered distribution
of underlying causes of ICH. For example, studies con‑
ducted in Asian populations report high mortality and
an increased proportion of deep ICH locations, in line
with hypertension being the dominant cause of ICH in
this group8,10. In the USA, disparities in stroke mortality
seem to be particularly profound for Native American,
Asian and Hispanic populations (who each have about a
1.5‑fold higher risk of death) and for African-American
populations (who have a fivefold higher risk of death)
compared with white populations84.
Long-term mortality. Mortality ranging from 12.5%
to 38.9% has been reported in studies with follow‑up
durations of 6–17 months; the highest rates were found
in the oldest studies11,17,85,86. One Finnish85 and one
Dutch16 study of young patients with ICH involved
longer follow‑up periods (median 9.7 years85 and mean
11.3 years16). All-cause cumulative mortality was 27.6%
at 10 years in the Finnish study 85 and 31.4% at 20 years
in the Dutch study 16. In the Dutch study, the standard‑
ized mortality ratio (SMR) was estimated to be 4.8 for
patients aged 40–50 years — suggesting a nearly fivefold
excess mortality compared with that of the background
population of the same age — whereas the SMR for
patients aged <40 years was 1.3, pointing to no excess
mortality in this age group16.
Most deaths seem to occur during the first few weeks
after ICH and are attributable to neurological compli‑
cations. Little information is available about the long-
term causes of death in patients after ICH, although the
majority of deaths are thought to be caused by factors
not directly related to the index ICH16. Thus, the base‑
line risk factors associated with long-term mortality are
probably different from the predictors of early mortal‑
ity in this population. After adjustment for age and the
presence of intraventricular haematoma, only male sex
and diabetes mellitus were identified as predictors of
increased long-term mortality in a multivariable analysis
of the Finnish study 85.
Recurrent strokes. Two early studies conducted in
Mexico11 and Ecuador 13 found high ICH recurrence
rates in young patients (4.9% at 7.8 months13 and 9.0%
at 17.0 months11 of follow‑up). The Mexico study sug‑
gested that the risk of recurrence was increased in ICHs
caused by hypertension or brain tumour 11, and another
study by the same authors (conducted in a cohort con‑
sisting exclusively of young patients with hypertension
and ICH) observed a recurrence rate of 15.4% at a
mean of 18.7 months of follow-up87. The Finnish85 and
Dutch16 studies described above showed similar cumu‑
lative risks of recurrent ICH at 10 years (11.2%85 and
12.2%16). Further, the 1 year risk of recurrence was 1.9%
in the Finnish study 85 and the 5‑year risk of recurrence

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was 8.4% in the Dutch study 16, pointing to similar risks
in two separate European populations. In these two
studies, most instances of recurrent bleeding had an
underlying structural cause (such as arteriovenous mal‑
formation, cavernoma or moyamoya vasculopathy) that
was known to be present at the time of the index ICH.
Seizures and epilepsy. Cumulative rates of post-ICH
epilepsy were 22.9%85 and 31.0%88 (23.0% of whom had
recurrent seizures88) in the two studies with ~10 years
of follow‑up. The risk of post-ICH epilepsy in young
adults is twofold to sixfold higher than the risk of post-
ICH ischaemic stroke or transient ischaemic attack in
this group and seems to be highest during the first year
after ICH88.
Functional outcome. The few studies that used validated
scales for functional outcome assessment reported that
34.9%−39.9% of the patients achieved a good outcome
(that is, a Glasgow Outcome Scale score of 4–5 or a
modi­fied Rankin Scale score of 0–2) either at discharge
or at 1 month after ICH8,9,16. Severe initial symptoms and
hypertensive ICH seem to confer an increased likelihood
of a poor functional outcome16,87. In general, older age
is a strong predictor of poor outcome early after ICH89,
and some studies suggest an interaction between age and
sex, such that young men have an increased probability
of a poor outcome, whereas in older men, the opposite
is true90.
Long-term functional outcomes have been evalu‑
ated in studies with follow‑up periods ranging from
7.8 months to 9.7 years. Studies with follow‑up periods
at the low end of the range (mean 7.8–49.7 months)
reported that 39.0–59.5% of patients had attained a
good outcome, defined as independent daily living 11,13,23.
In a Finnish study of 131 ICH survivors aged ≤50 years
at the time of the index ICH, 75.8% were living inde‑
pendently (modified Rankin Scale score of 0–2), 51.1%
were completely recovered or had only mild symptoms
(modified Rankin Scale score of 0–1), and 25.2% were
moderately or severely disabled (modified Rankin
Scale score of 3–5) at follow‑up (median 9.7 years)85.
In a Dutch study of 67 patients with ICH, also aged
≤50 years at the time of the index ICH, 50.7% of all
patients were living independently at follow‑up (mean
9.1 years)91. The Dutch study also employed an instru‑
ment to assess activities of daily living in ICH survi‑
vors, which suggested a rate of independent living of
81.8%91, which is in accordance with the results of the
Finnish study 85. Multivariable analysis of the factors
associated with a poor functional outcome found that
increasing age (OR 1.09 per year), increasing initial
NIH Stroke Scale scores (OR 1.17 per point) and intra‑
ventricular extension of the haemorrhage (OR 3.26)
were independently associated with unfavourable out‑
comes85. Notably, haematoma volume and infraten‑
torial location were not associated with unfavourable
outcome, even in the univariable analysis85. Compared
with ischaemic stroke in young patients, ICH in young
patients carries an increased risk of poor functional
­outcome in the long term91.
Other outcomes. Data from the US Agency for Healthcare
Research and Quality Healthcare Cost and Utilization
Project database show that ~40% of young adults (age
18–44 years) with ICH are routinely discharged home
and that ~25% are discharged to a rehabilitation centre or
nursing home92. Another study that reported residential
status at follow‑up (median 9.7 years) found that 84.0%
of ICH survivors were living at home without requiring
assistance outside their families, 10.7% were receiving
daily external assistance but remained living at home,
and 5.3% were in institutional care85.
One Finnish single-centre study has assessed long-
term cognitive and psychosocial outcomes in 130 ICH
survivors who experienced their index event at a young
age93. The researchers used structured interviews and
validated scales to assess mood, pain, sleep problems
and cognition. The results showed that 23.1% of the
patients had depression, 40.0% had symptoms of anxi­
ety and 46.9% reported fatigue. Mild, moderate and
severe pain was reported by 50.8%, 7.7% and 0.8% of
patients, respectively. The degree of disability was associ‑
ated with depression, anxiety and pain. The limited data
available indicate that roughly half of survivors of ICH
at a young age are able to return to work at some point,
with younger patients having better odds of returning to
work93,94. Notably, ICH is associated with a much higher
risk of not being able to return to work than are the other
main stroke subtypes94,95.
Conclusions and future perspectives
ICH is a common disease worldwide, and its prevalence
in young populations is increasing. Determination of the
mechanism underlying ICH in young patients poses a
multidisciplinary challenge to clinicians. Although some
observations suggest a considerable mortality benefit
from surgical haematoma evacuation in young patients
with ICH, the benefit of this treatment remains to be
confirmed in randomized controlled trials, and whether
this strategy leads to improved functional outcomes
remains unknown. This Review highlights evidence of
the high early mortality and high long-term mortality
of ICH in young patients, as well as the high risk of ICH
recurrence and the large proportion of survivors who
have residual symptoms after experiencing an ICH at
a young age. We believe that young patients with ICH
should be managed in dedicated stroke centres with a
multidisciplinary team. These patients should be offered
aggressive treatment to reduce mortality and increase
the probability of good neurological recovery.
A clear need exists for large-scale collaborative
­studies to investigate ICH in young adults. Multicentre
ran­domized controlled trials should be initiated to
investi­gate critical aspects of the disease — such as
the role of early aggressive treatments, including anti-
oedema agents, early haematoma evacuation with vari­
ous techniques and early decompressive craniectomy
— as well as strategies for neuroprotection, rehabilita‑
tion and primary and secondary prevention, including
both conservative and surgical approaches. In addition,
local, national and international hospital-based (or pref‑
erably population-based) registries should be established

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to collect detailed clinical, imaging and laboratory data
(including autopsy data) over long-term follow‑up
­periods; these data would help to characterize the natural
history, uncommon causes and outcomes of this disease.
A biobank that combines neuroimaging, clinical and
autopsy data with genotypes and biological specimens
(such as CSF and brain biopsy samples or autopsy tis‑
sue) would help to elucidate the genetic underpinnings
of young-onset ICH and aid in studying tissue-level
events at various time points. Ultimately, these studies
and schemes might eventually lead to the discovery of
effective treatments.

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Acknowledgements
The authors thank A. Eräkanto for secretarial help.
Author contributions
J.P. and T.T. conducted the literature search for the article. All
authors contributed to the original idea and planning for the
article, to drafting the initial version and to critical revision or
editing of the manuscript before submission.
Competing interests
T.T. declares that he has received grants for research into
intracerebral haemorrhage from Helsinki University Central
Hospital, Sahlgrenska University Hospital, University of
Gothenburg, and the Sigrid Juselius Foundation. The other
authors declare no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.
Review criteria
The authors searched the PubMed, MEDLINE and Scopus data-
bases using the MeSH terms “intracerebral hemorrhage”,
“intracerebral haemorrhage”, “intracerebral bleeding”, “intra­
cranial hemorrhage”, “intra­cranial haemorrhage”, and “intracra-
nial bleeding” in combination with “young adult”, “adult” and
“middle aged” from 1946 to September 2016. Additional
searches were done to identify literature related to disease enti-
ties linked to intracerebral haemorrhage (ICH) in young adults
using the terms “arteriovenous malformations”, “cavernous hae-
mangioma” or “cavernoma”, “moyamoya”, “illicit drugs”, “revers-
ible cerebral vasoconstriction syndrome”, “cerebral venous
thrombosis” and “sickle-cell anaemia”. The authors also identi-
fied papers by reviewing the reference lists of relevant articles
and searching the authors’ personal libraries. Only articles pub-
lished in English were considered. Papers describing isolated
intraventricular haemorrhage were included, but those on con-
fined subarachnoid haemorrhage without brain parenchymal
haematoma, spinal haemorrhage, traumatic, iatrogenic (opera-
tion-related) and tumour-related ICH were excluded (except
when such patients were included in nonselected ICH cohorts).
RELATED LINKS
The International Stroke Genetics Consortium: http://www.
strokegenetics.org

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