Spontaneous Intracerebral Hemorrhage: Pathogenesis, Clinical Features, and Diagnosis

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Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis
Authors: Guy Rordorf, MD, Colin McDonald, MD

Section Editor: Scott E Kasner, MD
Deputy Editor: Janet L Wilterdink, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2018. | This topic last updated: Dec 04, 2013.
INTRODUCTION — Intracerebral hemorrhage (ICH) is the second most common cause of stroke, trailing
only ischemic stroke in frequency [1,2]. Estimates of the annual incidence range from 16 to 33 cases per
100,000 [3]. There are many underlying pathological conditions associated with ICH; hypertension, amyloid
angiopathy, ruptured saccular aneurysm, and vascular malformation account for the majority of cases.
The pathogenesis, epidemiology, clinical features, and diagnosis of ICH will be reviewed here, with an
emphasis upon hypertensive hemorrhage. The prognosis and treatment of ICH are discussed separately.
(See "Spontaneous intracerebral hemorrhage: Treatment and prognosis".)
PATHOGENESIS
Etiologies — Causes of nontraumatic ICH include [4-6]:
● Hypertension
● Cerebral amyloid angiopathy
● Vascular malformations
● Hemorrhagic infarction (including venous sinus thrombosis)
● Septic embolism, mycotic aneurysm
● Brain tumor
● Bleeding disorders, liver disease, anticoagulants, thrombolytic therapy
● Central nervous system (CNS) infection (eg, herpes simplex encephalitis)
● Moyamoya
● Vasculitis
● Drugs (cocaine, amphetamines) [7]. Phenylpropanolamine in appetite suppressants, and possibly cold
remedies, may be an independent risk factor for intracranial hemorrhage (including intracerebral
hemorrhage and subarachnoid hemorrhage) in women [8,9]. Caffeine-containing medications have also
been associated with ICH [10].
Hypertensive vasculopathy is the most common etiology of spontaneous ICH. Cerebral amyloid angiopathy is
the most common cause of nontraumatic lobar ICH in the elderly, while vascular malformations are the most
common cause of ICH in children [11]. These disorders are discussed elsewhere in appropriate topic reviews.
(See "Cerebral amyloid angiopathy" and "Vascular malformations of the central nervous system".)
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Hypertensive hemorrhages occur in the territory of penetrator arteries that branch off major intracerebral
arteries, often at 90º angles with the parent vessel. These small penetrating arteries may be particularly
susceptible to the effects of hypertension, as they are directly exposed to the pressure of the much larger
parent vessel, without the protection of a preceding gradual decrease in vessel caliber [12].
The blood vessels that give rise to hypertensive hemorrhage generally are the same as those affected by
hypertensive occlusive disease and diabetic vasculopathy, which cause lacunar strokes. These vessels
supply the pons and midbrain (penetrators off the basilar artery), thalamus (thalamostriate penetrators off the
P1 and P2 segments of the posterior cerebral arteries), and putamen and caudate (lenticulostriate
penetrators off the M1 segment of the middle cerebral artery). One exception is hypertensive cerebellar
hemorrhage; lacunar infarctions are uncommon in the deep cerebellar nuclei, while hypertensive cerebellar
hemorrhages occur more frequently. Hypertensive vasculopathy is also believed to play a role in the
development of white matter disease, which may explain the finding of an association between white matter
disease and risk of ICH [13].
Pathologic examination of the blood vessels in patients with chronic hypertension and in those with
intracerebral hemorrhage (ICH) has led to a theory of how hypertensive hemorrhage occurs. The penetrator
vessels in patients with chronic hypertension develop intimal hyperplasia with hyalinosis in the vessel wall;
this predisposes to focal necrosis, causing breaks in the wall of the vessel. These "pseudoaneurysms" have
been associated with small amounts of blood outside their walls. Pseudoaneurysm formation with subclinical
leaks of blood may be relatively common; massive hemorrhage can occur when the clotting system is unable
to compensate for the disruption in the vessel wall.
Cerebral microbleeds — Neuroimaging data suggest that pseudoaneurysm formation with subclinical leaks
of blood is relatively common in patients with spontaneous ICH. Gradient echo, susceptibility weighted and
T2*-weighted MRI can detect small regions of focal or multifocal hemosiderin deposition in these patients that
represent remnants of clinically silent cerebral microbleeds [14,15]. These microbleeds or microhemorrhages
may be a marker of bleeding-prone microangiopathy due to hyalinosis (chronic hypertension) or amyloid
deposition [16]. These have also been described in patients with infective endocarditis [17], and appear to be
more common in patients who are on antithrombotic therapy (warfarin or antiplatelet agents) [18].
In population-based studies, cerebral microhemorrhages are detected in 5 to 23 percent of older individuals

[19-23]. Baseline characteristics of the population studied and the sensitivity of the MRI techniques used
probably account for some of the variability in the observed prevalences. In a systematic review, the
prevalence of microbleeds visible on MRI was 5 percent in healthy adults, 34 percent in patients with
ischemic stroke, and 60 percent in patients with nontraumatic ICH [24]. Population-based studies have
shown that microbleeds are more prevalent in those with advanced age and male sex [20,21]. Pathologic
examination may show a somewhat higher prevalence of microbleeds; in one cohort of elderly patients (ages
71 to 105 years), these were found in 22 of 33 individuals and appeared to arise at the capillary level in many
cases [25].
Increasing evidence suggests that the anatomic distribution of microbleeds varies with their etiology, with
hypertensive microbleeds arising in the deep subcortical and infratentorial regions and amyloid microbleeds
in more superficial lobar regions of the cerebral hemispheres. This regional distribution is consistent with the
usual location of ICH in these conditions. In one study, deep microbleeds were associated with
cardiovascular mortality, while lobar microbleeds were not [26]. In another study, blood pressure variability
was associated with progression of microbleeds in the deep subcortical and infratentorial regions but not of
those in the cortex [27]. Other studies have found that microbleeds with a lobar distribution are associated
with the APOE genotype, cognitive impairment and regional amyloid deposition on PET studies, features that
are associated with cerebral amyloid angiopathy. (See "Cerebral amyloid angiopathy", section on
'Microhemorrhages'.)
In different populations, microbleeds have been associated with hypertension (odds ratio [OR] 3.9), diabetes
mellitus (OR 2.2), and cigarette smoking [19,24,28-30]. In the Framingham study, blood pressure was
associated with the presence of microbleeds in the crude analysis, but the relationship was not significant
after adjustment for age and sex [20]. One explanation for this result is that a higher percentage (73 percent)
of cerebral microbleeds were found in cortical/subcortical regions in the Framingham study population than in
other studies (55 to 57 percent) of healthy volunteers [31,32], and lesions in the cortical/subcortical region are
more likely to be related to cerebral amyloid angiopathy (CAA) than to hypertensive microangiopathy. (See
"Cerebral amyloid angiopathy", section on 'Microhemorrhages'.)
Associations between the incidence of microbleeds and lacunar stroke and white matter hyperintensities
have also been reported [19,29]. In one study, a lobar distribution of microbleeds consistent with CAA was
predictive of subsequent stroke-related death, while nonlobar microbleeds were associated with
cardiovascular mortality [26]. Other studies have found that the presence of microbleeds predicts subsequent
ischemic stroke as well as intracerebral hemorrhage [33,34]. Hemorrhages that occur in deep brain locations
are associated with microbleeds in that region as well.
Chronic obstructive pulmonary disease appeared to be a risk factor for both prevalent and incidental
microbleeds (OR 3.3 and 7.1 respectively) in the Rotterdam study, an association that was independent of
smoking status, age, and other comorbidities that might expect to be potential confounding factors [35].
Mechanisms of brain injury — There are several mechanisms of brain injury in ICH, including primary
direct mechanical injury to brain parenchyma by the expanding clot and cytotoxic perilesional edema. Both
clot volume and perilesional edema contribute to the mass effect and increased intracranial pressure (ICP),
which in turn can cause reduced cerebral perfusion and ischemic injury, and in very large ICH, cerebral
herniation [36].
● Secondary brain injury after the initial hemorrhage is an important contributing process; however, the
exact mechanism(s) underlying this remain uncertain. Neuroimaging and pathologic studies have yielded
some insights. One study using 18F-fluorodeoxyglucose positron emission tomography (FDG-PET)
demonstrated a perihematomal region of increased glucose metabolism two to four days after ICH [37].
Postcontrast enhancement may be noted in the perihematomal area on CT and MRI, representing blood-
brain barrier disruption [38,39]. One MRI study described a pattern of punctate areas of contrast
enhancement in the sulcal areas both contiguous and remote from the hemorrhage in patients with acute
primary ICH suggesting that ICH may be associated with more diffuse breakdown of the blood-
cerebrospinal fluid barrier as well [40].
Perihematomal edema is present on CT or MRI in at least half of patients when the patient is first imaged
and progresses, reaching maximum volume 7 to 12 days after onset; the most rapid expansion occurs in
the first 48 hours [41-43]. Hemorrhage volume and a higher admission hematocrit and PTT appear to
correlate with peak edema volume. The perihematomal region exhibits delayed perfusion and increased
diffusivity, mixed with areas of reduced diffusion suggesting the presence of both vasogenic and
cytotoxic edema [44]. The latter may be related to ICH mass effect, local neuronal ischemia or the
accumulation of cytotoxic factors [45]:
● Decreased blood flow to the area surrounding the clot causes local neuronal ischemia, which leads to
further cytotoxic edema and the toxic release of excitatory amino acids and inflammatory mediators [46].
This sequence of events is supported by studies in a rat model, which showed that the ischemic zone
surrounding an ICH can be decreased by various neuroprotective treatments, including N-methyl-D-
aspartate (NMDA) receptor antagonism (which blunts excitatory amino acid-mediated neuronal cell
death) and immunosuppression (which diminishes microglia-mediated neuronal injury) [47]. These
studies have also found that edema and ischemia persist after removal of the hematoma, emphasizing
the major contribution of secondary ischemic injury in ICH and explaining in part why surgical evacuation
of the hematoma often produces disappointing results. Disruption in cerebral autoregulation may
contribute to perihematomal ischemic injury [48]. (See "Spontaneous intracerebral hemorrhage:
Treatment and prognosis", section on 'Surgery'.)
● Thrombin-induced activation of the inflammatory cascade and overexpression of matrix

metalloproteinases (MMPs) is an additional mechanism that contributes to breakdown of the blood brain
barrier and edema formation in ICH [49-51]. MMPs appear to promote extracellular matrix proteolysis,
attack the basal lamina, and degrade cellular fibronectin (c-Fn), a glycoprotein that is important for
hemostasis [52]. Elevated serum levels of MMP-9 have been associated with an increased volume of
peripheral edema surrounding ICH [53,54].
A number of studies have found that a significant number of patients with ICH have acute ischemic lesions on
diffusion-weighted MRI imaging that are not contiguous to the hematoma [55-58]. The mechanism underlying
this phenomenon and the implication of these findings for clinical brain injury and prognosis are as yet
undefined [59]. Increased intracranial pressure and resulting reduction in cerebral perfusion pressure may
play a role; this phenomenon may be exacerbated by blood pressure lowering. An underlying angiopathy
from hypertension or other cause may also contribute to ischemic injury; in one study these lesions were
more common in patients with baseline microbleeds and white matter leukoaraiosis and also predicted future
cerebrovascular events and vascular death [57]. Another study with follow-up imaging found that these
lesions continue to appear beyond the acute ICH period [58].
Hemorrhage enlargement — Serial CT scans in patients with hypertensive hemorrhage have shown that
the hemorrhage enlarges in the first six hours after presentation in a subset of patients [45,60,61]. In a
prospective series of 103 patients with ICH, significant hematoma growth (a >33 percent volume increase)
occurred in 38 percent of patients over the first 24 hours [61].
Pathologic studies prior to CT scanning found that bleeding points occurred in the rim of the hemorrhage and
postulated that this new recruitment of bleeding sites would lead to enlargement of the clot. As the clot
expands, surrounding vessels are stretched, causing new sites of vessel rupture. Although the precise
mechanism of hemorrhage enlargement is not yet defined and may be heterogeneous, blood brain barrier
breakdown and dysregulation of hemostasis via inflammatory cascade activation and MMP overexpression,
as discussed above, is probably one important pathway [45]. Elevated plasma concentrations of c-Fn and the
inflammatory mediator interleukin-6 (IL-6) in the early acute phase of ICH have been associated with ICH
enlargement [62]. However, the clinical utility of MMP, c-Fn, or IL-6 blood levels in early ICH is not yet clear.
Risk factors for hematoma expansion include antithrombotic therapy, sustained elevated blood pressure,
large hematoma size, and evidence of contrast extravasation on initial CT imaging [45,63]:
● The relationship of systemic blood pressure to hematoma enlargement is not clear [60,64,65]. Some
studies have found that systolic blood pressure at the time of hospital admission is associated with
hematoma enlargement [66], while others have not [61,67-69].
Elevated or maximal systolic blood pressure (SBP) after admission may be a more important measure
[67]. This observation is supported by a retrospective observational study of 76 patients with
hypertensive ICH [70]. Hematoma enlargement occurred in 16 patients (21 percent) and was
significantly and independently associated with the maximum SBP recorded between the first and
second head CT scan. In addition, hematoma enlargement was significantly associated with treatment
target SBPs of 160 mmHg or greater compared with target SBPs of 150 or 140 mmHg. These results
must be interpreted cautiously because of small patient numbers and the retrospective observational
nature of the study.
● Contrast extravasation within the hematoma on CT angiography (CTA “spot sign”) has been linked to
hematoma expansion and poor outcomes in several studies [71-79]. In a retrospective analysis of 367
patients with acute ICH, this was found in 19 percent of patients and was independently associated with
hematoma expansion [71]. Similar results were reported other retrospective and prospective series,
which have also linked this finding to increased mortality and morbidity [72-77].
A "spot sign" score which grades the number of spot signs, their maximum dimension and attenuation,
has been found to be the strongest predictor of hematoma expansion among other clinical factors; of
these features, the number of spot signs appears to be most predictive [71,79,80]. Similarly,
accumulation of contrast extravasation within the hematoma on postcontrast CT also predicts
subsequent hematoma expansion [81].
In one cohort study, patients with warfarin were more likely to present with a spot sign, and among
patients with lobar hemorrhage, the apolipoprotein E ε2 allele was associated with the spot sign [82].
However, in another case series, the spot sign was more likely to be present in patients with chronic
hypertension, and less likely in those with probable cerebral amyloid angiopathy [83].
● The relationship of antiplatelet and anticoagulant therapy and hematoma expansion is discussed
separately. (See "Spontaneous intracerebral hemorrhage: Treatment and prognosis", section on
'Preceding antithrombotic use'.)
● The association of hematoma expansion risk with specific etiologies of ICH have not been systematically
studied. One study indicated that possession of the APOE ε2 genotype was associated with hemorrhage
expansion, particularly in patients with cerebral amyloid angiopathy [84].
Enlargement of the hematoma is associated with neurologic deterioration and worse outcomes. These
observations indicate that significant improvements in patient outcome from ICH may be achieved by
minimizing both secondary brain ischemia and hematoma enlargement. (See "Spontaneous intracerebral
hemorrhage: Treatment and prognosis", section on 'Hematoma growth and clinical deterioration' and
"Spontaneous intracerebral hemorrhage: Treatment and prognosis", section on 'Initial treatment'.)
Expansion of ICH into the intraventricular space occurs in 40 to 60 percent of patients and is associated with
complications and worse outcomes [85-87]. Anticoagulant and antiplatelet therapy is also a risk factor for this
complication. (See "Spontaneous intracerebral hemorrhage: Treatment and prognosis" and "Intraventricular
hemorrhage".)
EPIDEMIOLOGY — Nontraumatic intracerebral hemorrhage (ICH) causes 8 to 15 percent of all first-ever

strokes in Australia, England, and the United States [88,89]; it accounts for 25 percent of strokes in Japan
[90]. The overall incidence of ICH ranges from 12 to 31 per 100,000 people, and it varies by race [91-94]. The
incidence of ICH increases with age, doubling every 10 years after age 35 [2,95].
The rate of occurrence is highest in Asians, intermediate in blacks, and lowest in whites. The higher rate of
ICH in black compared with white Americans is predominately attributable to excess ICH in deep cerebral
and brainstem locations where hypertension is the major risk factor [92]. Mexican Americans also have a
higher incidence of ICH than non-Hispanic whites [96,97].
Data from the United Kingdom suggests that incidence of hypertensive ICH has declined since the early
1980s with improved control of hypertension, but overall rates of ICH have remained stable, in part due to an
increase in ICH associated with antithrombotic therapy [98]. As the population ages, the incidence of ICH
may rise in the future due to amyloid angiopathy.
Gender does not appear to have a significant impact on risk [94].
Risk factors — Hypertension is the most important risk factor for the development of intracerebral
hemorrhage (ICH) [99-102]. In one study of 331 consecutive cases, hypertension more than doubled the risk
of ICH [103].
The relative contribution of hypertension may be greater for deep than for lobar ICH [102,104]. In a meta-
analysis that pooled data from 28 studies, hypertension was twice as common in patients with deep ICH as in
patients with lobar ICH (odds ratio [OR] 2.1, 95% CI 1.82-2.42) [105]. In data from a subset of three studies in
the meta-analysis meeting more rigorous methodologic criteria, the association of hypertension with deep
ICH remained significant (OR 1.5, 95% CI 1.09-2.07).
At least in some studies, hypertension has also been shown to be a risk factor for ICH in the setting of other
underlying etiologies for ICH (eg, cerebral amyloid angiopathy, antithrombotic-associated ICH) [106,107].
(See "Cerebral amyloid angiopathy" and 'Antithrombotic therapy' below.)
In addition to hypertension, a systematic review [108] and a large population-based study [109] have
identified the following risk factors for ICH:
● Older age
● High alcohol intake
● Black ethnicity
● Lower cholesterol and lower LDL cholesterol
● Lower triglycerides
Findings from a surveillance study and a prospective cohort have found that the risk factors of race and age
appear to interact, such that while young (45 to 60 years) blacks have a higher risk of ICH than whites; this
risk is significantly lower, perhaps absent in older patients (>80 years) [109,110].
A number of additional studies have found an inverse relationship between total and LDL-cholesterol and the
risk of ICH [111-120]. At least one study suggested that the association is stronger for subcortical or
hypertensive ICH than lobar hemorrhage [115]. Another study found that lower cholesterol and LDL was
associated with more severe ICH and higher mortality [121]. However, treatment with statins does not appear
to increase the risk of primary ICH or to negatively impact prognosis according to a number of studies and
meta-analyses [120,122-129].
Chronic kidney disease (CKD) was found to be a risk factor for ICH in a population-based study cohort study
with 4937 participants [130]. Study limitations included that there were relatively few, 88, hemorrhagic
strokes, and the study did not distinguish between ICH and subarachnoid hemorrhage. One explanation for
this possible association is that CKD is associated with platelet dysfunction and a propensity to bleeding. An
alternate explanation is that CKD may be a marker of cerebrovascular small vessel disease, which is the
major mechanism of hypertensive ICH. Supporting the latter theory is one study’s findings associating CKD
with a greater presence and number of cerebral microbleeds among patients with ICH [131]. In another large
cohort study in Japan, the observed excess risk of hemorrhagic stroke among patients with chronic kidney
disease appeared to be confined to individuals who also regularly consumed alcohol [132]. (See "Platelet
dysfunction in uremia" and 'Pathogenesis' above.)
Selective serotonin reuptake inhibitors have been associated with bleeding risk in general as well as with
intracranial hemorrhage specifically, perhaps because of an effect on platelet aggregation. In one meta-
analysis of 16 observational studies, the associated adjusted risk ratio was 1.42, and the authors concluded
that absolute risks were likely to be very low [133]. (See "Selective serotonin reuptake inhibitors:
Pharmacology, administration, and side effects", section on 'Bleeding'.)
Most cases of ICH are not believed to have a genetic component. One exception is cerebral amyloid
angiopathy-related ICH which has been shown to have an association with APOE genotype [120]. (See
"Cerebral amyloid angiopathy", section on 'Apolipoprotein E'.) A large-scale genetic association study of 2189
ICH cases and 4041 controls revealed that APOE allele ε4 was also associated with deep ICH (OR = 1.21), a
location not typical for cerebral amyloid angiopathy [134], however, in another large study, APOE ε2 or ε4
allele was specifically associated with lobar and not deep ICH [104]. Other studies are investigating the role
of other genetic factors in the occurrence of ICH [135-139].
An association between migraine and ICH has been variably reported in individual studies. A meta-analysis
of eight studies concluded that migraine was associated with an increased risk of stroke (effect estimate
1.48), with moderate statistical heterogeneity [140].
Antithrombotic therapy — Anticoagulation with warfarin increases the risk of ICH two- to fivefold,
depending upon the intensity of anticoagulation. This is discussed separately.
In addition to an increased risk of ICH, retrospective evidence suggests that warfarin therapy with an
international normalized ratio (INR) >3 is a risk factor for larger initial hemorrhage volume as well as poorer
outcomes after ICH [141]. (See "Spontaneous intracerebral hemorrhage: Treatment and prognosis", section
on 'Preceding antithrombotic use'.)
There is probably a very small absolute increased risk of primary ICH associated with the use of aspirin or
antiplatelet agents, based on meta-analyses of randomized, controlled trials [142,143], although other case-
control studies have not find increased risk [111,144]. A subsequent review estimated the risk of ICH
associated with the use of aspirin for primary and secondary prevention of coronary heart disease to be 0.2
events per 1000 patient years [145]. Dual antiplatelet therapy with aspirin plus clopidogrel increases the risk
of ICH twofold compared with aspirin alone (0.4 versus 0.2 percent) [146]. NSAIDs do not appear to increase
the risk of ICH [147-150].
Hypertension is a risk factor for ICH among patients taking antithrombotic agents. In a cohort study of 4009
patients taking antiplatelet agents and/or warfarin, the risk of ICH was associated with average systolic and
diastolic BP [151]. The optimal cutoff BP level to predict ICH risk was >130/81.
The presence of microbleeds on MRI is another risk factor for ICH among antithrombotic users (OR = 12.1)
[18].
The risk of recurrent ICH associated with antiplatelet and anticoagulation therapy is discussed separately.
(See "The use of antithrombotic therapy in patients with an acute or prior intracerebral hemorrhage" and
"Spontaneous intracerebral hemorrhage: Treatment and prognosis", section on 'Resumption of antiplatelet
therapy'.)
CLINICAL PRESENTATION — Some hypertensive hemorrhages occur with exertion or intense emotional
activity. However, most cases take place during routine activity. The neurologic symptoms usually increase
gradually over minutes or a few hours (figure 1). In contrast to brain embolism and subarachnoid
hemorrhage, the neurologic symptoms do not begin abruptly and are not maximal at onset.
Headache, vomiting, and a decreased level of consciousness develop if the hematoma becomes sufficiently
large. Headache and vomiting occur in approximately one-half of patients with intracerebral hemorrhage
(ICH) (figure 2). Headache may be due to traction on meningeal pain fibers, increased intracranial pressure
(ICP), or blood in the cerebrospinal fluid (CSF); it is most common with cerebellar and lobar hemorrhages.
These symptoms are absent with small hemorrhages; the clinical presentation in this setting is that of a
gradually progressing stroke. Patients may complain of a stiff neck and have meningismus on physical
examination, if there is intraventricular blood.
Seizures in the first days after ICH occur in 4 to 29 percent of patients; they are more common in lobar
hemorrhages (affecting cortical tissue) than in deep or cerebellar ICHs [89,152-155]. In a series of 63 patients
with ICH in an intensive care unit who had continuous electroencephalogram monitoring, seizures within 72
hours of admission occurred in 29 percent and were often nonconvulsive [154]. In addition, the presence of
seizures was independently associated with midline brain shift and neurologic deterioration.
Stupor or coma in ICH is an ominous sign. The only exception is patients with thalamic hemorrhage, in whom
involvement of the reticular activating system is the cause of stupor rather than diffuse brain injury; these
patients may recover after blood is reabsorbed.
Some patients have abnormalities on the electrocardiogram (ECG), including a prolonged QT interval,
depressed ST segment, flat or inverted T waves, U waves, and tall peaked T waves. These changes are
predominately reflective of ischemia in the subendocardium of the left ventricle, which is most likely due to a
centrally mediated release of catecholamines induced by hypoperfusion of the posterior hypothalamus. Mild
elevations in serum myocardial enzymes often accompany the ECG changes, and ventricular arrhythmias
may occur with brainstem compression [156].
Neurologic signs — Neurologic signs vary depending upon the location of the hemorrhage. Bleeding into
the putamen occurs in approximately 35 percent of cases, subcortex in 30 percent, cerebellum in 16 percent,
thalamus in 15 percent, and pons in 5 to 12 percent [157].
Putamenal hemorrhage — Spread of hemorrhage into the putamen most commonly occurs along white
matter fiber tracts, causing hemiplegia, hemisensory loss, homonymous hemianopsia, gaze palsy, stupor,
and coma.
Cerebellar hemorrhage — Cerebellar hemorrhages usually originate in the dentate nucleus, extend into
the hemisphere and fourth ventricle, and possibly into the pontine tegmentum. These bleeds cause an
inability to walk due to imbalance, vomiting, headache (which may be referred to the neck or shoulder,
usually occipital), neck stiffness, gaze palsy, and facial weakness. There is notably no hemiparesis. The
patient may become stuporous due to brainstem compression if the hemorrhage is unrecognized or
untreated. Cerebellar hemorrhage is a crucial diagnosis to make since these patients frequently deteriorate
and require surgery.
Thalamic hemorrhage — A thalamic hemorrhage may extend in a transverse direction to the posterior
limb of the internal capsule, downward to put pressure on the tectum of the midbrain, or may rupture into the
third ventricle. Symptoms include hemiparesis, hemisensory loss, and occasionally transient homonymous
hemianopsia. There may also be an upgaze palsy with miotic pupils that are unreactive, peering at the tip of
the nose, skewed, or "wrong way eyes" toward the weak side (in contrast to hemispheric cortical injury in
which the eyes are deviated away from the hemiparesis). Aphasia may occur if the bleed affects the
dominant hemisphere or neglect in the nondominant hemisphere.
Lobar hemorrhage — Lobar hemorrhages vary in their neurologic signs depending upon location. They
most often affect the parietal and occipital lobes. These bleeds are associated with a higher incidence of
seizures. Occipital hemorrhages frequently present with a very dense contralateral homonymous
hemianopsia. Hemorrhages in the frontal region will bring about a contralateral plegia or paresis of the leg
with relative sparing of the arm.
Pontine hemorrhage — Pontine hemorrhage is characterized by a medial hematoma that extends into
the base of the pons. These often lead to deep coma over the first few minutes following the hemorrhage,
probably due to disruption of the reticular activating system. The motor examination is marked by total
paralysis. The pupils are pinpoint and react to a strong light source. Horizontal eye movements are absent,
and there may be ocular bobbing, facial palsy, deafness, and dysarthria when the patient is awake.
EVALUATION AND DIAGNOSIS — ICH is a neurologic and medical emergency because it is associated
with a high risk of ongoing bleeding, progressive neurologic deterioration, permanent disability, and death
[89].
The acute evaluation of patients with suspected stroke, including issues related to the history, physical
examination, airway and breathing, and immediate laboratory studies, is discussed in detail separately. (See
"Initial assessment and management of acute stroke".)
The clinical diagnosis of intracerebral hemorrhage (ICH) is based upon features such as gradually
progressive worsening of symptoms and increasing neurologic deficit. (See 'Clinical presentation' above.)
Neuroimaging with brain CT or MRI is essential to confirm the diagnosis of ICH and to exclude ischemic
stroke and stroke mimics as possible causes. Both CT and MRI are considered first-choice imaging options
for the emergency diagnosis and assessment of ICH [89,158]. However, head CT should be obtained in
patients with contraindications to MRI.
Head CT — Noncontrast cranial CT is the study most widely used to evaluate for the presence of acute ICH,
which is evident almost immediately. CT can define the size and location of the hematoma. It also provides
information about extension into the ventricular system, the presence of surrounding edema, and shifts in
brain contents (herniation). Hyperacute blood will appear hyperdense unless the patient is severely anemic,
in which case it might appear isodense. Over weeks, the blood will become isodense and may have a ring
enhancement appearance. Chronically, the blood is hypodense.
Primary ICH needs to be distinguished from hemorrhagic transformation of a cerebral infarction. While there
are no defined radiologic criteria for this distinction, a patchy appearance of the hyperdensity within a larger
area of low attenuation is an important feature, as is a wedge-shaped abnormality that extends to the cortex.
A delay from stroke onset to CT examination, however, can be problematic in CT interpretation and has been
shown to reduce inter-observer reliability [159]. When an ICH clot retracts and surrounding edema develops,
the appearance of a primary ICH can resemble that of a hemorrhagic cerebral infarction.
An estimate of ICH volume is useful to communicate hemorrhage severity and make early assessments of
prognosis. (See "Spontaneous intracerebral hemorrhage: Treatment and prognosis", section on 'Initial ICH
volume and level of consciousness'.) The formula is calculated using the centimeter scale on the CT (or MRI)
images as follows [160]:
● A is the greatest hemorrhage diameter on the CT slice with the largest area of hemorrhage.
● B is the largest diameter 90 degrees to A on the same (index) CT slice.
● C is the approximate number of CT slices with hemorrhage multiplied by the slice thickness in
centimeters. To calculate C, each CT slice with hemorrhage is visually compared with the index CT slice
[160]. An individual hemorrhage slice is counted as one full slice for determining C if the hemorrhage
area is >75 percent of the area on the slice with the largest hemorrhage. A slice is counted as one-half if
the hemorrhage area is approximately 25 to 75 percent of the area on the largest hemorrhage slice. The
slice is not counted if the area is <25 percent of the largest hemorrhage slice.
● ABC/2 gives the ICH volume in cubic centimeters.
● In children, ICH volume may instead be measured as a percent of total brain volume as ABC/XYZ,
where X, Y, and Z are perpendicular measures of the supratentorial intracranial space [161].
Contrast-enhanced CT and/or CT angiography (CTA) may reveal a focus of contrast extravasation (“spot
sign”) that suggests that the patient is at risk for hematoma expansion [78,162]. (See 'Hemorrhage
enlargement' above and "Spontaneous intracerebral hemorrhage: Treatment and prognosis", section on
'Hematoma growth and clinical deterioration'.)
Brain MRI
Hemorrhage appearance — Accumulating evidence has confirmed that hyperacute parenchymal

hemorrhage can be accurately detected using MRI with T2-sensitive pulse sequences such as gradient echo
(GRE) [163-169]. These sequences are highly sensitive to the nonuniform static magnetic fields produced by
paramagnetic molecules such as deoxyhemoglobin. This property of paramagnetic molecules is termed the
magnetic susceptibility effect; it results in rapid dephasing of proton spins causing signal loss (darkening or
hypointensity) that is best seen in T2*-weighted images.
Acute ICH can be diagnosed by MRI with up to 100 percent sensitivity and accuracy by experienced readers
[168]. This was illustrated in the Hemorrhage and Early MRI Evaluation (HEME) study, a prospective two-
center study that evaluated 200 patients presenting with focal stroke symptoms [169]. All patients had MRI
with gradient echo (GRE) and diffusion-weighted (DWI) sequences within six hours of symptom onset
followed by CT. The study was stopped early because MRI was detecting cases of hemorrhagic
transformation that CT did not reveal. MRI and CT were equivalent for the detection of acute ICH, and MRI
was significantly more accurate than CT for the detection of chronic ICH.
The appearance of blood on MRI images depends upon the paramagnetic properties of the various stages of
hemoglobin and on the mode of imaging acquisition:
● Hyperacute hematoma. The ability of MRI to detect hyperacute ICH, within the first one to six hours, is
based upon the magnetic susceptibility effect of deoxyhemoglobin [164]. Hyperacute hematoma on MRI
appears to be composed of three distinct areas (picture 1) [166]:
• A center that is isointense to hyperintense on susceptibility weighted and T2-weighted imaging. The
center may be smaller or larger than the periphery and may be heterogeneous in appearance. It
may be entirely absent by two hours as the periphery expands towards the center [166].
• A periphery that appears hypointense or dark on susceptibility weighted imaging due to

deoxyhemoglobin. This signal loss gradually expands from the periphery toward the center. This
effect is best seen on sequences that are T2* weighted, such as GRE.
• A rim that appears hypointense on T1-weighted imaging and hyperintense on T2-weighted imaging,
representing vasogenic edema encasing the hematoma.
● Subacute hematoma. ICH appears as high signal intensity on T1 due to the presence of methemoglobin,
particularly in the periphery. The appearance on T2 is initially dark, then later becomes bright as the red
blood cells lyse and methemoglobin becomes extracellular.
● Chronic hematoma. Hemosiderin is produced by phagocytes ingesting methemoglobin; this appears as a

low signal on T2 and T1, enhanced by susceptibility weighted images such as GRE sequences.
Microbleeds — Cerebral microbleeds are small hemosiderin deposits that are best visualized as punctate
areas of low signal on T2* weighted GRE sequences. Hypertension and cerebral amyloid angiopathy are the
two most important pathologies associated with microbleeds. (See 'Cerebral microbleeds' above.)
The location of microbleeds is suggestive of the underlying pathology.
● Microbleeds in deep gray and infratentorial brain regions such as the pons, thalamus, and basal ganglia,
are characteristic of hypertensive bleeding prone microangiopathy
● Microbleeds in the cortical-subcortical junction (gray-white junction) are characteristic of cerebral amyloid
angiopathy (see "Cerebral amyloid angiopathy")
Underlying etiology — Contrast-enhanced MRI (along with magnetic resonance angiography, magnetic
resonance venography) can be useful to evaluated for underlying structural lesions (eg, vascular
malformations, tumors), when there is clinical or radiologic suspicion for these [162]. CT angiography and/or
conventional angiography may also be used in selected patients to evaluate for a possible macrovascular
cause (vascular malformation, aneurysm) of ICH [5,6].
In addition, a finding of microhemorrhages or white matter disease in a specific anatomic distribution may
suggest that hypertensive arteriopathy as the cause, when located in the basal ganglia or cerebral amyloid
angiopathy if the findings are cortically distributed [170]. (See 'Cerebral microbleeds' above.)
Other studies — The necessity for further evaluation to determine the cause of ICH varies with the clinical
setting. In particular the patient's age, the presence/absence of hypertension, and the hemorrhage location
are primary considerations [171]. No further diagnostic tests are necessary in the severely hypertensive
patient with a well-circumscribed and homogeneous hematoma that is located in a typical location for
hypertensive ICH (eg, putamen/internal capsule, caudate nucleus, thalamus, pons, or cerebellum); the
clinician can be confident that such a patient has a hypertensive hemorrhage. Similarly, a traumatic etiology
can be diagnosed with confidence in the patient who has had recent trauma and lesions in the location and
with the appearance of contusion and traumatic hemorrhages (eg, anterior and/or orbital frontal lobes and
temporal lobes at the surface).
Evaluation for a bleeding disorder (platelet count, prothrombin time, and activated partial thromboplastin time)
should be performed in every patient with an ICH, especially if the cause is not immediately clear. A bleeding
tendency can cause or contribute to bleeding initiated by other etiologies. (See "Approach to the adult patient
with a bleeding diathesis".)
Iatrogenic prescription of anticoagulants is the most common bleeding disorder leading to brain
hemorrhages. In one series of 24 such patients, 18 were hypertensive, but only one had simultaneous
bleeding in other organs [172]. These bleeds are most often lobar or cerebellar. Anticoagulant hemorrhages
often develop gradually and may become progressively larger over hours or even a few days [172,173].
Amyloid angiopathy, bleeding into a tumor, and vascular malformations are likely etiologies of hemorrhages
that are lobar or atypical in appearance. (See "Cerebral amyloid angiopathy" and "Clinical manifestations and
diagnosis of aneurysmal subarachnoid hemorrhage" and "Vascular malformations of the central nervous
system".)
● Hemorrhages related to amyloid angiopathy are usually lobar, but they are occasionally cerebellar. They
predominantly involve the posterior portions of the brain, including the parietal and occipital lobes. The
hemorrhages are usually multiple; gradient-echo MRI may show the presence of old small hemorrhages.
Patients with amyloid angiopathy are typically over the age of 65. (See "Cerebral amyloid angiopathy".)
● Other bleeding lesions should be excluded in patients under the age of 60 if the blood pressure is not
sufficiently elevated to make a firm diagnosis of hypertensive lobar hemorrhage. A repeat MRI after the
blood has been reabsorbed (four to eight weeks) may show residual vascular malformations or a brain
tumor.
Vascular imaging using contrast CT angiography (CTA) or magnetic resonance angiography (MRA) of
the intracranial circulation are useful screening tests for vascular malformations and aneurysms [174-
177]. Contrast angiography by arterial catheterization may be necessary in patients with a CTA or MRA
suggestive of vascular malformation. A finding of a "spot sign" on CTA has been found to be associated
with a high risk of hematoma expansion. (See "Clinical manifestations and diagnosis of aneurysmal
subarachnoid hemorrhage" and "Vascular malformations of the central nervous system" and "Brain
arteriovenous malformations" and "Spontaneous intracerebral hemorrhage: Treatment and prognosis".)
● Patients with ICH after cocaine use (but not amphetamines) have a relatively high incidence of
underlying aneurysms and vascular malformations. They require vascular imaging tests (eg, CTA, MRA,
and/or angiography).
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics”
and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer short, easy-to-
read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want
in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail
these topics to your patients. (You can also locate patient education articles on a variety of subjects by
searching on “patient info” and the keyword(s) of interest.)
● Basics topics (see "Patient education: Hemorrhagic stroke (The Basics)" and "Patient education:
Arteriovenous malformations in the brain (The Basics)")
● Beyond the Basics topics (see "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)"
and "Patient education: Hemorrhagic stroke treatment (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
● Hypertensive vasculopathy is the most common etiology of spontaneous intracerebral hemorrhage

(ICH). Cerebral amyloid angiopathy is the most common cause of nontraumatic lobar ICH in the elderly,
while vascular malformations are the most common cause of ICH in children. Additional causes include
tumors, coagulopathies, and others. (See 'Etiologies' above.)
● In addition to hypertension, older age, and antithrombotic therapy are risk factors. (See 'Risk factors'
above.)
● Patients typically present with an acute onset of a focal neurologic deficit that corresponds to the part of
the brain affected. (See 'Clinical presentation' above.)
With large hemorrhages, there is elevated intracranial pressure and suppressed level of consciousness.
Seizures may complicate 5 to 30 percent of hemorrhages, particularly if the hematoma is more

superficial than deep.
● A noncontrast head computed tomogram (CT) is ordered in all patients with this presentation and is
reliable at demonstrating the hematoma, although the cause may remain obscure. (See 'Head CT'
above.)
● A contrast enhanced magnetic resonance imaging (MRI) study is useful to detect underlying causative
lesions such as a vascular malformation, tumor, and cerebral amyloid angiopathy and should be
performed when these are suspected or the cause of ICH otherwise remains obscure. (See 'Brain MRI'
above.)
● Patients without hypertension or other known etiology for the hemorrhage should have other studies to
evaluate potential causes such as coagulation studies, toxicology screen, and other vascular imaging
such as MR or CT angiography. (See 'Other studies' above.)
Use of UpToDate is subject to the Subscription and License Agreement.
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Topic 1133 Version 12.0
GRAPHICS
Time course of neurologic changes in intracerebral

hemorrhage
Schematic representation of rapid downhill course in terms of unusual behavior

(green), hemimotor function (blue), and consciousness (red) in a patient with
intracerebral (intraparenchymal) hemorrhage.
Graphic 61491 Version 2.0
Headache and vomiting in stroke subtypes
The frequency of sentinel headache, onset headache, and vomiting in three

subtypes of stroke: subarachnoid hemorrhage (SAH), intraparenchymal
(intracerebral) hemorrhage (IPH), and ischemic stroke (IS). Onset headache was
present in virtually all patients with SAH and about one-half of those with IPH;
all of these symptoms were infrequent in patients with IS.
Data from: Gorelick PB, Hier DB, Caplan LR, et al, Neurology 1986; 36:1445.
Hyperacute intracerebral hemorrhage
CT and MRI studies were obtained less than six hours from symptom onset in a patient
with spontaneous acute intracerebral hemorrhage. The CT scan shows a hyperdense
hemorrhage predominantly in the left frontal lobe. On MRI, the central portion of the
hematoma is isointense to brain parenchyma on the T1-weighted image and hyperintense
on the T2-weighted and T2* gradient echo images, consistent with hemorrhage containing
oxyhemoglobin. On the T2-weighted and T2* gradient echo images, the periphery of the
hemorrhage is hypointense, consistent with deoxygenation that occurs more rapidly at the
borders. On the T2 weighted image, tissue adjacent to and surrounding the hematoma is
hyperintense, consistent with vasogenic edema.
Contributor Disclosures
Guy Rordorf, MD Nothing to disclose Colin McDonald, MD Equity Ownership/Stock Options: Specialists
on Call [Medical Management (Emergency Neurology Telemedicine)]. Scott E Kasner,
MD Grant/Research/Clinical Trial Support: WL Gore and Associates [Stroke (PFO closure)]; Acorda [Stroke
(dalfampridine)]; AstraZeneca [Stroke (ticagrelor)]; Bayer [Stroke (rivaroxaban)]; Bristol Meyers Squibb
[Stroke]. Consultant/Advisory Boards: Bayer [Stroke]; BMS [Stroke]; Novartis [Stroke]; Merck [Stroke]; Daiichi
Sankyo [Stroke]; Boehringer Ingelheim [Stroke]; Abbvie [stroke]; J&J [stroke]. Janet L Wilterdink,
MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
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provided to support the content. Appropriately referenced content is required of all authors and must conform
to UpToDate standards of evidence.
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Spontaneous Intracerebral Hemorrhage: Pathogenesis, Clinical Features, and Diagnosis

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Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis

Authors: Guy Rordorf, MD, Colin McDonald, MD

Etiologies — Causes of nontraumatic ICH include [4-6]:

● Cerebral amyloid angiopathy

● Hemorrhagic infarction (including venous sinus thrombosis)

● Septic embolism, mycotic aneurysm

● Bleeding disorders, liver disease, anticoagulants, thrombolytic therapy

● Central nervous system (CNS) infection (eg, herpes simplex encephalitis)

In population-based studies, cerebral microhemorrhages are detected in 5 to 23 percent of older individuals

● Thrombin-induced activation of the inflammatory cascade and overexpression of matrix

EPIDEMIOLOGY — Nontraumatic intracerebral hemorrhage (ICH) causes 8 to 15 percent of all first-ever

Gender does not appear to have a significant impact on risk [94].

● High alcohol intake

● Lower cholesterol and lower LDL cholesterol

● B is the largest diameter 90 degrees to A on the same (index) CT slice.

● ABC/2 gives the ICH volume in cubic centimeters.

Hemorrhage appearance — Accumulating evidence has confirmed that hyperacute parenchymal

• A periphery that appears hypointense or dark on susceptibility weighted imaging due to

● Chronic hematoma. Hemosiderin is produced by phagocytes ingesting methemoglobin; this appears as a

The location of microbleeds is suggestive of the underlying pathology.

SUMMARY AND RECOMMENDATIONS

● Hypertensive vasculopathy is the most common etiology of spontaneous intracerebral hemorrhage

Seizures may complicate 5 to 30 percent of hemorrhages, particularly if the hematoma is more

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Topic 1133 Version 12.0

Time course of neurologic changes in intracerebral

Schematic representation of rapid downhill course in terms of unusual behavior

Graphic 61491 Version 2.0

Headache and vomiting in stroke subtypes

The frequency of sentinel headache, onset headache, and vomiting in three

Graphic 60831 Version 3.0

Hyperacute intracerebral hemorrhage

Graphic 81767 Version 1.0

Conflict of interest policy

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