Seminar

Spontaneous subarachnoid haemorrhage

R Loch Macdonald, Tom A Schweizer

Subarachnoid haemorrhage is an uncommon and severe subtype of stroke aecting patients at a mean age of 55 years, Lancet 2017; 389: 65566
leading to loss of many years of productive life. The rupture of an intracranial aneurysm is the underlining cause in Published Online
85% of cases. Survival from aneurysmal subarachnoid haemorrhage has increased by 17% in the past few decades, September 13, 2016
http://dx.doi.org/10.1016/
probably because of better diagnosis, early aneurysm repair, prescription of nimodipine, and advanced intensive care
S0140-6736(16)30668-7
support. Nevertheless, survivors commonly have cognitive impairments, which in turn aect patients daily
Division of Neurosurgery
functionality, working capacity, and quality of life. Additionally, those decits are frequently accompanied by mood (Prof R L Macdonald PhD,
disorders, fatigue, and sleep disturbances. Management requires specialised neurological intensive care units and T A Schweizer PhD) and Labatt
multidisciplinary clinical expertise, which is better provided in high-volume centres. Many clinical trials have been Family Centre of Excellence in
Brain Injury and Trauma
done, but only two interventions are shown to improve outcome. Challenges that remain relate to prevention of
Research (Prof R L Macdonald,
subarachnoid haemorrhage by improved screening and development of lower-risk methods to repair or stabilise T A Schweizer), St Michaels
aneurysms that have not yet ruptured. Multicentre cooperative eorts might increase the knowledge that can be Hospital, Toronto, ON, Canada;
gained from clinical trials, which is often limited by small studies with diering criteria and endpoints that are done and Department of Surgery,
University of Toronto, Toronto,
in single centres. Outcome assessments that incorporate ner assessment of neurocognitive function and validated
ON, Canada
surrogate imaging or biomarkers for outcome could also help to advance the specialty. (Prof R L Macdonald,
T A Schweizer)
Introduction and, less commonly, progesterone, have been postulated Correspondence to:
This Seminar reviews spontaneous subarachnoid to have protective eects and thus to contribute to Prof R Loch Macdonald,
Division of Neurosurgery,
haemorrhage, which accounts for 5% of strokes the increased incidence in postmenopausal women.4
St Michaels Hospital, University
(range 16).1 Despite subarachnoid haemorrhage being However, a meta-analysis4 showed that these hormones of Toronto, Toronto,
less common than ischaemic stroke and intracerebral might aect the risk of subarachnoid haemorrhage but ON M5B 1W8, Canada
haemorrhage, the young age of those aected and the the data were conicting and no consistent conclusions macdonaldlo@smh.ca
high morbidity and mortality makes its eect on years of could be reached.
life lost similar to that of the more common types of Risk factors for aneurysm formation, rupture of an
stroke.2 Diagnosis and management involves emergency unruptured aneurysm, and subarachnoid haemorrhage
and general physicians, specialists in neurology, are largely similar (appendix). Studies of risk factors have
neurocritical care, interventional neuroradiology, and yielded some conicting results that could be related to
neurosurgery, and thus requires multidisciplinary bias in the studies and point to incomplete understanding
collaboration to achieve the best patient outcome. of aneurysms. Modiable risk factors for subarachnoid
haemorrhage include smoking, hypertension, and excess
Epidemiology alcohol intake, which all roughly double the risk
The incidence of subarachnoid haemorrhage in individually, whereas a weaker protective eect is
population-based studies, including out-of-hospital associated with regular exercise and increased cholesterol.57
deaths, is 91 cases per 100 000 people per year These factors are associated with an attributable risk for
(95% CI 8895), with some regional variation.3 Finland subarachnoid haemorrhage of about two-thirds.6 The data
(197 cases per 100 000 people per year, 181213) and for the eect of serum lipids on incidence are inconclusive.
Japan (227 cases per 100 000 people per year, 219235) Non-modiable risk factors include increasing age, female
have the highest reported incidences. Controversy exists sex, family history, possibly Japanese or Finnish ethnic
as to whether these variations in incidence are real or are origin, and history of subarachnoid haemorrhage.3
due to dierences in case ascertainment.3 The incidence
of subarachnoid haemorrhage is fallingby 06% per
year from 1955 to 2003.3 About 85% of spontaneous Search strategy
events are aneurysmal and 10% are non-aneurysmal peri- We searched the Cochrane Library, MEDLINE, and Embase and
mesencephalic. The remaining 5% have diverse causes used a library of downloaded citations on subarachnoid
(gure 1, appendix). Non-aneurysmal perimesencephalic haemorrhage that was updated every few months and See Online for appendix
subarachnoid haemorrhage has a specic pattern on spanned all time on MEDLINE. We used the search term
initial CT and has more favourable outcome than does subarachnoid hemorrhage. Publications in the past 5 years
the typical aneurysmal subtype. were preferentially selected, but older highly cited papers or
classically important publications were also included. The
Risk factors reference lists of articles from the last 5 years that were
The occurrence of subarachnoid haemorrhage peaks identied by this search strategy were reviewed and any
between age 50 and 60 years.3 The condition is 16 times relevant additional references were selected. The reference list
more common in women than in men, but this dierence was modied on the basis of comments from peer reviewers.
becomes evident only after the fth decade.3 Oestrogen

www.thelancet.com Vol 389 February 11, 2017 655

 Seminar
A B C D E
F G H I J degree relatives showed that 21% had unruptured
K L M N O population, but similar to the general population in
Figure 1: CT of dierent types of subarachnoid haemorrhage
CT scans of patients with aneurysmal subarachnoid haemorrhage from aneurysms of the right middle cerebral
artery (A), right internal carotid artery (B), anterior communicating artery (C), left middle cerebral artery (D),
and right superior cerebellar artery (E). CT of patients with non-aneurysmal perimesencephalic subarachnoid
haemorrhage (FH, J) resemble aneurysmal subarachnoid haemorrhage from a basilar bifurcation aneurysm (I),
showing that CT or catheter angiography are necessary in all patients with this condition. Non-aneurysmal
subarachnoid haemorrhage due to cerebral venous thrombosis (K, L), trauma (M), pituitary apoplexy (N), and
pseudo-subarachnoid haemorrhage due to increased intracranial pressure, brain swelling, and compression of the
basal cisterns (O). The patients right side is displayed on the left side of the CT scans.
The eect of these factors on the risk of rupture of a
known unruptured aneurysm diers and has been
studied in cohorts of patients with unruptured aneurysms
who are followed up over time. In these studies, the most
important factors for rupture were hypertension, age,
possibly Japanese or Finnish ethnic origin, larger
aneurysm, particular aneurysm locations, and irregular
aneurysm shape.810 Patients with a family history of
aneurysms might have an increased risk of rupture but
this assumption is based on limited data.11,12 Aneurysms
that are growing or symptomatic should be expeditiously
referred for repair. Smoking, alcohol intake, exercise,
serum cholesterol, and sex seem to be less important in
predicting risk of rupture of an unruptured intracranial
aneurysm. Risk factors for aneurysm formation would
best be obtained by population-based screening or
unbiased autopsy studies. Such studies suggest that
aneurysms are more likely with increased age, in women,
in people with autosomal dominant polycystic kidney
disease (ADPKD), and in those with a history of
subarachnoid haemorrhage (appendix).5,1316
Half of subarachnoid haemorrhage cases in one study17
occurred during sleep or at rest but 19% occurred during
or within 2 h of moderate or heavy exercise (odds ratio
[OR] 27, 95% CI 1646). The absolute number of
exertion-related cases was low and the benets of regular
exercise outweigh the risks.18
656
Family history and genetics
Family history of subarachnoid haemorrhage, dened as
two rst-degree relatives with the condition, accounts for
11% of events whereas ADPKD accounts for 03% of
cases.19 Screening of 548 relatives who were smokers or
who had hypertension in families with two aected
siblings or three or more aected rst-degree or second-
aneurysms.12 The aneurysms of two patients subsequently
ruptured, resulting in a familial risk of 12% per year
(95% CI 01443%). This risk is 17 times higher than a
non-contemporaneous matched cohort.10,12 The risk of
subarachnoid haemorrhage is three-to-seven times higher
in rst-degree relatives of patients than in the general
second-degree relatives.20 Genome wide association studies
have identied six denite and one probable loci with
common variants associated with intracranial aneurysms.21
These loci explain 5% of genetic risk, suggesting that
familial clustering might equally be due to common
environmental risk factors. About 10% of patients with
ADPKD have asymptomatic intracranial aneurysms.22
Pathophysiology
Saccular cerebral aneurysms are acquired lesions that
develop at branch points of major arteries of the circle of
Willis. They develop in response to haemodynamic
stress-induced degeneration of the internal elastic lamina
with secondary thinning and loss of the tunica media.
Multiple pathophysiological mechanisms have been
proposed (appendix). The average size of a ruptured
aneurysm is 67 mm.23
Aneurysmal subarachnoid haemorrhage injects blood
into the subarachnoid space in almost all cases (gure 2).
Bleeding into the ventricles and brain itself are common,
but bleeds into the subdural space are uncommon (<5%).
This is important in diagnosis of a ruptured aneurysm,
in that an acute subdural haematoma by itself is unlikely
to be caused by a ruptured aneurysm.
Brain injury from subarachnoid haemorrhage occurs
in two phases (gure 2). There is early brain injury that is
shown by the neurological grade of the patient, which is
caused by transient global ischaemia and toxic eects of
subarachnoid blood.24,25 Direct destruction of brain tissue
by an intracerebral haemorrhage is another factor
(gure 2).24 Subarachnoid haemorrhage is unique in that
there is a delayed phase of brain injury in which delayed
neurological deterioration due to delayed cerebral
ischaemia develops in a third of patients 314 days after
the haemorrhage.26
There is a systemic response to subarachnoid
haemorrhage that can aect the lungs (pulmonary
oedema, acute respiratory distress syndrome), heart
(arrhythmias, contractility abnormalities), and uid and
electrolyte balance, and can cause systemic inammatory
response syndrome.27 Common mechanisms for this
systemic response are increased sympathetic nervous
www.thelancet.com Vol 389 February 11, 2017
 Seminar

system activity, with increased catecholamines, natriuretic

A
peptides, renin or angiotensin system activation, and Ruptured intracranial aneurysm
inammatory cytokines.

Diagnosis Subarachnoid haemorrhage Transient global ischaemia

Sudden onset of the most severe headache of a persons
life is the cardinal symptom of subarachnoid
haemorrhage.28 About 70% of patients present with Early brain injury
headache, which is of sudden onset (thunderclap headache,
dened as reaching maximum severity within 1 min of
onset) in 50% of these patients. Sudden onset is a more
important feature for diagnosis than severity.29 Headache Microcirculatory constriction Excitotoxicity
Endothelial cell apoptosis Ion channel dysfunction
is the only symptom in about half of cases; in the remainder Bloodbrain barrier disruption Thrombin activation
there is nausea, vomiting, transient or ongoing loss of Impaired autoregulation Oxidative stress
Cerebral oedema Inflammation
consciousness, or focal neurological decits. 56 (12%) of Increased MMPs
482 patients with subarachnoid haemorrhage between Altered nitric oxide
1996 and 200130 were initially misdiagnosed, most
commonly as having migraine or tension headache. B Midline shift or herniations:
Increased intracranial pressure
Misdiagnosis is most common in neurologically intact Posterior cerebral artery infarction
patients who complain only of headache and is associated
with increased risk of death and severe disability.
Decision rules help to identify which patients with
headache to investigate for subarachnoid haemorrhage.29
Of 2131 neurologically healthy patients older than 15 years
with non-traumatic acute headache reaching maximum
intensity within 1 h, 132 (6%) had subarachnoid
haemorrhage.29 The use of the Ottawa subarachnoid Subdural haematoma Intraventricular
haemorrhage rule (including age 40 years, neck pain or (<5%) haemorrhage (>50%)
stiness, witnessed loss of consciousness, onset of
headache during exertion, instantaneous onset of
headache, or limited neck exion on examination) Ruptured aneurysm
resulted in a diagnosis with a sensitivity of 100% (95% CI
97100%) and a specicity of 15% (1417%). Clinical
judgment is required when applying these criteria and in
deciding whether or not to investigate the patient, but in
general a low threshold for investigation is appropriate Intracerebral Duret brainstem
given the high morbidity and mortality of subarachnoid haematoma haemorrhage
(30%)
haemorrhage and the low risk of the investigations
required to make the diagnosis. Subarachnoid haemorrhage (>99%)
Non-contrast CT is the diagnostic test of choice for Pulmonary oedema Sympathetic hyperactivity
subarachnoid haemorrhage.31 Failure to obtain a CT scan Acute respiratory distress Increased catecholamines
is the most common diagnostic error leading to missed syndrome Increased natriuretic peptides
Arrhythmias Increased renin/angiotensin
diagnosis.30 A prospective multicentre study assessed Contractility Inflammatory cytokines
CT scans on 3132 neurologically normal patients with Systemic inflammatory
response
non-traumatic headache reaching maximum severity
within 1 h.31 For 953 patients scanned within 6 h, the
Figure 2: Pathophysiology of subarachnoid haemorrhage
sensitivity of CT for subarachnoid haemorrhage was Haemorrhage into various compartments (subarachnoid, intraventricular, intracerebral, subdural) can cause brain
100%, but declined with increasing time from headache shift, increased intracranial pressure, herniation, Duret brainstem haemorrhages, and death. Systemic eects of
onset. This study made use of third generation, subarachnoid haemorrhage include cardiac and pulmonary complications. Brain injury from this condition initially
multidetector CT scanners, and imaging interpretation is due to transient global ischaemia and eects of the haemorrhage. Delayed neurological complications can ensue.
MMPs=matrix metalloproteinases.
was done by qualied radiologists. Although
multidetector CT scanners are highly accurate, sensitivity
depends on the interval between symptom onset and is not necessary. Lumbar puncture ndings support the
image acquisition. In the rst 72 h, sensitivity is greater diagnosis of subarachnoid haemorrhage if erythrocytes
than 97% but is only 50% after 5 days. The high sensitivity or xanthochromia are present in the cerebrospinal uid
within 6 h suggests that subarachnoid haemorrhage can (CSF). However, omitting the use of lumbar puncture
be eectively ruled out by CT and that lumbar puncture from diagnosis is controversial, and if subarachnoid

www.thelancet.com Vol 389 February 11, 2017 657

 Seminar

Subarachnoid haemorrhage

Aneurysmal pattern Non-aneurysmal perimesencephalic pattern Non-aneurysmal, non-perimesencephalic

or no SAH on CT but positive LP pattern (eg, convexity SAH)

CTA DSA CTA CTA

Cause of No cause Cause of No cause Cause of No cause Cause of No cause

SAH for SAH SAH for SAH SAH for SAH SAH for SAH
found found found found found found found found

Repair aneurysm or
responsible lesion, DSA
required as part of
endovascular treatment or
if neurosurgeon needs it
for surgical planning
Repeat CTA or DSA days
later if no cause for SAH is
found, MRI/A is sometimes
done but yield is very low
Repair aneurysm or
responsible lesion, DSA
required as part of
endovascular treatment or
if neurosurgeon needs it for
surgical planning
Consider DSA if CTA
unavailable or it does not
disclose a cause for SAH
Repair aneurysm or treat Consider DSA if CTA
responsible lesion such as unavailable or it does not
PRES, venous thrombosis, disclose a cause for SAH
vasculitis, DSA required as
part of endovascular
treatment or if
neurosurgeon needs it for
surgical planning

No cause for SAH found, No cause for SAH found No cause for SAH found
no further investigations,
some advocate repeat
delayed angiography No further investigations MRI/A, additional medical
necessary investigations may be
indicated

Figure 3: An algorithm for investigation of patients with subarachnoid haemorrhage with CT or lumbar puncture
An algorithm for investigation of patients with subarachnoid haemorrhage present on CT scan or LP. SAH=subarachnoid haemorrhage. CTA=CT angiography. MRA=MR angiography. DSA=digital
subtraction angiography. LP=lumbar puncture. PRES=posterior reversible encephalopathy syndrome.

haemorrhage is suspected and CT scan does not result in
a denitive diagnosis, then additional testing by lumbar
puncture is recommended.32
Any erythrocytes or haemoglobin breakdown product
in the CSF is evidence of subarachnoid haemorrhage.
However, extraneous blood can contaminate the sample
(traumatic tap), which can make the diagnosis
problematic (appendix). None of the methods to
dierentiate these possibilities is infallible and
subarachnoid haemorrhage cannot be ruled out unless a
CSF sample has no erythrocytes and no xanthochromia
as measured by spectrophotometry. Xanthochromia is a
yellow discolouration of CSF, and occurs more than 12 h
after diagnosis because of formation in vivo of bilirubin.32
Erythrocytes will lyse in vitro and release haemoglobin
that will colour the supernatant uid so CSF should be
centrifuged immediately and the supernatant uid
removed for analysis. The sample should then be stored
in the dark to avoid the degradation of bilirubin.
Spectrophotometry should be done as soon as possible,
and a clear CSF sample would rule out a subarachnoid
haemorrhage diagnosis. Unfortunately diagnosis with
this method is dicult, since spectrophotometry is not
available in many countries, the 12 h time is likely to be
variable, and visual inspection (in the absence of
spectrophotometry) is unreliable.33 If subarachnoid
haemorrhage cannot be excluded, a CT angiogram can
be useful to exclude an aneurysm.
Once a diagnosis of subarachnoid haemorrhage is
made, vascular imaging is required to identify the source
of the bleed. Digital subtraction angiography with three
dimensional (3D) reconstructions is the gold standard for
detection of the cause of the haemorrhage and for
planning treatment, but the procedure is invasive,
expensive, time consuming, and has risks.34 Complications
with digital subtraction angiography occurred in 32% of
cases in one series,34 which were mostly transient and
included rare instances of death, permanent neurological
decits, and aneurysm rebleeding. The main imaging
advance for diagnosis has been CT angiography, which
can replace digital subtraction angiography in some cases
(gure 3).35 A systematic review and meta-analysis showed
that CT angiography had a pooled sensitivity of 9798%
(95% CI 9598) compared with digital subtraction
angiography with or without the use of 3D reconstruction.35
The decision to clip or coil the ruptured aneurysm can
often be made on the basis of CT angiography and many
neurosurgeons proceed to neurosurgical clipping without

658 www.thelancet.com Vol 389 February 11, 2017


the need for invasive digital subtraction angiography in
uncomplicated cases. Digital subtraction angiography is
required for endovascular coiling, complex aneurysms,
and if CT angiography does not show a cause for
subarachnoid haemorrhage that is not the
perimesencephalic pattern. For patients with an
aneurysmal pattern of haemorrhage and no cause
identied, digital subtraction angiography should be
repeated days to weeks later. This repeated angiography
shows an aneurysm in 10% of patients (74136).36
Investigation of perimesencephalic subarachnoid
haemorrhage is controversial since CT angiography is
almost as sensitive as 3D digital subtraction angiography
for detecting aneurysms, and it has been questioned
whether patients with perimesencephalic haemorrhage
and normal CT angiography require such angiography.37
About 10% of posterior circulation aneurysms
haemorrhage with a perimesencephalic pattern and about
10% of perimesencephalic subarachnoid haemorrhage are
due to posterior circulation aneurysms (gure 1). The
decision to obtain digital subtraction angiography should
be individualised. Most would not advocate follow-up
imaging in such patients if initial studies are normal.37
A systematic review and meta-analysis38 of MRI and
magnetic resonance (MR) angiography (usually time-of-
ight MR angiography) for detection of aneurysms
showed that sensitivity was 95% (95% CI 8998) and
pooled specicity was 89% (8095). Newer methods such
as contrast enhanced MR angiography and imaging with
higher resolution, 3 Tesla scanners, might be more
sensitive. The limitations of MRI and MR angiography are
the diculties in imaging critically ill patients who might
have monitoring devices (eg, pacemakers) in place that are
not MR compatible and that the sensitivity for detecting
aneurysms is lower than that of CT angiogram methods.
Haemosiderin-sensitive MRI sequences, such as
gradient-echo T2*-weighted and susceptibility-weighted
images, could be useful to detect subarachnoid
haemorrhage in patients who present weeks after a
possible haemorrhage.39 Other applications for MRI and
MR angiogram are for investigation of subarachnoid
haemorrhage with unknown cause, follow-up of coiled
aneurysms to assess for recanalisation, and as a research
method to examine brain structure and function after
subarachnoid haemorrhage.40
Patients are graded clinically and by volume of
subarachnoid haemorrhage and intraventricular
haemorrhage on admission, which is important for
communication between the treating team, predicting
and detecting neurological deterioration, and estimating
prognosis (tables 1, 2).4150
Management
Once initial emergency support has been administered
and diagnosis made, treatable causes of ongoing primary
brain injury need to be addressed. The rst procedure is
surgical evacuation of space-occupying acute subdural
www.thelancet.com Vol 389 February 11, 2017
Seminar
Hunt and Hess41 WFNS42 PAASH43
Grade #1 Asymptomatic or mild headache and GCS 15 GCS 15
slight nuchal rigidity
Grade #2 Moderate to severe headache, nuchal GCS 1413 without major focal GCS 1114
rigidity, no focal neurological decit decit (aphasia or
other than cranial nerve palsy hemiparesis/hemiplegia)
Grade #3 Confusion, lethargy, or mild focal GCS 1413 with major focal decit GCS 810
neurological decit other than cranial
nerve palsy
Grade #4 Stupor or moderate to severe GCS 127 with or without major GCS 47
hemiparesis focal decit
Grade #5 Coma, extensor posturing, moribund GCS 63 with or without major GCS 3
appearance focal decit
These scales are the Hunt and Hess, WFNS, and PAASH scales.4144 The WFNS and PAASH scores rely on the GCS and
have similar interobserver agreement that is higher than the Hunt and Hess scale.43 GCS=Glasgow coma score.
PAASH=prognosis on admission of aneurysmal subarachnoid haemorrhage. WFNS=World Federation of Neurological
Surgeons. SAH=subarachnoid haemorrhage.
Table 1: Commonly used clinical grading scales for SAH
and intracerebral haemorrhages, which is best
accompanied by clipping the ruptured aneurysm
(gure 4).5153 Second, insertion of a ventricular catheter
can be life saving in patients with acute hydrocephalus.
The main causes of early death include brain damage
from the initial subarachnoid haemorrhage and
rebleeding of the aneurysm before it is repaired. Death in
the 314 day interval is usually due to rebleeding, medical
complications, delayed cerebral ischaemia, or withdrawal
of care in patients who fail to improve over time or who
develop complications that preclude functional recovery.54,55
Rebleeding is reported within 72 h of subarachnoid
haemorrhage in 823% of cases,56 5090% of which occur
within the rst 6 h. Rebleeding occurs at 3% per year after
the rst month. This rebleeding has a mortality of
2060%, which does not include patients who die before
hospital admission.56 Risk factors for rebleeding are poor
neurological grade, admission hypertension, a large
aneurysm, and an association has been suggested with
the use of antiplatelet drugs.56 Catheter angiography done
within 6 h of haemorrhage was also associated with
rebleeding but this is probably related to the natural
history rather than to angiography.56,57 The negative eect
of rebleeding on outcome suggests that early aneurysm
repair should improve outcome. Guidelines recommend
this procedure should be done as soon as possible or
within 72 h in all but the most severely aected patients.5860
Another potential treatment to reduce rebleeding
is antibrinolytic drugs such as tranexamic acid.
A randomised clinical trial61 suggested a short course
(1 g every 6 h up to 72 h) of tranexamic acid given until
the aneurysm is repaired reduced the risk of rebleeding,
although a signicant improvement in outcome was not
shown. Tranexamic acid and similar antibrinolytic
lysine derivatives increase the risk of thromboembolic
complications and might induce seizures.62,63 Additional
studies of short-term antibrinolytic administration
are needed.
659
 Seminar

Fisher scale44
Grade #0
Grade #1 No SAH or intraventricular
haemorrhage
Grade #2 Diuse deposition of thin layer with Minimal or thin SAH, with
all vertical layers of blood
(interhemispheric ssure, insular both lateral ventricles
cistern, ambient cistern) <1 mm thick
Grade #3 Vertical layers of blood 1 mm thick
or localised clots (clots dened as
>3 5 mm)
Grade #4 Diuse or no subarachnoid blood,
but with intracerebral or
intraventricular clots
Claassen scale46 Modied Fisher scale47 Hijdra scale, grade each of
ten cisterns and each of the
four ventricles48
No SAH or intraventricular No SAH or intraventricular No blood in cistern, no blood in
haemorrhage haemorrhage ventricle
Minimum or thin SAH, no Localised or diuse thin SAH with Small amount of blood in cistern,
intraventricular haemorrhage in no intraventricular haemorrhage sedimentation of blood in
either lateral ventricle posterior part of ventricle
No or localised or diuse thin SAH Moderate amount of blood in
intraventricular haemorrhage in but with intraventricular cistern, ventricle partly lled with
haemorrhage blood
Thick SAH completely lling Localised or diuse thick SAH with Cistern completely lled with
two or more cisterns or ssures, no intraventricular haemorrhage blood, ventricle completely lled
no intraventricular haemorrhage with blood
in both lateral ventricles
Thick SAH completely lling Localised or diuse thick SAH with
two or more cisterns or ssures, intraventricular haemorrhage
with intraventricular haemorrhage
in both lateral ventricles

The severity of subarachnoid and intraventricular haemorrhage on the initial CT scan is the most important factor predicting delayed cerebral ischaemia and cerebral
infarction and is a prognostic factor for outcome.47 Qualitative, semiquantitative, and quantitative scales have been proposed to measure the extent of damage.49,50
SAH=subarachnoid haemorrhage.

Table 2: Scales used to determine severity of SAH and intraventricular haemorrhage using the Fisher, Claassen, Modied Fisher, and Hijdra scales

US guidelines58 suggest that treatment in centres that
manage a high number of patients improves outcome
from subarachnoid haemorrhage, and this observation has
been supported by a meta-analysis.64 Although it is unclear
whether patients at dierent sites are matched for
prognostic factors for outcome, referral to high-volume
centres is recommended.
Whether to repair an aneurysm by endovascular coiling
or neurosurgical clipping depends on patient age; clinical
condition, including presence of large intracranial
haematomas that need urgent extraction; associated
illnesses; the size, shape, and location of the ruptured
aneurysm; any additional aneurysms present and the
certainty that exists as to which one bled; estimated risks
of treatment of the aneurysm by clipping or coiling; and
the available equipment and skills of the individuals
doing the procedure.65 For aneurysms treatable by either
endovascular coiling or neurosurgical clipping, endo-
vascular repair is recommended. A meta-analysis of four
randomised trials66 showed that coiling reduced the risk
of unfavourable outcome at 1 year to 23% compared with
34% after clipping (OR 148, 95% CI 124176), with no
dierence in mortality. In the largest trial,67 the odds of
being alive and independent after 10 years were
signicantly better after coiling (134, 107167) than
after clipping.
Acute hydrocephalus occurs in 20% of patients with
aneurysmal subarachnoid haemorrhage.68,69 Insertion of a
ventricular catheter is indicated in patients with grade 2 or
higher on the World Federation of Neurosurgical Surgeons
scale and can be life saving.70 Hydrocephalus resolves
spontaneously within 24 h in 30% of patients but can
worsen and be rapidly lethal (gure 4).71 Deterioration
occurred in 143 (22%) of 660 patients in one study72 and
was predicted by further subarachnoid haemorrhages
identied by CT, intraventricular haemorrhage,
hydrocephalus, and use of tranexamic acid. Reluctance to
insert a ventricular catheter is based on the risks of
infection, intracerebral haemorrhage or intraventricular
haemorrhage, and precipitating rebleeding of the
aneurysm. Dey and colleagues73 analysed 33 studies with
9667 cases from the scientic literature and showed a
pooled infection prevalence of 79% (95% CI 6384) and
haemorrhage prevalence of 84% (57111).
Most infections are readily treatable and haemorrhage
associated with ventricular drainage that is symptomatic is
rare, with a prevalence of 07% (0411).73 Rebleeding
from the aneurysm is reported in association with
ventricular drainage in 043% of cases but many believe
that this rebleeding is rarely due to the ventricular drainage
itself.70 With the risks of untreated hydrocephalus and low
risk of ventricular drainage, one should not hesitate to
insert a ventricular catheter if in doubt. Rebleeding could
be minimised by avoidance of excessive intracranial
pressure reduction and by early aneurysm repair.
Patients unable to be weaned from drainage or who
develop delayed hydrocephalus require permanent
CSF diversion (gure 4). In a retrospective Australian
cohort74 of 10 807 patients with subarachnoid
haemorrhage, 701 (7%) required shunts. This gure
varies widely dependent on physician practice.
Multivariate analysis showed that poor grade at
admission, acute hydrocephalus, intraventricular
haemorrhage, ruptured vertebral artery aneurysm,
meningitis, and long-lasting ventricular drainage were
predictors of shunt dependency.74 Fenestration of the

660 www.thelancet.com Vol 389 February 11, 2017


lamina terminalis and third ventriculostomy have been
used to try to reduce the need for permanent
CSF diversion.75,76 There are no randomised trials that
make use of these techniques and a meta-analysis of
studies of fenestration of the lamina terminalis showed
that the technique was ineective.75
An alternative to ventricular drainage is lumbar
drainage but this technique can be done only when there
are no intracranial space-occupying haematomas or
substantial intraventricular haemorrhage. Even in the
absence of these conditions there is risk of neurological
deterioration after this procedure due to herniation.
Lumbar drainage was studied in a randomised trial77 and
shown to reduce delayed cerebral ischaemia but to have
no eect on outcome at 6 months.
Increased intracranial pressure (>20 mm Hg) occurs in
more than 50% of patients with aneurysmal subarachnoid
haemorrhage.78 Causes include brain swelling from the
initial haemorrhage, acute hydrocephalus, cerebral
infarction, and cerebral oedema. Reducing increased
intracranial pressure associated with acute hydrocephalus
or intracerebral haemorrhage can be life saving and
increases the chances of favourable outcome (gure 4).79
However, in cases of extensive cerebral infarction and
brain swelling, this increased pressure could indicate
irreversible brain damage and treatment might be futile.
There are few studies of treatments for increased
intracranial pressure after subarachnoid haemorrhage
and most recommendations are derived from traumatic
brain injury, which recommend some combination of
maintaining intracranial pressure at less than 20 mm Hg
and cerebral perfusion pressure at 5070 mm Hg.80
Extrapolation of these recommendations to subarachnoid
haemorrhage is speculative and might require revision
when studies of intracranial pressure and cerebral
perfusion pressure thresholds are done in this condition.
Partial or generalised seizures or abnormal movements
occur at the time of aneurysmal subarachnoid
haemorrhage in 426% of patients and later in the acute
hospital course in 128% of patients.81 In one randomised
trial,82 nine (65%) of 14 seizures that occurred after
admission but before aneurysm repair were associated
with rebleeding, probably as a result rather than as a
cause of rebleeding. Long-term epilepsy develops in 2%
of patients with subarachnoid haemorrhage but severity
of the haemorrhage is a key factor in the risk for
developing epilepsy, with more than 25% risk in patients
with a severe haemorrhagic outcome. Risk factors for
seizures in hospital and in the long term include younger
age, loss of consciousness at ictus, history of hypertension,
middle cerebral artery aneurysm, severe subarachnoid
haemorrhage on CT, intracerebral haematoma, subdural
haematoma, aneurysm repair by clipping compared with
coiling, and delayed cerebral ischaemia.81,83
To our knowledge, no randomised trials have been
done of anticonvulsant drugs in patients with aneurysmal
subarachnoid haemorrhage, so drug selection, duration
www.thelancet.com Vol 389 February 11, 2017
Seminar
A B C D E
F G H I J
K L M N O
Figure 4: Management of acute and chronic hydrocephalus and intracerebral haemorrhage in three cases
A 56-year-old woman collapsed and was brought to hospital. Initial modied Glasgow Coma Score was 6T or
9 (imputed). She was intubated and CT scan showed subarachnoid haemorrhage (A) and acute hydrocephalus (B),
measured as above the 95th percentile for age by the ventriculocranial or bicaudate ratio (VCR), measured by
thewidth of the frontal horns at the level of the foramen of Monro where the lateral walls of the frontal horns are
parallel, divided by the internal diameter of the skull at the same level (VCR 215/1011 = 021).51 The upper
95th percentile is 016 for less than 30 years old, 018 for 50 years old, 019 at 60 years old, 021 for 80 years old, and
025 for 100 years old. A ventricular catheter was inserted 11 h after the ictus and the left middle cerebral aneurysm
clipped through a pterional craniotomy 17 h after the ictus. Preoperative CT angiography (C) showed that the
aneurysm that was repaired as supported by intraoperative indocyanine green angiography. The patient remained in
poor condition and was transferred to chronic care. The patient remained bedridden and minimally responsive to her
family 3 months later, when a CT scan (D) showed chronic hydrocephalus (VCR 314/986 = 032).
A ventriculoperitoneal shunt was inserted. 8 months later, a year after subarachnoid haemorrhage, the patient
almost fully recovered and was at home, independent, and functioning normally apart from fatigue and anxiety
about having another subarachnoid haemorrhage (E, VCR 197/999 = 020). A 28-year-old woman had sudden onset
severe headache. She had a modied Glasgow Coma Score of 15 and a CT scan (F, G) showed diuse subarachnoid
haemorrhage with mild ventricular enlargement (VCR 142/1134 = 013). A CT angiography showed an anterior
communicating artery aneurysm (H). Her consciousness deteriorated 11 h later. A CT scan showed dilation of the left
lateral ventricle and obliteration of the subarachnoid sulci. (I). Mannitol did not result in improvement. Both pupils
became dilated 14 h later and a ventricular catheter was inserted. The intracranial pressure progressively increased,
was intractable to medical management, and the patient was brain dead 2 days later (J). A 49-year-old woman
developed sudden headache and right hemiparesis. Modied Glasgow Coma Score was 12 and CT scan showed
subarachnoid haemorrhage and intracerebral haemorrhage (K, L) consistent with left middle cerebral artery
aneurysm. During transport to the neurosurgical centre, she deteriorated and had a modied Glasgow Coma Score of
4. She was intubated on arrival 4 h after ictus and underwent CT and CT angiography that showed an increase in the
left intracerebral haemorrhage and a left middle cerebral artery aneurysm (M, N). She underwent immediate
craniotomy, clipping of the aneurysm, evacuation of the haemorrhage, insertion of a ventricular catheter, and
decompressive craniectomy. The bone ap was replaced 3 months later (O). She was ambulatory with a cane but had
residual dysphasia and hemiparesis and was unable to resume work 30 months later.
of treatment, type of patient population, and drug dosage
are open to question. Anticonvulsants, particularly
phenytoin, have been associated with unfavourable
outcome after subarachnoid haemorrhage.84 We
recommend anticonvulsants only in patients with
documented seizures.
Patients might deteriorate days after subarachnoid
haemorrhage for many reasons (appendix).26 Delayed
cerebral ischaemia occurs 314 days after haemorrhage
and is the most important complication because no
661
 Seminar
highly eective treatment exists.85 Delayed cerebral
ischaemia is diagnosed when other causes are ruled out
or deemed insucient to cause the neurological
changes.86 Cerebral infarction from delayed cerebral
ischaemia remains the most important cause of
morbidity in patients surviving the initial haemorrhage.87,88
The pathophysiology of delayed cerebral ischaemia is
postulated to include an interaction of delayed onset
of angiographic vasospasm, impaired autoregulation,
microthrombosis, capillary transit time heterogeneity,
and cortical spreading ischaemia.26,8991
The strongest predictors of delayed cerebral ischaemia
are the severity of subarachnoid haemorrhage on
admission CT scan and poor neurological grade, but
multiple factors contribute and prediction remains
inaccurate.26,92 Diagnosis also is imprecise and made
more dicult since many patients are sedated or already
neurologically impaired.93 Algorithms for diagnosis of
delayed cerebral ischaemia vary from clinical examination
alone to invasive monitoring and frequent
CT angiography, CT perfusion studies, and even routine
digital subtraction angiography.26,59
Despite many randomised trials,26,94 the only
pharmacological drug shown to reduce the risk of delayed
cerebral ischaemia and unfavourable outcome is
nimodipine. Guidelines suggest oral nimodipine be
started within 96 h of subarachnoid haemorrhage.5860
Meta-analyses53,95,96 of fasudil, intrathecal brinolytics,
and cilostazol randomised trials hint at ecacy but these
ndings require further study. In an eort to understand
why many treatments have not shown ecacy, an
international cooperative group has pooled individual
patient data from multiple randomised trials and
databases to inform clinical trial design, develop common
data elements, and promote conduct of early stage trials
at multiple centres rather than independent, staggered
designs with incomparable protocols.9799
Principles of management of delayed cerebral
ischaemia are to counteract reduced delivery of oxygen
and glucose to the brain.26,59 These principles include
monitoring of the neurological exam and maintaining
normal body temperature, body uid volumes,
haemoglobin, glucose, electrolytes (particularly sodium
and magnesium), maintain adequate nutrition, and
mobilise the patient (panel). Aneurysmal subarachnoid
haemorrhage is associated with natriuresis (salt wasting)
and decreased body water secondary to raised natriuretic
peptides, renin activity, aldosterone, catecholamines, and
arginine vasopressin.100 Maintenance of normovolaemia
and normal serum sodium is recommended, but how
monitoring of these variables can be achieved is not
dened.5860
Prophylactic treatments for delayed cerebral ischaemia,
such as inducing hypervolaemia, hypertension,
hypermagnesaemia, and hypothermia, have not been
benecial and are not recommended.5860 Treatment of a
patient who deteriorates from delayed cerebral ischaemia
662
is one of the most controversial areas in management of
aneurysmal subarachnoid haemorrhage. None of the
widely used so-called rescue therapies have been studied
or proven ecacious in randomised trials; their use
varies greatly between countries and centres and they
might be ineective or even detrimental.101 Guidelines
from the American Heart Association state that induced
hypertension is recommended for patients with delayed
cerebral ischaemia unless their blood pressure is already
raised. In this case, endovascular pharmacological or
mechanical angioplasty is a reasonable option.58 The
European Stroke Organization simply states that there is
no evidence from controlled studies for use of induced
hypertension and does not address endovascular
therapies.60 Probably the most common approach for
delayed cerebral ischaemia is to institute induced
hypertension and angioplasty with balloons or selective
vasodilator drug infusions.26,59
Guidelines from several countries and associations
have been created to address the management of
systemic complications (panel).5860 Rebleeding and
delayed cerebral ischaemia have declined as causes of
morbidity and mortality and as a result, medical
complications are an increasingly important factor in
outcome.54,55 Up to 80% of patients will develop a serious
medical complication, which increases the risk of
secondary brain injury and delayed cerebral ischaemia.102
In one series102 of 580 patients, fever, hyperglycaemia, or
anaemia occurred in 3054% of patients and were
independently associated with poor outcome after
adjustment for the prognostic variables of age, clinical
grade, aneurysm size, rebleeding, and cerebral infarction
due to angiographic vasospasm.
Prognosis
Regarding short-term outcome, a meta-analysis103 of
33 studies found a case fatality of 83667% in patients
with subarachnoid haemorrhage. The median of patients
who died before arrival to hospital was 83%. In another
meta-analysis,104 there was an absolute annual reduction
rate in 30 day mortality of 09% (95% CI 0315)
between 1980 and 2005, for an overall 50% reduction.
Data for functional outcome in population-based studies
are scarce. It is estimated that 55% of patients regain
independent function, 19% remain dependent, and 26%
die.103 Many outcome scales have been developed to
assess neurological and cognitive outcomes and quality
of life after brain injury, including the Glasgow and
extended Glasgow outcome scales, modied Rankin
scale, Short Form-36, Mini-Mental Status Examination,
Montreal cognitive assessment, and Barthel index. None
of these tests were developed specically for
subarachnoid haemorrhage. Patients with favourable
outcome (eg, modied Rankin scale 3 or Glasgow
outcome scale 4) frequently have decits in cognitive
domains (eg, verbal memory, language, and executive
function), decreased decision-making capacity expressed
www.thelancet.com Vol 389 February 11, 2017

by cognitive inexibility, enhanced risk-taking behaviour,
and decreased quality of life for years after subarachnoid
haemorrhage.105 Additionally, these decits are frequently
accompanied by mood disorders, fatigue, and sleep
disturbances.105
A systematic review106 identied factors at hospital
admission that were associated with unfavourable
outcome according to the Glasgow outcome score or
modied Rankin score and included worse admission
neurological condition, older age, aneurysm repair by
clipping rather than coiling, more severe subarachnoid
haemorrhage on CT scan, history of hypertension, larger
aneurysm, and posterior circulation aneurysm. Only
25% of the variation in outcome is explained by these
variables, indicating that other factors (eg, genetic,
epigenetic, disease-related factors) have substantial
eects on outcome or that outcome scales are imprecise.
In the long term, many patients who survive
subarachnoid haemorrhage continue to have the above-
noted decits in cognition, quality of life, mood, and
fatigue.105 Patients who have had subarachnoid
haemorrhage have a 15 times higher risk of a second
haemorrhagic event than do the general population.107
Their long-term standardised mortality ratio is 15, in
excess of the general population, and mostly related to
cardiovascular and cerebrovascular disease.108
Prevention
Subarachnoid haemorrhage could be prevented by
repairing aneurysms before they rupture or by reducing
aneurysm formation. Unruptured aneurysms had a
prevalence of 32% in 83 study populations.11 No
randomised trials exist on which to base the decision to
repair an unruptured aneurysm, and the risks of rupture
have to be weighed against the risks of repair.11 Several
systems have been developed to aid the clinician in
decision making. A systematic review8 pooled analysis of
8382 patients who had 230 subarachnoid haemorrhages
during 29 166 combined years of follow-up and showed
that age, hypertension, aneurysm size and location, and
geographical location were associated with rupture. These
factors were used to develop a risk score (PHASES:
population, hypertension, age, size, earlier subarachnoid
haemorrhage, site). Another system developed by Delphi
consensus by a panel of experts and included these factors
plus family history, medical comorbidities, life expectancy,
presence of daughter loci, growth or de-novo aneurysm
formation, symptoms other than rupture, and risk of
repair, which was not addressed in PHASES.109
Formation of new aneurysms in patients who have had
subarachnoid haemorrhage is increasingly recognised.
In one study110 of 752 patients followed up for 6016 patient-
years, recurrent subarachnoid haemorrhage occurred in
32% (95% CI 1549) or about 22 times more
frequently than in the general population. Increased
likelihood of recurrence was observed with smoking
(hazard ratio [HR] 65, 95% CI 17240), increased age and 51 (91117) if there were two rst-degree relatives.
www.thelancet.com Vol 389 February 11, 2017
Seminar
Panel: Recommended management of subarachnoid haemorrhage
Admit to hospital and monitor patient with frequent clinical and neurological
assessments in critical care settings.
CT and vascular imaging (CT or catheter angiography) and aneurysm repair to be done
as soon as possible.
Urgent surgery to evacuate space-occupying intracerebral haemorrhage and clip
aneurysm or insert ventricular catheter to drain symptomatic hydrocephalus.
Administer enteral nimodipine.
Administer antihypertensives to reduce blood pressure before aneurysm repair, but
should be avoided after aneurysm repair unless blood pressure is substantially raised.
Maintain normal body temperature and avoid fever, hypothermia, extremes in
glucose concentration, hypercarbia, hypoxia, hypomagnesaemia, decreased cerebral
perfusion pressure, hypovolaemia, and hyponatraemia.
Maintain normovolaemia and use measures necessary to do so (intravenous uids,
monitor volume status, possible central venous access, bodyweights).
Rapidly investigate neurological deterioration and treat underlying causes and consider
perfusion imaging to nd out whether arterial narrowing is a cause of deterioration.
Apply graduated compression stockings or intermittent pneumatic compression
devices on lower limbs and consider pharmacological prophylaxis for venous
thromboembolism beginning 24 h after aneurysm repair.
Give anticonvulsants for the treatment of seizures (not prophylaxis).
After electrocardiography on admission, consider investigation for cardiac injury if
there are clinical signs of this or there is stunned myocardium, takotsubo
cardiomyopathy, or increased cardiac troponin I.
Minimise blood loss, maintain normal haemoglobin, or transfuse for anaemia, but
transfusion thresholds are unknown.
If a patient develops delayed cerebral ischaemia, treat with induced hypertension.
Endovascular balloon or pharmacological angioplasty are reasonable. Both are of
unproven eectiveness and carry substantial risks.
Follow up the patient after discharge and provide physical, neurological, occupational,
and cognitive rehabilitation. Consider diagnosis and treatment of depression, anxiety,
and post-traumatic stress disorder and whether patient and family members should
be screened for aneurysms in follow up.
Support adequate and well-controlled randomised clinical trials since other than
enteral nimodipine and timely aneurysm repair by coiling, none of the above
recommendations are based on robust data. The history of subarachnoid
haemorrhage is similar to other areas of medicine in which anecdote leads to adoption
of management that is of unproven ecacy and safety until shown in high-quality
randomised trials.
(05 per 10 years, 0308), and multiple aneurysms at
time of their rst haemorrhage (55, 22141).110 In
another series,111 220 patients with subarachnoid
haemorrhage were followed up for 317 years (mean of
11 years). The cumulative risk of recurrence was 22% at
10 years and 90% at 20 years, rates that were more than
ten times higher than those in the general population.
The incidence of aneurysms identied by screening
depends on the population screened such as the number
with a positive family history and risk factors for
aneurysm formation and rupture (appendix).
In a study from Sweden, 112 the odds ratio for
subarachnoid haemorrhage was 2 (95% CI 1826) if
the patient had one rst-degree relative with the disorder,
663
 Seminar
Bor and colleagues113 screened 458 patients with a family
history of aneurysms or subarachnoid haemorrhage and
showed that 10% had aneurysms. Screening every
5 years in subsets of these patients detected new
aneurysms in about 5%, even if no aneurysms were
initially seen. A familial aneurysm study12 identied
aneurysms in 21% of family members of a high-risk
subgroup of hypertensive smokers.
Screening is recommended for rst-degree relatives if
the patient has two or more rst-degree relatives with
aneurysms or subarachnoid haemorrhage.11 Angiography
with CT or MR are acceptable methods for screening
these patients. Patients with coarctation of the aorta,
ADPKD, and twins if one twin has an aneurysm or
subarachnoid haemorrhage, are suggested for screening
at an arbitrary interval of 5 years.114 The screening interval,
whether to screen other lower-risk groups, and the eect
of screening on quality of life have been controversial.11
Screening might be done in lower-risk groups if siblings
of patients who have had a subarachnoid haemorrhage at
a young age volunteer and if an unruptured aneurysm is
identied and not repaired. Patients who have a
subarachnoid haemorrhage at a young age, especially if
they are female, smokers, or have multiple aneurysms
also full this criteria.11,114,115 Screening should be repeated
yearly for 13 years, and then less frequently if the
aneurysm remains unchanged in size and shape.11,115
Contributors
TS searched the literature, wrote the initial draft of the manuscript and
made revisions. RLM searched the literature, rewrote the initial draft,
made multiple revisions, designed the illustrations and submitted the
manuscript.
Declaration of interest
RLM is Chief Scientic Ocer of Edge Therapeutics, Inc. TAS declares
no competing interests.
Acknowledgments
TAS receives grant support from the Canadian Institutes of Health
Research, Ministry of Research and Development, and the Heart and
Stroke Foundation of Canada. RLM receives grant support from the
Physicians Services Incorporated Foundation, Brain Aneurysm
Foundation, Canadian Stroke Network, and the Heart and Stroke
Foundation of Ontario. This work was conducted independently of the
funders and does not necessarily reect their opinions.
References
1 Feigin VL, Lawes CM, Bennett DA, Barker-Collo SL, Parag V.
Worldwide stroke incidence and early case fatality reported in
56 populationbased studies: a systematic review. Lancet Neurol
2009; 8: 35569.
2 Johnston SC, Selvin S, Gress DR. The burden, trends, and
demographics of mortality from subarachnoid hemorrhage.
Neurology 1998; 50: 141318.
3 de Rooij NK, Linn FH, van der Plas JA, Algra A, Rinkel GJ.
Incidence of subarachnoid haemorrhage: a systematic review with
emphasis on region, age, gender and time trends.
J Neurol Neurosurg Psychiatry 2007; 78: 136572.
4 Algra AM, Klijn CJ, Helmerhorst FM, Algra A, Rinkel GJ.
Female risk factors for subarachnoid hemorrhage: a systematic
review. Neurology 2012; 79: 123036.
5 Weir B. Unruptured intracranial aneurysms: a review. J Neurosurg
2002; 96: 342.
6 Andreasen TH, Bartek J Jr, Andresen M, Springborg JB, Romner B.
Modiable risk factors for aneurysmal subarachnoid hemorrhage.
Stroke 2013; 44: 360712.
664
7 Feigin VL, Rinkel GJ, Lawes CM, et al. Risk factors for
subarachnoid hemorrhage: an updated systematic review of
epidemiological studies. Stroke 2005; 36: 277380.
8 Greving JP, Wermer MJ, Brown RD Jr, et al. Development of the
PHASES score for prediction of risk of rupture of intracranial
aneurysms: a pooled analysis of six prospective cohort studies.
Lancet Neurol 2014; 13: 5966.
9 Morita A, Kirino T, Hashi K, et al. The natural course of unruptured
cerebral aneurysms in a Japanese cohort. N Engl J Med 2012;
366: 24782.
10 Wiebers DO, Whisnant JP, Huston J 3rd, et al. Unruptured
intracranial aneurysms: natural history, clinical outcome, and risks
of surgical and endovascular treatment. Lancet 2003; 362: 10310.
11 Brown RD Jr, Broderick JP. Unruptured intracranial aneurysms:
epidemiology, natural history, management options, and familial
screening. Lancet Neurol 2014; 13: 393404.
12 Broderick JP, Brown RD Jr, Sauerbeck L, et al. Greater rupture risk
for familial as compared to sporadic unruptured intracranial
aneurysms. Stroke 2009; 40: 195257.
13 Vlak MH, Rinkel GJ, Greebe P, Algra A. Independent risk factors
for intracranial aneurysms and their joint eect: a case-control
study. Stroke 2013; 44: 98487.
14 Li MH, Chen SW, Li YD, et al. Prevalence of unruptured cerebral
aneurysms in Chinese adults aged 35 to 75 years:
a cross-sectional study. Ann Intern Med 2013; 159: 51421.
15 Horikoshi T, Akiyama I, Yamagata Z, Nukui H. Retrospective
analysis of the prevalence of asymptomatic cerebral aneurysm in
4518 patients undergoing magnetic resonance angiographywhen
does cerebral aneurysm develop? Neurol Med Chir (Tokyo) 2002;
42: 10512.
16 Taylor CL, Yuan Z, Selman WR, Ratcheson RA, Rimm AA.
Cerebral arterial aneurysm formation and rupture in 20,767 elderly
patients: Hypertension and other risk factors. J Neurosurg 1995;
83: 81219.
17 Anderson C, Ni Mhurchu C, Scott D, Bennett D, Jamrozik K,
Hankey G. Triggers of subarachnoid hemorrhage: role of physical
exertion, smoking, and alcohol in the Australasian Cooperative
Research on Subarachnoid Hemorrhage Study (ACROSS).
Stroke 2003; 34: 177176.
18 Vlak MH, Rinkel GJ, Greebe P, van der Bom JG, Algra A.
Trigger factors and their attributable risk for rupture of intracranial
aneurysms: a casecrossover study. Stroke 2011; 42: 187882.
19 Ruigrok YM, Buskens E, Rinkel GJ. Attributable risk of common
and rare determinants of subarachnoid hemorrhage. Stroke 2001;
32: 117375.
20 Bromberg JE, Rinkel GJ, Algra A, et al. Subarachnoid haemorrhage
in rst and second degree relatives of patients with subarachnoid
haemorrhage. BMJ 1995; 311: 28889.
21 Kurki MI, Gal EI, Kettunen J, et al. High risk population isolate
reveals low frequency variants predisposing to intracranial
aneurysms. PLoS Genet 2014; 10: e1004134.
22 Perrone RD, Malek AM, Watnick T. Vascular complications in
autosomal dominant polycystic kidney disease. Nat Rev Nephrol
2015; 11: 58998.
23 Beck J, Rohde S, Berkefeld J, Seifert V, Raabe A. Size and location of
ruptured and unruptured intracranial aneurysms measured by
3-dimensional rotational angiography. Surg Neurol 2006; 65: 1825.
24 Fujii M, Yan J, Rolland WB, Soejima Y, Caner B, Zhang JH. Early
brain injury, an evolving frontier in subarachnoid hemorrhage
research. Transl Stroke Res 2013; 4: 43246.
25 Matz PG, Fujimura M, Lewen A, Morita-Fujimura Y, Chan PH.
Increased cytochrome c-mediated DNA fragmentation and cell
death in manganese-superoxide dismutase-decient mice after
exposure to subarachnoid hemolysate. Stroke 2001; 32: 50615.
26 Macdonald RL. Delayed neurological deterioration after
subarachnoid haemorrhage. Nat Rev Neurol 2014; 10: 4458.
27 Chen S, Li Q, Wu H, Krat PR, Wang Z, Zhang JH. The harmful
eects of subarachnoid hemorrhage on extracerebral organs.
Biomed Res Int 2014; 2014: 858496.
28 Ducros A, Bousser MG. Thunderclap headache. BMJ 2013;
346: e8557.
29 Perry JJ, Stiell IG, Sivilotti ML, et al. Clinical decision rules to rule
out subarachnoid hemorrhage for acute headache. JAMA 2013;
310: 124855.
www.thelancet.com Vol 389 February 11, 2017

30 Kowalski RG, Claassen J, Kreiter KT, et al. Initial misdiagnosis and
outcome after subarachnoid hemorrhage. JAMA 2004; 291: 86669.
31 Perry JJ, Stiell IG, Sivilotti ML, et al. Sensitivity of computed
tomography performed within six hours of onset of headache for
diagnosis of subarachnoid haemorrhage: prospective cohort study.
BMJ 2011; 343: d4277.
32 Backes D, Rinkel GJ, Kemperman H, Linn FH, Vergouwen MD.
Time-dependent test characteristics of head computed tomography
in patients suspected of nontraumatic subarachnoid hemorrhage.
Stroke 2012; 43: 211519.
33 Arora S, Swadron SP, Dissanayake V. Evaluating the sensitivity of
visual xanthochromia in patients with subarachnoid hemorrhage.
J Emerg Med 2010; 39: 1316.
34 Kaufmann TJ, Huston J 3rd, Mandrekar JN, Schleck CD,
Thielen KR, Kallmes DF. Complications of diagnostic cerebral
angiography: evaluation of 19,826 consecutive patients.
Radiology 2007; 243: 81219.
35 Westerlaan HE, van Dijk JM, Jansen-van der Weide MC, et al.
Intracranial aneurysms in patients with subarachnoid hemorrhage:
CT angiography as a primary examination tool for diagnosis:
a systematic review and meta-analysis. Radiology 2011; 258: 13445.
36 Bakker NA, Groen RJ, Foumani M, et al. Repeat digital subtraction
angiography after a negative baseline assessment in
nonperimesencephalic subarachnoid hemorrhage: a pooled data
meta-analysis. J Neurosurg 2014; 120: 99103.
37 Agid R, Andersson T, Almqvist H, et al. Negative CT angiography
ndings in patients with spontaneous subarachnoid hemorrhage:
when is digital subtraction angiography still needed?
AJNR Am J Neuroradiol 2010; 31: 696705.
38 Sailer AM, Wagemans BA, Nelemans PJ, de Graaf R, van Zwam WH.
Diagnosing intracranial aneurysms with MR angiography: systematic
review and meta-analysis. Stroke 2014; 45: 11926.
39 Lummel N, Bernau C, Thon N, Bochmann K, Linn J. Prevalence of
supercial siderosis following singular, acute aneurysmal
subarachnoid hemorrhage. Neuroradiology 2015; 57: 34956.
40 Schweizer TA, Al-Khindi T, Loch Macdonald R. Diusion tensor
imaging as a surrogate marker for outcome after perimesencephalic
subarachnoid hemorrhage. Clin Neurol Neurosurg 2012; 114: 798800.
41 Hunt WE, Hess RM. Surgical risk as related to time of intervention
in the repair of intracranial aneurysms. J Neurosurg 1968; 28: 1420.
42 Drake CG, Hunt WE, Sano K, et al. Report of World Federation of
Neurological Surgeons Committee on a universal subarachnoid
hemorrhage grading scale. J Neurosurg 1988; 68: 98586.
43 Degen LA, Dorhout Mees SM, Algra A, Rinkel GJ. Interobserver
variability of grading scales for aneurysmal subarachnoid
hemorrhage. Stroke 2011; 42: 154649.
44 van Heuven AW, Dorhout Mees SM, Algra A, Rinkel GJ. Validation
of a prognostic subarachnoid hemorrhage grading scale derived
directly from the Glasgow Coma scale. Stroke 2008; 39: 134748.
45 Fisher CM, Kistler JP, Davis JM. Relation of cerebral vasospasm to
subarachnoid hemorrhage visualized by computerized tomographic
scanning. Neurosurgery 1980; 6: 19.
46 Claassen J, Bernardini GL, Kreiter K, et al. Eect of cisternal and
ventricular blood on risk of delayed cerebral ischemia after
subarachnoid hemorrhage: The Fisher scale revisited. Stroke 2001;
32: 201220.
47 Frontera J, Claassen J, Schmidt JM, et al. Prediction of symptomatic
vasospasm after subarachnoid hemorrhage: the modied Fisher
scale. Neurosurgery 2006; 59: 2127.
48 Hijdra A, Brouwers PJ, Vermeulen M, van Gijn J. Grading the
amount of blood on computed tomograms after subarachnoid
hemorrhage. Stroke 1990; 21: 115661.
49 Kramer AH, Hehir M, Nathan B, et al. A comparison of 3 radiographic
scales for the prediction of delayed ischemia and prognosis following
subarachnoid hemorrhage. J Neurosurg 2008; 109: 199207.
50 Klimo P Jr, Schmidt RH. Computed tomography grading schemes
used to predict cerebral vasospasm after aneurysmal subarachnoid
hemorrhage: a historical review. Neurosurg Focus 2006; 21: E5.
51 van Gijn J, Hijdra A, Wijdicks EF, Vermeulen M, van Crevel H.
Acute hydrocephalus after aneurysmal subarachnoid hemorrhage.
J Neurosurg 1985; 63: 35562.
52 Gresir E, Beck J, Vatter H, et al. Subarachnoid hemorrhage and
intracerebral hematoma: incidence, prognostic factors, and
outcome. Neurosurgery 2008; 63: 108893.
www.thelancet.com Vol 389 February 11, 2017
Seminar
53 Liu GJ, Wang ZJ, Wang YF, et al. Systematic assessment and
metaanalysis of the ecacy and safety of fasudil in the treatment
of cerebral vasospasm in patients with subarachnoid hemorrhage.
Eur J Clin Pharmacol 2012; 68: 13139.
54 Lantigua H, Ortega-Gutierrez S, Schmidt JM, et al. Subarachnoid
hemorrhage: who dies, and why? Crit Care 2015; 19: 309.
55 Komotar RJ, Schmidt JM, Starke RM, et al. Resuscitation and
critical care of poorgrade subarachnoid hemorrhage.
Neurosurgery 2009; 64: 397410.
56 Larsen CC, Astrup J. Rebleeding after aneurysmal subarachnoid
hemorrhage: a literature review. World Neurosurg 2013; 79: 307-12.
57 Fujii Y, Takeuchi S, Sasaki O, Minakawa T, Koike T, Tanaka R.
Ultra-early rebleeding in spontaneous subarachnoid hemorrhage.
J Neurosurg 1996; 84: 3542.
58 Connolly ES Jr, Rabinstein AA, Carhuapoma JR, et al. Guidelines
for the management of aneurysmal subarachnoid hemorrhage:
a guideline for healthcare professionals from the American Heart
Association/American Stroke Association. Stroke 2012; 43: 171137.
59 Diringer MN, Bleck TP, Hemphill CJ 3rd, et al. Critical care
management of patients following aneurysmal subarachnoid
hemorrhage: recommendations from the Neurocritical Care
Societys Multidisciplinary Consensus Conference. Neurocrit Care
2011; 15: 21140.
60 Steiner T, Juvela S, Unterberg A, Jung C, Forsting M, Rinkel G.
European Stroke Organization guidelines for the management of
intracranial aneurysms and subarachnoid haemorrhage.
Cerebrovasc Dis 2013; 35: 93112.
61 Hillman J, Fridriksson S, Nilsson O, Yu Z, Saveland H,
Jakobsson KE. Immediate administration of tranexamic acid and
reduced incidence of early rebleeding after aneurysmal
subarachnoid hemorrhage: a prospective randomized study.
J Neurosurg 2002; 97: 77178.
62 Foreman PM, Chua M, Harrigan MR, et al. Antibrinolytic therapy
in aneurysmal subarachnoid hemorrhage increases the risk for
deep venous thrombosis: a casecontrol study.
Clin Neurol Neurosurg 2015; 139: 6669.
63 Lecker I, Wang DS, Romaschin AD, Peterson M, Mazer CD,
Orser BA. Tranexamic acid concentrations associated with human
seizures inhibit glycine receptors. J Clin Invest 2012; 122: 465466.
64 Boogaarts HD, van Amerongen MJ, de Vries J, et al. Caseload as
a factor for outcome in aneurysmal subarachnoid hemorrhage:
a systematic review and meta-analysis. J Neurosurg 2014; 120: 60511.
65 Darsaut TE, Kotowski M, Raymond J. How to choose clipping
versus coiling in treating intracranial aneurysms.
Neurochirurgie 2012; 58: 6175 (in French).
66 Li H, Pan R, Wang H, et al. Clipping versus coiling for ruptured
intracranial aneurysms: a systematic review and meta-analysis.
Stroke 2013; 44: 2937.
67 Molyneux AJ, Birks J, Clarke A, Sneade M, Kerr RS. The durability
of endovascular coiling versus neurosurgical clipping of ruptured
cerebral aneurysms: 18 year followup of the UK cohort of the
International Subarachnoid Aneurysm Trial (ISAT). Lancet 2015;
385: 69197.
68 Tso MK, Ibrahim GM, Macdonald RL. Predictors of
shunt-dependent hydrocephalus following aneurysmal
subarachnoid hemorrhage. World Neurosurg 2016; 86: 22632.
69 Germanwala AV, Huang J, Tamargo RJ. Hydrocephalus after
aneurysmal subarachnoid hemorrhage. Neurosurg Clin N Am 2010;
21: 26370.
70 Gigante P, Hwang BY, Appelboom G, Kellner CP, Kellner MA,
Connolly ES. External ventricular drainage following aneurysmal
subarachnoid haemorrhage. Br J Neurosurg 2010; 24: 62532.
71 Lu J, Ji N, Yang Z, Zhao X. Prognosis and treatment of acute
hydrocephalus following aneurysmal subarachnoid haemorrhage.
J Clin Neurosci 2012; 19: 66972.
72 Vermeij FH, Hasan D, Vermeulen M, Tanghe HL, van Gijn J.
Predictive factors for deterioration from hydrocephalus after
subarachnoid hemorrhage. Neurology 1994; 44: 185155.
73 Dey M, Stadnik A, Riad F, et al. Bleeding and infection with
external ventricular drainage: a systematic review in comparison
with adjudicated adverse events in the ongoing Clot Lysis
Evaluating Accelerated Resolution Of Intraventricular
Hemorrhage Phase III (CLEARIII IVH) trial. Neurosurgery 2015;
76: 291300.
665
 Seminar
74 Lai L, Morgan MK. Predictors of in-hospital shunt-dependent
hydrocephalus following rupture of cerebral aneurysms.
J Clin Neurosci 2013; 20: 113438.
75 Komotar RJ, Hahn DK, Kim GH, et al. Ecacy of lamina terminalis
fenestration in reducing shunt-dependent hydrocephalus following
aneurysmal subarachnoid hemorrhage: a systematic review.
Clinical article. J Neurosurg 2009; 111: 14754.
76 Grand W, Leonardo J, Chamczuk AJ, Korus AJ. Endoscopic third
ventriculostomy in 250 adults with hydrocephalus: patient selection,
outcomes, and complications. Neurosurgery 2016; 78: 10919.
77 Al-Tamimi YZ, Bhargava D, Feltbower RG, et al. Lumbar drainage
of cerebrospinal uid after aneurysmal subarachnoid hemorrhage:
a prospective, randomized, controlled trial (LUMAS). Stroke 2012;
43: 67782.
78 Heuer GG, Smith MJ, Elliott JP, Winn HR, LeRoux PD.
Relationship between intracranial pressure and other clinical
variables in patients with aneurysmal subarachnoid hemorrhage.
J Neurosurg 2004; 101: 40816.
79 Kolias AG, Kirkpatrick PJ, Hutchinson PJ. Decompressive
craniectomy: past, present and future. Nat Rev Neurol
2013; 9: 40515.
80 Mak CH, Lu YY, Wong GK. Review and recommendations on
management of refractory raised intracranial pressure in
aneurysmal subarachnoid hemorrhage. Vasc Health Risk Manag
2013; 9: 35359.
81 Lanzino G, DUrso PI, Suarez J. Seizures and anticonvulsants
after aneurysmal subarachnoid hemorrhage. Neurocrit Care 2011;
15: 24756.
82 Molyneux AJ, Kerr RS, Yu LM, et al. International subarachnoid
aneurysm trial (ISAT) of neurosurgical clipping versus
endovascular coiling in 2143 patients with ruptured intracranial
aneurysms: a randomised comparison of eects on survival,
dependency, seizures, rebleeding, subgroups, and aneurysm
occlusion. Lancet 2005; 366: 80917.
83 Ibrahim GM, Fallah A, Macdonald RL. Clinical, laboratory, and
radiographic predictors of the occurrence of seizures following
aneurysmal subarachnoid hemorrhage. J Neurosurg 2013;
119: 34752.
84 Rosengart AJ, Huo JD, Tolentino J, et al. Outcome in patients with
subarachnoid hemorrhage treated with antiepileptic drugs.
J Neurosurg 2007; 107: 25360.
85 Beseoglu K, Holtkamp K, Steiger HJ, Hnggi D. Fatal aneurysmal
subarachnoid haemorrhage: causes of 30-day in-hospital case
fatalities in a large single-centre historical patient cohort.
Clin Neurol Neurosurg 2013; 115: 7781.
86 Vergouwen MD, Vermeulen M, van Gijn J, et al. Denition of
delayed cerebral ischemia after aneurysmal subarachnoid
hemorrhage as an outcome event in clinical trials and observational
studies: proposal of a multidisciplinary research group. Stroke 2010;
41: 239195.
87 Rosengart AJ, Schultheiss KE, Tolentino J, Macdonald RL.
Prognostic factors for outcome in patients with aneurysmal
subarachnoid hemorrhage. Stroke 2007; 38: 231521.
88 Frontera JA, Fernandez A, Schmidt JM, et al. Dening vasospasm
after subarachnoid hemorrhage: what is the most clinically relevant
denition? Stroke 2009; 40: 196368.
89 Budohoski KP, Czosnyka M, Kirkpatrick PJ, Smielewski P,
Steiner LA, Pickard JD. Clinical relevance of cerebral autoregulation
following subarachnoid haemorrhage. Nat Rev Neurol
2013; 9: 15263.
90 Dreier JP. The role of spreading depression, spreading
depolarization and spreading ischemia in neurological disease.
Nat Med 2011; 17: 43947.
91 stergaard L, Aamand R, Karabegovic S, et al. The role of the
microcirculation in delayed cerebral ischemia and chronic
degenerative changes after subarachnoid hemorrhage.
J Cereb Blood Flow Metab 2013; 33: 182537.
92 Macdonald RL, Rosengart A, Huo D, Karrison T. Factors associated
with the development of vasospasm after planned surgical
treatment of aneurysmal subarachnoid hemorrhage. J Neurosurg
2003; 99: 64452.
93 Washington CW, Zipfel GJ. Detection and monitoring of vasospasm
and delayed cerebral ischemia: a review and assessment of the
literature. Neurocrit Care 2011; 15: 31217.
666
94 Dorhout Mees SM, Rinkel GJ, Feigin VL, et al. Calcium antagonists
for aneurysmal subarachnoid haemorrhage.
Cochrane Database Syst Rev 2007; CD000277.
95 Amin-Hanjani S, Ogilvy CS, Barker FG 2nd. Does intracisternal
thrombolysis prevent vasospasm after aneurysmal subarachnoid
hemorrhage? A meta-analysis. Neurosurgery 2004; 54: 32634.
96 Niu PP, Yang G, Xing YQ, Guo ZN, Yang Y. Eect of cilostazol in
patients with aneurysmal subarachnoid hemorrhage: a systematic
review and meta-analysis. J Neurol Sci 2014; 336: 14651.
97 Jaja BN, Attalla D, Macdonald RL, et al. The Subarachnoid
Hemorrhage International Trialists (SAHIT) repository: advancing
clinical research in subarachnoid hemorrhage. Neurocrit Care 2014;
21: 55159.
98 Macdonald RL, Jaja B, Cusimano MD, et al. SAHIT
investigatorson the outcome of some subarachnoid hemorrhage
clinical trials. Transl Stroke Res 2013; 4: 28696.
99 Macdonald RL, Cusimano MD, Etminan N, et al. Subarachnoid
Hemorrhage International Trialists Data Repository (SAHIT).
World Neurosurg 2013; 79: 41822.
100 Gress DR. Monitoring of volume status after subarachnoid
hemorrhage. Neurocrit Care 2011; 15: 27074.
101 Gathier CS, Dankbaar JW, van der Jagt M, et al. Eects of induced
hypertension on cerebral perfusion in delayed cerebral ischemia
after aneurysmal subarachnoid hemorrhage: a randomized clinical
trial. Stroke 2015; 46: 327781.
102 Wartenberg KE, Schmidt JM, Claassen J, et al. Impact of medical
complications on outcome after subarachnoid hemorrhage.
Crit Care Med 2006; 34: 61723.
103 Nieuwkamp DJ, Setz LE, Algra A, Linn FH, de Rooij NK, Rinkel GJ.
Changes in case fatality of aneurysmal subarachnoid haemorrhage
over time, according to age, sex, and region: a meta-analysis.
Lancet Neurol 2009; 8: 63542.
104 Lovelock CE, Rinkel GJ, Rothwell PM. Time trends in outcome of
subarachnoid hemorrhage: population-based study and systematic
review. Neurology 2010; 74: 1494501.
105 Al-Khindi T, Macdonald RL, Schweizer TA. Cognitive and functional
outcome after aneurysmal subarachnoid hemorrhage. Stroke 2010;
41: e51936.
106 Jaja BN, Cusimano MD, Etminan N, et al. Clinical prediction
models for aneurysmal subarachnoid hemorrhage: a systematic
review. Neurocrit Care 2013; 18: 14353.
107 Rinkel GJ, Algra A. Long-term outcomes of patients with
aneurysmal subarachnoid haemorrhage. Lancet Neurol 2011;
10: 34956.
108 Huhtakangas J, Lehto H, Sepp K, et al. Long-term excess mortality
after aneurysmal subarachnoid hemorrhage: patients with multiple
aneurysms at risk. Stroke 2015; 46: 181318.
109 Etminan N, Beseoglu K, Barrow DL, et al. Multidisciplinary
consensus on assessment of unruptured intracranial aneurysms:
proposal of an international research group. Stroke 2014;
45: 152330.
110 Wermer MJ, Greebe P, Algra A, Rinkel GJ. Incidence of recurrent
subarachnoid hemorrhage after clipping for ruptured intracranial
aneurysms. Stroke 2005; 36: 239499.
111 Tsutsumi K, Ueki K, Usui M, Kwak S, Kirino T. Risk of recurrent
subarachnoid hemorrhage after complete obliteration of cerebral
aneurysms. Stroke 1998; 29: 251113.
102 Bor AS, Rinkel GJ, Adami J, et al. Risk of subarachnoid
haemorrhage according to number of aected relatives: a
population based case-control study. Brain 2008; 131: 266265.
103 Bor AS, Rinkel GJ, van Norden J, Wermer MJ. Long-term,
serial screening for intracranial aneurysms in individuals with
a family history of aneurysmal subarachnoid haemorrhage:
a cohort study. Lancet Neurol 2014; 13: 38592.
104 Rinkel GJ. Natural history, epidemiology and screening of
unruptured intracranial aneurysms. Rev Neurol (Paris) 2008;
164: 78186.
115 Thompson BG, Brown RD Jr, Amin-Hanjani S, et al. Guidelines for
the management of patients with unruptured intracranial
aneurysms: a guideline for healthcare professionals from the
American Heart Association/American Stroke Association.
Stroke 2015; 46: 2368400.
www.thelancet.com Vol 389 February 11, 2017