Keywords:
Cerebral Hemorrhage - Stroke - Critical Care
Palavras-chave:
Hemorragia Cerebral - Acidente Vascular Cerebral - Cuidados Críticos
SEARCH STRATEGY
A PubMed search for articles published up to June 2019 was performed using the terms
“intracerebral hemorrhage” [Title] and (“spontaneous” [Title/Abstract]), which turned
out 1,102 articles. Additionally, the reference lists of the most recent guidelines
on the management of spontaneous intracerebral hemorrhage were searched. Articles
with at least one abstract in English or Portuguese were included.
BACKGROUND
Intracerebral hemorrhage (ICH) is defined as bleeding into the brain parenchyma that
may extend into the ventricles and, less frequently, the subarachnoid and subdural
spaces[1]. It accounts for 10 to 15% of all causes of stroke and is associated with the highest
mortality rates (around 35% at 7 days and 59% at 1 year)[1],[2],[3]. The annual incidence of 10 to 30 per 100,000 inhabitants has remained stable in
the last three decades[1],[4]. Although there was a 50% decrease in the incidence of ICH in patients below 60
years of age, an there was an 80% increase in patients above 74 years of age[4]. Advances in the field of stroke and neurocritical care have reduced mortality within
30 days - after ICH in the past years, although early case-mortality rates (within
48 hours) have not improved[5].
Spontaneous (non-traumatic) ICH can be primary or secondary. Primary ICH represents
78 to 88% of cases and originates from spontaneous rupture of small vessels, usually
from chronic hypertension and cerebral amyloid angiopathy (CAA)[1],[6]. Secondary ICH results from ruptured vascular abnormalities such as arteriovenous
malformations (AVM), cavernomas, and aneurysms. According to location, hematomas can
be classified as deep (37%), lobar (49%), infratentorial (9%) or of undetermined location
(5%)[1],[7]. Treatment strategies include blood pressure control, reversal of coagulopathy and
neurosurgery in selected cases[8].
ETIOPATHOLOGY
The main risk factors for ICH are hypertension, anticoagulation use, heavy alcohol
consumption, family history of ICH, personal history of ischemic stroke, low educational
levels, and APOE (2 or (4 genotype[9]. Alternatively, reduced prevalence of ICH was found in patients with a history of
hypercholesterolemia or moderate alcohol consumption (less than two glasses a day)[10]. Hypercholesterolemia has been described in many studies as a protective factor,
although statin use has not been related to a higher ICH risk and can even reduce
it[11].
Primary intracerebral hemorrhage
The main primary etiologies leading to vasculopathy and cerebral hemorrhage are hypertension
and CAA. Chronic hypertension induces lipohyalinosis of small perforating arteries,
leading to deep hemorrhages that frequently extend to the ventricles[1]. In 1868, Charcot and Bouchard attributed intracerebral bleeding to the rupture
of dilated arteriolar wall (microaneurysms). These morphological entities were posteriorly
identified as subadventitious hemorrhages or extravascular thrombi consequences of
endothelial damage from the hematoma. The main topographies of hypertensive ICH are
in the territories of the small ‘penetrating’ arteries originating off the stems of
the main cerebral arteries (the putamen, thalamus, pons, and cerebellum)[1].
Amyloid angiopathy is the most common etiology in patients over 70 years of age with
lobar ICH[4]. Progressive deposition of beta-amyloid peptide on the wall of leptomeningeal and
cortical vessels reduces their complacency, leading to a spectrum of hemorrhagic manifestations
including cerebral microbleeds (CMB), cortical superficial siderosis (cSS), and intracerebral
hemorrhage. The main characteristics of CAA are the presence of lobar, cortical or
cortical-subcortical hemorrhage, CMB, and cSS in patients above 55 years of age ([Figure 1])[12],[13]. The Boston criteria were proposed in 1995 and modified in 2010 to estimate the
chance of CAA in patients with ICH ([Table 1])[12],[14].
Figure 1 Imaging findings in cerebral amyloid angiopathy. Susceptibility weighted magnetic
resonance imaging in patient with cerebral amyloid angiopathy depicting: (A) cerebellar
microbleeds (white arrows), (B) superficial siderosis (yellow arrow), and (C) lobar
intracerebral hemorrhage (red arrow) and cortico-subcortical microbleeds (white arrows).
Table 1
Modified Boston criteria for the diagnosis of amyloid angiopathy in patients with
intracerebral hemorrhage.
|
Modified Boston criteria
|
|
Definite CAA
|
Full postmortem examination demonstrating:
• Lobar, cortical or cortical-subcortical hemorrhage
• Severe CAA with vasculopathy
• Absence of other diagnostic lesion
|
|
Probable CAA with supporting pathology
|
Clinical data and pathological tissue (evacuated hematoma or cortical biopsy) demonstrating:
• Lobar, cortical or cortical-subcortical hemorrhage (including ICH, CMB or cSS)
• Some degree of CAA in specimen
• Absence of other diagnostic lesion
|
|
Probable CAA
|
Clinical data and MRI or CT demonstrating:
• Multiple hemorrhages (ICH, CMB) restricted to lobar, cortical or cortical-subcortical
regions (cerebellar hemorrhage allowed) or single lobar, cortical or cortical-subcortical
hemorrhage and cSS (focal or disseminated)
• Age ≥55 years
• Absence of other cause of hemorrhage*
|
|
Possible CAA
|
•Clinical data and MRI or CT demonstrating:
•• Single lobar, cortical or cortical-subcortical ICH, CMB, or cSS (focal or disseminated)
•• Age ≥55 years
•• Absence of other cause of hemorrhage*
|
CAA: cerebral amyloid angiopathy; CMB: cerebral microbleed; cSS: cortical superficial
siderosis; CT: computed tomography; ICH: intracerebral hemorrhage; MRI: magnetic resonance
imaging.
*Other causes of hemorrhage (differential diagnosis of lobar hemorrhages): antecedent
head trauma, hemorrhagic transformation of an ischemic stroke, arteriovenous malformation,
hemorrhagic tumor, warfarin therapy with international normalization ratio >3, and
vasculitis.
Secondary intracerebral hemorrhage
An important and increasing cause of secondary ICH is anticoagulation, which significantly
increases the risk of intracranial hemorrhage, hematoma expansion, and mortality[15]. Warfarin use may increase the risk of ICH in 2 to 5 fold, depending on the intensity
of anticoagulation[16]. Congenital or acquired coagulation factor deficiencies, thrombocytopenic disorders,
and lymphoproliferative disorders are less frequent etiologies[17].
Structural lesions are potentially treatable causes of ICH and should be searched
for with vascular imaging studies, such as computerized tomographic angiography (CTA).
Up to 10% of brain aneurysms can result in intraparenchymal bleeding. Arteriovenous
malformations, angiomatous cavernomas, and tumors may also be involved in ICH development[7]. Other conditions include brain neoplasms or metastasis, cerebral venous thrombosis,
and reversible cerebral vasoconstriction syndromes[18].
SMASH-U classification
A tool for etiological classification published in 2012 entitled SMASH-U, classifies
ICH according to its different etiologies: structural lesions, related to medications,
amyloid angiopathy, systemic diseases, hypertension, and undetermined ([Table 2])[19],[20].
Table 2
Structural lesion, Medication, Amyloid angiopathy, Systemic/other disease, Hypertension,
Undetermined etiologic classification of intracerebral hemorrhage.
|
Etiologic classification SMASH-U
|
|
S - Structural lesion
|
Image or pathology confirming structural vascular malformation diagnosed on the site
of ICH
|
|
M - Medication
|
Warfarin use with INR greater than or equal to 2, direct oral anticoagulants within
3 days, therapeutic IV heparin, or systemic thrombolysis
|
|
A - Amyloid angiopathy
|
Lobar, cortical or subcortical hemorrhage and age ≥55 years
|
|
S - Systemic disease/other
|
Systemic disease or other ICH etiology except from anticoagulation, hypertension or
amyloid angiopathy
|
|
H - Hypertension
|
•Deep or infratentorial hemorrhage or pre-ICH hypertension, defined as:
•a) Most recent pre-ICH blood pressure ≥160×100 mmHg
•b) Mention of elevated blood pressure prior to ICH by patient, relative or medical
records, with left ventricular hypertrophy as a biomarker of hypertension
•c) Any use of blood pressure medication prior to ICH
|
|
U - Undetermined
|
None of the above
|
SMASH-U: Structural lesion, Medication, Amyloid angiopathy, Systemic/other disease,
Hypertension, Undetermined; ICH: intracerebral hemorrhage; INR: international normalized
ratio.
DIAGNOSIS
Patients with ICH are usually admitted to the hospital with sudden onset of focal
neurological deficits, severe acute headaches, nausea, vomiting, seizures, decreased
level of consciousness, and high blood pressures. Brain imaging is essential for diagnostic
confirmation and differentiation from ischemic stroke[8]. Both non-contrasted head CT and MRI are highly sensitive for the detection of acute
bleeding, although MRI (gradient-eco and susceptibility sequences) is more sensitive
in detecting prior hemorrhage[8]. Hematoma volume can be estimated using the ABC/2 method (A, maximal hematoma diameter
on axial imaging; B, maximal hematoma diameter perpendicular to A; and C, number of
axial slices with the hematoma multiplied by the slice thickness [slices with <25%
of hematoma volume are ignored, slices with 25 to 75% of hematoma volume count as
0.5, and those with >75% of hematoma volume count as 1]) ([Figure 2])[21].
Figure 2 Hematoma volume estimation. (A) Non-contrasted computed tomography axial slice with
maximal hematoma area with green lines indicating the maximum diameter (A line) measuring
3.21 cm and its maximum perpendicular diameter (B line) measuring 2.26 cm. (B) Axial
slice 10 mm cranial to A shows hematoma area of 75-100% of the reference slice. (C)
Axial slice 10 mm caudal to A shows hematoma area of 25-75% of the reference slice.
(D) Axial slice 20 mm caudal to A shows hematoma area below 25% of the reference slice.
Thus, the estimated hematoma volume is 2.26×3.21×(1.0+0.5+0.0)/2=5.44 mL.
Imaging and clinical data, such as the absence of hypertension and atypical location,
may help identify patients with possible structural etiologies that require further
investigation and vascular imaging[22],[23]. MRI findings indicating secondary etiologies include the presence of flow-voids
in arteriovenous malformations, lobar microbleeds in CAA and contrast enhancement
in tumors or inflammatory etiologies. If the first MRI is normal in suspected cases,
a follow-up imaging within four to six weeks is required[8].
Vascular imaging such as CTA, MR-angiography and digital subtraction angiography can
assist in etiological definition[8]. Imaging findings indicating vascular abnormalities include the presence of subarachnoid
hemorrhage, dilated vessels, peri-hematoma calcifications, hyperintensity within venous
sinus or cortical veins, unusual hematoma shape, unusual location, and disproportionally
large peri-hematoma edema[8],[23].
Hematoma expansion
Hematoma expansion is frequently seen on follow-up imaging. Patients presenting early
symptom onset and receiving anticoagulated are at higher risk for hematoma expansion.
The presence of expansion is associated with a worse prognosis, thus preventing it
is one of the treatment goals[8],[24]. Several tools have been proposed to predict hematoma expansion, including the BRAIN
algorithm ([Table 3]), the HEP and BAT scores,[24],[25] and image markers such as “spot sign”, “leakage sign”, “island sign”, “blend sign”,
“black hole sign”, and “satellite sign”. The “spot sign” is detected through CTA and
is characterized by a spot of contrast enhancement inside the hematoma. The “leakage
sign” is more sensitive than the spot sign and the image is acquired 5 minutes after
CTA (late phase). Images from both arterial and late phases are evaluated and an increase
in more than 10% of Hounsfield units between images determines a positive “leakage
sign”[26]. The “island sign”, “blend sign”, “black hole sign”, and “satellite sign” are seen
in the non-contrasted head-CT ([Figure 3]). The “island sign” is defined as scattered small hematomas apart from the main
hematoma and the “blend sign” is defined as blending of a relatively hypoattenuating
area with adjacent hyperattenuating region within a hematoma. The “black hole sign”
is defined as a relatively hypoattenuating area (black hole) encapsulated within the
hyperattenuating hematoma and the “satellite sign” is defined as small (maximal diameter
<10 mm) hemorrhage close to but completely isolated from the main hemorrhage in at
least a single slice[27],[28],[29],[30],[31].
Table 3
The BRAIN algorithm for hematoma expansion.
|
“BRAIN” score
|
|
B- Baseline ICH volume
|
•Milliliters per score:
•≤10=0
•10-20=5
•>20=7
|
|
R- Recurrent ICH
|
Yes=4
|
|
A - Anticoagulation with warfarin at onset
|
Yes=6
|
|
I - Intraventricular extension
|
•No=0
•Yes=2
|
|
N - Number of hours to baseline computed tomography
|
•≤1=5; 1-2=4; 2-3=3;
•3-4=2; 4-5=1; >5=0
|
|
Total
|
•Number of points and risk of expansion:
•0-5: 3.4-7.7%
•6-10: 11.3-23.1%
•11-15: 27.2-46.7%
•16-20: 52.1-71.9%
•20-24: 76.0-85.8%
|
ICH: intracerebral hemorrhage.
Figure 3 Non-contrasted computed tomography imaging of acute intracerebral hemorrhage with
expansion signs. Non-contrast computed tomography of acute intracerebral hemorrhage.
(A) Cerebellar intracerebral hemorrhage with “blend sign” (white arrows) and “black-hole
sign” (yellow arrow). (B) Lobar intracerebral hemorrhage with “satellite sign” (yellow
arrow). (C) Deep intracerebral hemorrhage with “island sign” (yellow arrows).
Diffusion-weighted imaging abnormalities
The occurrence of diffusion-weighted imaging (DWI) abnormalities is described in 15
to 46% of patients with ICH, and lesions can be found in perihematomal or remote regions.
The presence of DWI lesions in the perihematomal region is associated with higher
hematoma volumes, whereas remote lesions are associated with lobar hemorrhages, leukoaraiosis,
higher rates of anti-platelet medication, amyloid angiopathy, previous ICH, and atrial
fibrillation[32],[33],[34],[35],[36],[37],[38].
Potential embolic sources were described in patients with DWI lesions, such as atrial
fibrillation and performance of catheter angiography before MRI[32]. Another possible explanation for this phenomenon is the occurrence of hyperacute
and spontaneous hemorrhage following an ischemic stroke of embolic etiology with recanalization[39].
There is probably a sum of mechanisms influencing the appearance of these ischemic
lesions in the setting of acute ICH. Patients with brain hemorrhage usually have a
vulnerable microvasculature due to chronic hypertension or amyloid angiopathy, that
suffer from an acute state of blood pressure variability, raised intracranial pressure
(ICP) and failure in autoregulation, which may culminate in acute cerebral ischemia.
Additionally, patients could present with other risk factors for ischemic stroke and
even embolic sources causing the ischemia seen on MRI ([Figure 4])[35].
Figure 4 Possible mechanisms leading to ischemia in intracerebral hemorrhage.Adapted from
Prabhakaran, et al. Stroke. 2012
MEDICAL TREATMENT
ICH is a medical emergency and requires prompt diagnosis and management. Early deterioration
occurs in up to a third of patients in the first hours[8],[40]. Initial treatment starts with clinical assessment, airway protection, and hemodynamic
stabilization[40]. Neuroimaging must be performed as soon as possible in order to differentiate ischemic
from hemorrhagic stroke and initiate proper treatment[8]. Treatment should preferably be carried out in a tertiary center, with a multidisciplinary
team of neurologists, neuroradiologists, neurosurgeons and a neurointensive care unit[8]. Acute treatment includes blood pressure management, coagulopathy reversal, neurosurgical
interventions for hematoma evacuation, external ventricular drainage (EVD) and ICP
monitoring.
Blood pressure management
Intensive blood pressure management is thought to reduce hematoma expansion and improve
functional outcomes[41]. The Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage (INTERACT)
study showed that patients with aggressive blood pressure management with systolic
blood pressures (SBP) at a target of 140 mmHg or less had lower hematoma growth[42]. The INTERACT2 study included 2,800 patients with acute ICH[43]. Although it did not reach statistical significance on its primary outcome, defined
as moderately severe disability or less in 90 days, an ordinal analysis of modified
Rankin scores showed improved functional outcomes with intensive blood pressure lowering[43]. Systolic blood pressure reduction to levels close to 140 mmHg was safe and did
not increase the risk of perihematomal ischemia[43]. Because of this study, the current American Heart Association guidelines for the
management of ICH suggests lowering systolic blood pressure to 140 mmHg or less[8].
In June 2016, the Anti-hypertensive Treatment of Acute Cerebral Hemorrhage II (ATACH-II
) study was published, comparing standard (SBP of 140-179 mmHg) to intensive (110-139
mmHg) blood pressure management[41],[44]. The study was interrupted due to futility after the inclusion of 1,000 patients[44]. At first glance, ATACH-II results seem conflicting with INTERACT2, since the “intensive”
treatment was not superior to the “standard” one, but rather was associated with higher
complication rates (especially kidney impairment). However, it was observed that the
“standard” group maintained a mean SBP of about 140 mmHg, while the “intensive” group
had a mean SBP of about 120 mmHg[41],[44]. The final conclusion was that “very intensive” blood pressure reduction with SBP
levels below 120 mmHg does not offer additional benefits when compared to “intensive”
treatment with SBP levels around 140 mmHg[41],[44].
Reversal of coagulopathy
Coagulation disorders are a common cause of intracerebral hemorrhage and should be
promptly treated[8]. Reversal of anticoagulation in patients receiving vitamin K antagonists (warfarin)
is achieved through intravenous vitamin K administration (10 mg), followed by fresh
frozen plasma (FFP) or prothrombin complex concentrates (PCC). PCC is preferable in
comparison to FFP due to its faster action and greater effectiveness[8],[45]. The INR target should be of 1.4 or less and its measurement should be repeated
shortly after PCC administration. If the values are still above 1.4, FFP may be administered
for greater INR reduction.
For patients with ICH using factor Xa inhibitors (rivaroxaban, apixaban, edoxaban)
or thrombin inhibitors (dabigatran), treatment options include PCC, FEIBA or FVIIa.
Activated charcoal may be used if ingestion occurred within 2 hours[8],[45]. For direct reversal of dabigatran, idarucizumab 5 g IV in 2 doses or hemodialysis
can be performed[46]. Andexanet, a reversal agent for factor Xa inhibitors, was recently approved by
the Food and Drug Administration (FDA)[47].
In patients anticoagulated with unfractionated heparin (UFH), IV infusion must be
immediately discontinued and protamine sulfate should be administered (1 mg for every
100 UI of heparin given in the last 2-3 hours) at a maximum dosage of 50 mg[45]. In case partial thromboplastin time (PTTa) remains elevated, protamine can be readministered
at a dose of 0.5 mg for every 100 units of UFH[45]. Low molecular weight heparin can be reversed with protamine sulfate or recombinant
factor VII[45]. PCC and FFP are not recommended in these cases[45]. Platelet transfusion in patients using antiplatelet agents was proven ineffective
and even harmful[48]. Hemostatic medications in ICH patients without coagulopathy have been proven ineffective.
Factor VII and tranexamic acid did not improve survival or functional outcome after
ICH[49],[50].
Intensive care
Pneumatic compression is indicated for deep venous thrombosis prevention until the
documentation of bleeding cessation, when low molecular weight heparin (LMWH) or UFH
can be initiated in prophylactic doses. Glycemic and temperature control are crucial,
and dysglycemia and hyperthermia should be avoided[8]. Anti-seizure medication is solely indicated in the presence of seizure activity
and continuous electroencephalogram (EEG) is recommended in patients with decreased
level of consciousness not fully explained by the extent or location of the brain
lesion[8],[40].
SURGICAL TREATMENT
Patients evolving with hydrocephalus should receive an EVD with ICP monitoring, especially
if there is impaired consciousness. Cerebral perfusion pressure must be kept at 60-70
mmHg. Although studies have suggested the safety of intraventricular alteplase in
patients with intraventricular hemorrhage, treatment efficacy is uncertain[8]. Patients with cerebellar hemorrhage and progressive neurological decline, brainstem
compression or hydrocephalus should undergo hematoma evacuation[40],[45]. Decompressive craniectomy with or without hematoma evacuation should be considered
in comatose patients, in large hematomas with midline shifts or refractory elevated
ICP[8],[40]. Hematoma evacuation through minimally invasive surgery, endoscopic aspiration or
early evacuation do not have proven efficacy[8],[51]. The MISTIE III study prospectively evaluated minimally invasive surgery with thrombolysis
for hematoma evacuation in patients with ICH volumes ≥30 mL. Although the primary
outcome (modified Rankin scores of 0-3 at 1 year) was negative, the subgroup of patients
with residual hematoma of ≤15 mL or reduction of ≥70% had better functional outcomes
and survival rates[52]. A summary of treatment approaches with management algorithm is depicted in [Figure 5]
[53].
Figure 5 Acute intracerebral hemorrhage treatment algorithmEVD: external ventricular drainage;
FFP: fresh frozen plasma; ICH: intracerebral hemorrhage; ICU: intensive care unit;
ICP: intracranial pressure; INR: international normalized ratio; IV intravenous; LMWH:
low molecular weight heparin; PCC: prothrombin complex concentrate; SBP: systolic
blood pressure; UFH: unfractionated heparin.
PROGNOSIS
Baseline prognostic scoring systems are helpful in defining mortality risks. The most
commonly used score worldwide is the ICH score ([Table 4])[8],[40]. This scale stratifies 30-day mortality risk and varies from 0 to 6[54]. In the original study, mortality in patients scored 0 was 0%, while patients with
scores 4 or higher have mortality rates of almost 100% in the first 30 days[54]. Since the publication of the ICH score in 2001, other mortality prediction scales
have been developed. As an important limitation for these scales, patients who had
withdrawal of care in the first days of admission were included in the analysis. Caregivers
should be cautious when defining prognosis in ICH in order to avoid engaging a self-fulfilling
prophecy. Consequently, waiting at least 24 hours before deciding to withdraw care
is recommended[8],[55].
Table 4
Intracerebral hemorrhage scale and prognosis.
|
ICH scale and prognosis
|
|
Glasgow Coma Scale
|
•3-4
•5-12
•13-15
|
•2
•1
•0
|
|
Hematoma volume
|
•≥30 mL
•<30 mL
|
•1
•0
|
|
Intraventricular hemorrhage
|
•Yes
•No
|
•1
•0
|
|
Infratentorial origin
|
•Yes
•No
|
•1
•0
|
|
Age
|
•≥80 years
•<80 years
|
•1
•0
|
|
Total
|
•0
•1
•2
•3
•4
•5 and 6
|
•30-day mortality: 0%
•30-day mortality: 13%
•30-day mortality: 26%
•30-day mortality: 72%
•30-day mortality: 97%
•30-day mortality: 100%
|
ICH: intracerebral hemorrhage.
FINAL REMARKS
Intracerebral hemorrhage is a life-threatening acute neurological disorder requiring
emergent treatment. Neuroimaging is imperative for diagnosis, etiological classification,
prediction of hematoma growth, and prognosis. Although frequently detected, the mechanisms
and clinical significance of acute DWI imaging are still uncertain. Treatment mainstays
include blood pressure reduction and coagulopathy reversal, which should be promptly
initiated. Surgical treatment with EVD insertion, hematoma evacuation or decompressive
craniectomy is often necessary. The role of minimally invasive surgery is still uncertain,
although recent studies have shown promising results.
