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Clinical Review 15
CLINICAL REVIEW
ABSTRACT
Stroke is one of the leading causes of death globally and in Canada. There are two major classifications of
stroke: ischemic and hemorrhagic. Intracerebral hemorrhage (ICH) a subtype of hemorrhagic stroke is associated with substantial morbidity and mortality. The varied clinical presentation of ICH, ranging from minor
neurological deficits to fatal herniation syndromes arises from parenchymal damage, elevated intracranial
pressure and cardiopulmonary instability. Diagnosis is based on clinical presentation, laboratory investigations and imaging, which include computed tomography (CT), magnetic resonance imaging (MRI) and angiography. Validated clinical scoring systems for stroke, such as the ICH and FUNC scores, allow for improved
prognosis assessment. Management is comprised of surgical, endovascular and medical interventions. Surgical clipping and endovascular coiling are used as a preventative measure for cerebral aneurysms, while the
current medical therapies attempt to limit the neurological sequelae following stroke by limiting the extent of
parenchymal involvement. Currently there are no proven therapies for brain protection, although this is currently a major target for research. Thus, stratification of hemorrhagic stroke based on clinical, laboratory and
imaging findings enables appropriate treatment and assessment of patients at risk of hematoma expansion
in order to prevent clinical deterioration and adverse sequelae.
INTRODUCTION
troke is one of the leading causes of death in Canada,
accounting for approximately 14,000 deaths annually1
and is a significant source of morbidity. Stroke can be
classified into ischemic and hemorrhagic, with the former
representing the vast majority of cases (87%).2 In hemorrhagic stroke, bleeding can occur within the cerebral parenchyma
or within the meninges. Intracerebral hemorrhage (ICH) is
defined as bleeding into the brain parenchyma. The current
review excluded epidural hematoma, subdural hematoma
and subarachnoid haemorrhage but includes intraventricular
hemorrhage. Prognoses of hemorrhagic strokes depend on
the initial clinical presentation, rapidity of diagnosis and time
to initiation of intervention. This paper is a non-systematic
review of the current literature on intracranial hemorrhage
(ICH). An overview of the epidemiology, common risk factors, pathogenesis, clinical manifestations, diagnosis and
treatment approach to ICH are presented.
EPIDEMIOLOGY
The World Health Organization (WHO) estimates that 15
million patients worldwide suffer from stroke annually. Approximately one third of these cases die, one third are left
disabled and one third have a good outcome.3 High blood
pressure is a contributing factor in more than 12.7 million
strokes annually worldwide. 3 Incidence is greater among the
elderly and those of African and Asian decent.4,5 The overall incidence of new or recurrent hemorrhagic strokes in the
United States is 795,000 people pear year. The majority of
these are new strokes (approximately 610,000).6 In 2000,
stroke accounted for 7% of all deaths in Canada.7 Generally,
ICH accounts for ~10% of all strokes and is associated with
a 50% case fatality rate.8 Since 1980, the incidence of hypertensive ICH has declined, reflecting improved blood-pressure
control in the population.9
16
Clinical Review
RISK FACTORS
Modifiable
Modifiable risk factors for ICH include hypertension, anticoagulant therapy, thrombolytic therapy, high alcohol intake,
previous history of stroke, and illicit drug use (particularly
cocaine).10 Hypertension is by far the most common cause of
hemorrhagic stroke, accounting for up to 60% of all ICH cases. Moreover, approximately two thirds of patients with ICH
have a history of hypertension. Hypertensive ICH results from
tiny aneurysms that rupture and result in intracranial hemorrhage.9,11 Anticoagulation therapy causes a seven to tenfold increase in risk for hemorrhagic stroke.12
Intracranial aneurysms are commonly acquired lesions
found in 1-6% of postmortem autopsies.13 Most do not rupture
throughout a persons lifetime and remain undiagnosed. However, 27,000 new cases of subarachnoid hemorrhage following a ruptured aneurysm occur in the United States annually,
accounting for 5-15% of hemorrhagic stroke cases.13 The process of aneurysm formation and their rupture is incompletely
understood. However, hypertension and smoking have been
clearly documented to be associated with ruptured cerebral
aneurysms and both evidenced to cause structural defects by
inducing endovascular changes.13, 14 The tunica media layer is
often implicated, causing focal weakness in the vessel wall that
can result in aneurysmal ballooning at arterial bifurcations.13
Common locations of aneurysms are presented in Figure 1.18
Non-Modifiable
Non-modifiable risk factors for hemorrhagic stroke include advanced age, negroid ethnicity, cerebral amyloidosis, coagulopathies, vasculitis, arteriovenous malformations
(AVMs), and intracranial neoplasms.9,10,11,15
Intracranial hemorrhage associated with hereditary cerebral amyloid angiopathy (CAA) is caused by mutations in
the amyloid precursor protein (APP) or cystatin C protein
(CST3) genes inherited in an autosomal dominant pattern. 16
Although often asymptomatic, cerebral amyloid angiopathy
(CAA) is an important cause of primary lobar intracerebral
hemorrhage in the elderly.10 Coagulopathies predisposing to
excessive bleeding can be due to inherited factor deficiencies or due to acquired liver pathology. Acquired coagulopathies causing ICH may stem from the use of anticoagulants,
platelet antagonists and natural remedies with anticoagulant
properties amongst others. Some drugs without anticoagulant
properties are known to cause intracerebral hemorrhages.
These include amphetamines Phencyclidine and Cocaine. In
children, the most common cause of ICH are vascular malformations (AVMs), about tenth as frequent as cerebral aneurysms in adults with spontaneous intracranial haemorrhage.
There are a number of other causes that are beyond the scope
of this paper and have been reviewed in detail elsewhere. 9,11,17
PATHOGENESIS
ICH consists of three distinct phases: (1) initial hemorrhage, (2) hematoma expansion, and (3) peri-hematoma edema.19 The initial hemorrhage is caused by rupture of cerebral
arteries influenced by the aforementioned risk factors. The disease outcome depends primarily on the latter two phases of
progression. Hematoma expansion, occurring hours after initial symptom onset, involves an increase in intracranial pressure (ICP) that disrupts the integrity of the local tissue and the
blood-brain barrier. Additionally, obstructed venous outflow
induces the release of tissue thromboplastin, resulting in local
coagulopathy2. In over a third of patients, hematoma expansion is associated with hyperglycemia,20, 21,22 hypertension,23
and anticoagulation.24-26 The initial size of the hemorrhage
and the rate of hematoma expansion are important prognostic variables in predicting neurologic deterioration. Hematoma
size >30 ml is associated with greatly increased mortality.27
Following the expansion, cerebral edema forms around the
hematoma, secondary to inflammation and disruption of the
blood-brain barrier. This peri-hematoma edema is the primary
etiology for neurological deterioration and develops over days
following the initial insult.
In up to 40% of ICH cases, the hemorrhage extends into
the cerebral ventricles causing intraventricular hemorrhage
(IVH).28 This is associated with acute obstructive hydrocephalus and substantially worsened prognosis.2,28 ICH and
accompanying edema may also disrupt or compress adjacent
MUMJ
Clinical Review 17
(%)
96
63
54
53
23
20
11
9
6
5
1
DIAGNOSIS
Clinical
As with any medical emergency, a thorough and focused
history eliciting specific risk factors and preceding events is
critical for every patient presenting with stroke-like symptoms. Important risk factors include any recent trauma, hypertension, prior strokes, diabetes, smoking, alcohol, overthe-counter, prescription or recreational drugs (specifically
cocaine, warfarin, aspirin, and other anticoagulants), hematologic disorders, liver disease, neoplasm, infections and AVM.33
Although risk factors and patient comorbidities have implications for clinical management and outcome, clinical presentation alone is insufficient to reliably differentiate stroke from
other clinical entities.2 The difficulty for most physicians lies
in the ability to distinguish stroke from those that mimic it
such as syncope, sepsis and seizures. To improve diagnostic
accuracy in stroke diagnosis, tools such as the ROSIER Scale
(Table 2) have been developed for use in the emergency room
to help reduce the number of unnecessary referrals for nonstroke cases.32 The ROSIER Scale is a rapid stroke assessment tool that uses clinical signs such as asymmetrical weakness, speech and visual disturbances, to help rule out stroke
mimics. The ROSIER scale ranges from -2 to +5 points, with
any patient scoring greater than 0 having a 90% likelihood of
stroke. The ROSIER scale has a sensitivity of 92%, specificity
of 86%, positive predictive value (PPV) of 88%, and negative
predictive value (NPV) of 91%.32
Although tools such as the ROSIER scale have helped
to improve diagnostic accuracy for stroke in general in the
emergency department to 80-95%32, no signs or symptoms
reliably distinguish ICH from ischemic stroke. Therefore,
neurological imaging plays an increasingly important role in
the diagnosis of ICH.32-35 Laboratory investigations for diagnosis and prognosis assessment consist of CBC, electrolytes,
a hemostasis screen including INR and PT, a -HCG test in
women of childbearing age and a toxicology screen to test for
cocaine and other prescription drugs.33,36 Patients with an elevated PT or INR due to anticoagulant therapy have a greater
risk of hematoma expansion and, when possible, their anticoagulation therapies should be, at least temporarily, reversed.
Table 2. The ROSIER Scale is a rapid stroke assessment tool
that uses clinical signs to help rule out stroke mimics. The
scale ranges from -2 to +5 points, with any patient scoring
greater than 0 being likely to have a stroke
Components
Asymmetrical facial weakness
Asymmetrical arm weakness
Asymmetrical leg weakness
Speech disturbances
Visual field defect
Seizure
Loss of consciousness
Points
1
1
1
1
1
-1
-1
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Clinical Review
Imaging
The primary purpose of diagnostic imaging is to differentiate between ischemic and hemorrhagic strokes and to rule
out other CNS lesions.35 Computed tomography (CT) and
magnetic resonance imaging (MRI) are both first line imaging modalities, supported by level 1 evidence (RCTs).37 If an
MRI can be ordered as quickly as the CT, it should be considered first. 35 In patients with contraindications to MRI, namely
those with metallic fragments or devices in the brain, eyes
or spinal canal, a CT scan should be obtained.2 CT may be
superior at showing ventricular extension, while MRI better
detects structural lesions, edema, and herniation.2 The noncontrast CT (NCCT) is the most readily available tool providing rapid feedback and is thus commonly used in emergency
departments. It is thought to be nearly 100% sensitive for
detecting clinically relevant acute hemorrhages. Moreover,
it may elucidate hematoma location and expansion and the
presence of edema.38 MRIs are most frequently utilized as
follow-up investigations to identify secondary causes of ICH,
such as arteriovenous malformation (AVM), amyloid angiopathy, or associated neoplasm.
With advances in imaging, CT angiography (CTA) has
proven to be a useful tool in predicting hematoma expansion
in patients with ICH. Wada et al. (2007) demonstrated foci
of contrast enhancement in 91% of expanded hematomas.39
CTA and contrast-enhanced CT may identify patients at risk
for hematoma expansion through this novel discovery of the
spot sign (Figure 2).38 The spot sign has helped enhance visualization of hematoma expansion with the ability to stratify
risk of hemorrhagic stroke. The literature has noted a particularly high specificity (85-89%) of the spot sign for ICH, with
negative predictive values of 76-96% and a positive likelihood ratio of 2.7-8.5.39-42
In the absence of CTA, it would be difficult to accurately
detect structural causes of the hemorrhage, such as bleeding
from a cerebral aneurysm or a vascular malformation. If no
Figure 2. Patient with spot sign demonstrating extravasation and hematoma expansion. A. Unenhanced CT demonstrates
left posterior putaminal and internal capsule hematoma with mild surrounding edema. B. A small focus of enhancement is
seen peripherally, consistent with the spot sign (black arrow). C. Post-contrast CT demonstrates enlargement of the spot sign,
consistent with extravasation (white arrow). D. Unenhanced CT image 1 day after presentation reveals hematoma enlargement
and intraventricular hemorrhage.39
MUMJ
Clinical Review 19
with an ICH Score of 5 died within the 30 days.48 The limitation of the ICH score is that it is solely used to prognosticate survival at 30 days without accounting for functional
outcome. The ICH score should thus be used in combination
with the FUNC score to assess functional outcome.
Table 3. The ICH Score predicts 30-day mortality using
factors including GCS score, ICH volume, presence of
intraventricular hemorrhage (IVH), and age. The scale ranges
from 0 to 6 points. In the original study all patients with a
score of 0 survived and all patients with a score of 5 died
within 30 days. The limitation of the ICH score that is does
not account for functional outcome
Component
GCS score
3-4
5-12
13-15
Points
2
1
0
1
0
1
0
1
0
1
0
ICH location
Lobar
Deep
Infratentorial
GCS score
9
8
Points
4
2
0
2
1
0
2
1
0
2
0
1
0
TREATMENT
Surgical
Two surgical interventions are available for treating aneurysms. The surgical approach entails placement of permanent
alloy clips across the neck of the aneurysm through craniotomy access. The patient is typically under general anesthesia.
This prevents blood flow from reaching the aneurysm and
lowers the risk of rupture.14
The aneurysm can also be coiled through endovascular
access while the patient is under general anesthesia or sedation.14 Intra-procedural neurologic function is observed
through neurophysiological monitoring. Using fluoroscopy
and digital subtraction angiography, a catheter is advanced
through the femoral artery, aorta, carotid artery and into the
aneurysm. A sufficient number of detachable coils are then
positioned into the aneurysm to minimize the amount of
blood filling the aneurysm.14,52-54 Systematic reviews have associated the use of coils with lower rates of inpatient mortality, shorter hospital stay and decreased treatment costs.14
Medical
The patients vital signs must be immediately stabilized
according to ATLS guidelines.34 Patients with ICH are often
unable to protect their airway and may need endotracheal intubation (criteria for intubation, GCS <8). Rapid sequence
intubation is the preferred approach with administration of
20
Clinical Review
MUMJ
Clinical Review 21
CONCLUSION
Given the high mortality rate of ICH, early recognition
and correct diagnosis is vital. While making the diagnosis,
one must distinguish stroke mimics from actual stroke signs
and identify common signs such as acute onset, limb weakness or speech disturbances. Among their diagnostic arsenals
and prognostic tools, ICH can be assessed through the Rosier
scale (diagnostic) and the ICH and FUNC scores (prognostic). However, such tools are limited in their interpretation of
mid-range scores. Neurological imaging techniques, such as
CT and MRI are playing an increasingly central role in the
early diagnosis of ICH. The spot sign has been suggested as
a marker of hematoma expansion as identified on CTA.
A major limitation in stroke management is that no effective targeted therapy for hemorrhagic stroke yet exists.
Rather, symptoms and complications are individually
managed, with increased ICP and neurological deterioration
being particularly important. The recent advent of endovascular coiling of aneurysms as a preventative measure against
ICH has improved clinical outcomes in appropriately selected patient populations.
21.
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Author Biographies
Fabio Magistris graduated from the University of Western Ontario with a degree in Medical Sciences before attending
McMaster University. He is currently in his first year of the MD program.
Stephanie Bazak graduated from Acadia University with a Bachelor of Science in Psychology. She is currently in her
second year of medicine at McMaster University
Jason Martin completed three years of the Medical Sciences program at the University of Western Ontario before attending
McMaster University. He is currently in his second year of the MD program. He has an active interest in neuroradiology.