Ischemic Brain Injury After Intracerebral Hemorrhage: A Critical Review

Shyam Prabhakaran and Andrew M. Naidech

Stroke. 2012;43:2258-2263; originally published online July 19, 2012;
doi: 10.1161/STROKEAHA.112.655910
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2012 American Heart Association, Inc. All rights reserved.
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Progress Review
Ischemic Brain Injury After Intracerebral Hemorrhage
A Critical Review
Shyam Prabhakaran, MD, MS; Andrew M. Naidech, MD, MSPH

ntracerebral hemorrhage (ICH) is the second most common

cause of stroke and accounts for 8% to 15% of strokes in
Western societies with an estimated incidence of 10 to 25 per
100 000 persons.13 Despite advances in the field of stroke
and neurocritical care,4 the 30-day mortality has not changed
significantly over the past 20 years.3 Indeed, ICH has the
highest rates of dependence or death among stroke types and
proven treatments are lacking.
Clinical trials aimed at limiting hemorrhage growth, procoagulant agents for hemostasis,5 and surgical evacuation6
have not translated into improved clinical outcomes. Antihypertensive therapy for the purpose of reducing hematoma
growth has been a mainstay of acute management. Guidelines
recommend maintaining mean arterial pressure 130 mm Hg
during the acute phase7; however, controversies exist given
the lack of randomized clinical trial data and uncertainties
about the rapidity and target level of blood pressure (BP)lowering. Recent Phase 2 clinical trials evaluating acute BP
control have shown promise in reducing hematoma expansion
with an adequate safety profile and Phase 3 trials are
underway.8,9
Besides hematoma growth, other pathophysiological processes occur in the setting of ICH and may serve as potential
therapeutic targets. In the acute period after ICH, a rapid rise
in intracranial pressure (ICP) from an expanding hematoma
may reduce cerebral perfusion pressure. In this setting,
interventions aimed at BP-lowering and hemostasis may
theoretically induce thrombosis or exacerbate brain ischemia,
particularly in patients with pre-existing cerebrovascular
disease. A recent publication suggests that aggressive BPlowering may actually cause acute brain ischemia and worsen
outcomes after ICH.10
In this review, we outline the data on secondary acute
ischemic injury after ICH, review the prevalence of remote
ischemic lesions and risk factors associated with their occurrence, explore potential mechanisms and clinical impact of
these lesions, and discuss future directions in this arena of
research.

Prevalence of Secondary Ischemic Injury

After ICH
After arteriolar rupture and parenchymal hemorrhage in the
brain, a combination of local compression, cytotoxic injury,

inflammation, and surrounding edema ensues. Imaging studies in patients with ICH have demonstrated these effects at
varying stages of hemorrhage and within and surrounding
the hematoma bed. Although there is restricted diffusion
within the hematoma during the first 2 weeks,11 an effect
of increased viscosity and suspectibility effects from blood
breakdown products, much more attention has been paid to
the potential for ischemia in the surrounding tissue.
That aggressive BP-lowering might promote cerebral ischemia adjacent to the hematoma has been cited as a potential
hazard of aggressive antihypertensive therapy; however, imaging studies using single-photon emission CT, positron
emission tomography, and CT and MR single-photon emission computed tomography and perfusion studies1218 have
failed to show any significant rim of perihematomal ischemia.
There appears to be decreased cerebral blood flow in the
perihematomal region but it is accompanied by a decreased
cerebral metabolic rate of oxygen and lowered, not elevated,
oxygen extraction fraction.16,18 Thus, the data suggest that
perihematomal hypoperfusion in ICH is a consequence of
hypometabolism, which may be mediated by toxic effects
from the hematoma itself.19 Other studies, however, using
single-photon emission computed tomography20 and jugular
venous oxygen tension21 have observed reduced hemispheric
cerebral blood flow and impaired cerebral autoregulation in
the setting of aggressive BP-lowering. It is also known that
complex phasic variations in cerebral blood flow and metabolism may exist after ICH such that very aggressive BPlowering or persistent modest lowering in the later periods of
metabolic normalization may lead to cerebral ischemia both
in the perihematomal and distant brain regions.22
Diffusion-weighted imaging (DWI) offers greater spatial
resolution (12 mm) than single-photon emission CT, positron emission tomography, or CT-based techniques (5
10 mm); can detect very small foci of acute neuronal injury;
and is a sensitive marker of acute brain ischemia.23 The
occurrence of DWI lesions, remote from the primary site of
injury and delayed from the ictus, has been described in other
types of brain injury including ischemic stroke,24 transient
ischemic attack,25 and subarachnoid hemorrhage.26 Its recent
application in ICH suggests that remote ischemic lesions are
found in approximately 25% of patients.10,2731 The lesions

Received February 29, 2012; accepted March 26, 2012.

From Department of Neurology, Northwestern University-Feinberg School of Medicine, Chicago, IL.
Correspondence to Shyam Prabhakaran, MD, MS, 710 N Lakeshore Drive, Suite 1417, Chicago, IL 60611. E-mail shyam.prabhakaran@
northwestern.edu
(Stroke. 2012;43:2258-2263.)
2012 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org

DOI: 10.1161/STROKEAHA.112.655910

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Prabhakaran and Naidech

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Mechanisms and Pathophysiology

Mechanisms of secondary ischemic injury after ICH are
uncertain. However, based on the recent publications,10,2731
several potential factors have been consistently associated
with acute ischemic lesions. These include BP-lowering,
markers of microvasculopathy, and ICP elevation (Table).
We theorize that these mechanisms interact in complex ways
(Figure 2). Acting on a background-enhanced thrombotic
milieu (stroke-prone state) after ICH, vulnerable patients
with pre-existing cerebral microangiopathy due to atherosclerotic risk factors and/or cerebral amyloid angiopathy (CAA)
may have lower thresholds for brain ischemia. In such
patients, elevations of ICP, failure of autoregulation, and
aggressive early BP-lowering could provoke acute brain
ischemia.
BP-Lowering
Three studies10,30,31 have independently suggested a relationship between degree of BP-lowering and DWI lesions,
whereas 2 have not found an association.27,28 In the positive
studies, change in BP, in absolute and relative terms, correlated
with presence of DWI lesions. This relationship may be heightened in the first few hours after BP treatment (Figure 3).
Cerebral blood flow is regulated across a wide range of
mean arterial pressure or cerebral perfusion pressure in the
normal state. Cerebral autoregulation is right-shifted in
chronic hypertension and may be lost in the setting of acute
brain injury such that cerebral blood flow responds linearly to
cerebral perfusion pressure.32 Aggressive BP reductions beyond the lower limits of cerebral autoregulation, therefore,
have the potential of inducing cerebral ischemia. Elevated
ICP and use of vasoactive substances with the potential of
exacerbating ICP may further compromise cerebral perfusion
pressure in patients with ICH.

Figure 1. Example of DWI lesions after ICH. DWI indicates

diffusion-weighted imaging; ICH, intracerebral hemorrhage.

are typically subcortical, often multiple or bilateral, and very

small (Figure 1). Additionally, they were noted in 27% of
patients on subacute or delayed imaging at 30 days, of which
83% were incident lesions not present on the initial scan.30
These composite data suggest that a stroke-prone state may
exist after either hemorrhagic or ischemic stroke, may be
provoked by several factors, and may last weeks to months.

Table.

Summary of Recent Publications on DWI Lesions After ICH

Sample size
Design
Timing of MRI
Age, y
Race
ICH cause
Prevalence of DWI lesion

Kimberly et al29

Prabhakaran et al31

Gregoire et al27

Garg et al10

Menon et al30

Kang et al28
97 (100% ICH)

78 (87% ICH)

118 (100% ICH)

114 (100% ICH)

95 (100% ICH)

138 (100% ICH)

Retrospective casecontrol

Retrospective

Multicenter casecontrol

Prospective

Prospective

Prospective

Median, 4 d

Median, 1 d

Median, 7 d

Median, 2 d

Median, 2 d and 35 d

Median, 3 d

78.2

59.6

70.7

64.1

59.8

59.1

White?

Nonwhite 67%

White?

Nonwhite 62%

Nonwhite 73%

Asian

100% CAA

70% HTN

34% CAA

62% HTN

62% HTN

83% HTN

15%

23%

13%

41%

Acute: 35%

27%

1 mo: 27%
Associations

Total MBs

Prior stroke

CAA etiology

Acute: BP-lowering

Leukoaraiosis

Craniotomy

Lobar MBs

BP-lowering

IVH

MBs 2

BP-lowering

Leukoaraiosis

ICH volume

HTN etiology

Total MBs
1 mo: prior stroke
Baseline MB
Baseline DWI

DWI indicates diffusion weighted imaging; ICH, intracerebral hemorrhage; MB, microbleeds; CAA, cerebral amyloid angiopathy; HTN, hypertension; BP, blood
pressure; IVH, intraventricular hemorrhage.

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Figure 2. A multihit hypothesis for development of

brain ischemia after intracerebral hemorrhage.

Cerebral Microangiopathy
Five of the studies consistently reported an association with
either microhemorrhage burden on gradient-echo imaging or
white matter hyperintensity burden on fluid-attenuated inversion recovery sequences.2730 A history of stroke was associated with DWI lesions in another study.31 As markers of
chronic cerebral vasculopathy, these factors may identify
those with significant pre-existing cerebrovascular disease
and who are more prone to ischemic injury after ICH.
Ischemic stroke and ICH share many risk factors and
pathological substrates. The characteristic locations of hypertensive ICH include the basal ganglia, thalamus, pons, and
cerebellum, many of which are common sites for lacunar
ischemic infarction. They also share many vascular risk
factors including hypertension, diabetes mellitus, dyslipidemia, and smoking.33 It is well established that these risk
factors lead to distinct pathologies affecting arterioles (typically perforators) including fibrinoid changes, lipohyalinosis,
necrosis, and microaneurysm formation. These changes can
predispose them to occlusion and/or rupture.34 Further evidence of the link between ischemic stroke and ICH is drawn
from the observations that patients surviving ICH have
comparable risks for subsequent ischemic and hemorrhagic
stroke.35,36

Figure 3. Systolic blood pressure on the y-axis among those

with DWI (red) and without DWI lesions (blue) with time in hours
from presentation on the x-axis. DWI indicates diffusionweighted imaging.

In contrast to hypertensive vasculopathy, which affects the

deep and subcortical arterioles, CAA affects small superficial
and leptomeningeal arterioles. Beta-amyloid protein deposition in these vessel walls leads to degenerative changes that
predispose them to vessel fragility and rupture.37 Just as
hypertensive vasculopathy can manifest as ICH, ischemic
infarction, leukoaraiosis, and vascular dementia, patients
harboring CAA pathology can have multiple cerebrovascular
presentations including ICH, vasculitis and ischemic stroke,
leukoencephalopathy, and dementia.38 Indeed, white matter
disease is increased and cerebral blood flow responses are
impaired in patients with CAA compared with control
subjects.39,40
Thus, a chronic microangiopathy, either due to hypertension or CAA, may pre-exist in many patients with ICH. These
underlying disease processes may place such patients at risk
for both ischemic and hemorrhagic stroke. Vascular biological substrates may also play critical roles in determining the
response to hemodynamic alternations after ICH and precipitate secondary ischemic injury. For instance, pre-existing
microvascular flow impairment may be exacerbated by aggressive BP-lowering and/or thrombotic activation after ICH
and result in small ischemic infarcts.
Further support of an underlying microangiopathy in both
hemorrhagic and ischemic stroke comes from a recent report
of subclinical incident microhemorrhage occurrence (unrelated to hemorrhagic transformation) after acute ischemic
stroke. In a serial brain MRI study of 237 patients with
ischemic stroke, 12.7% of patients developed new microhemorrhages within days of the initial scan.41 A common microvascular disarray might underlie both hemorrhagic and ischemic stroke and promote a stroke-prone state after any acute
cerebrovascular insult.24 These may be mediated by endothelial dysfunction, active inflammation, and breakdown of the
blood brain barrier in ICH.42 We, therefore, speculate that
hypertensive and CAA-mediated changes in the microvasculature lead to hemorrhagic or ischemic stroke in isolation in
most patients but can occur in rapid sequence or simultaneously in some patients.
Other Mechanisms and Provoking Factors
As noted, ICP elevation in moderate- or large-volume hemorrhages or those associated with intraventricular hemorrhage

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Prabhakaran and Naidech

and hydrocephalus may lower the threshold for ischemia in
the setting of relatively modest but rapid BP-lowering.
Volume of ICH and intraventricular extension, probably as
surrogate markers of ICP, have been associated with DWI
lesions.30,31 Alternatively, many patients with ICH with
vascular risk factors may ingest antithrombotic agents and
harbor large-artery stenosis or cardiac sources of embolism at
baseline. Thus, ischemic stroke may simply be occurring in
high-risk patients in the setting of antiplatelet therapy
withdrawal.43
Another possibility is that frank hemorrhagic transformation of an embolic ischemic stroke may be misdiagnosed as
spontaneous ICH with remote DWI lesions providing evidence of embolism. This would unlikely explain such a large
proportion of patients with this finding, however. Other
unlikely mechanisms include local vascular compression due
to the mass effect from the hematoma. A small percentage of
patients also undergo craniotomy, during which low BPs,
anesthetic agents, manipulation of arteries, and thrombotic
activation with surgery may promote ischemia. Vasospasm,
which is common after subarachnoid hemorrhage, is not
known to occur after spontaneous ICH in the absence of an
unusual amount of subarachnoid blood or a reversible vasculopathy that may present with ischemic and hemorrhagic
stroke (ie, Call-Fleming or reversible cerebral vasoconstriction syndrome). Finally, given the delayed incident lesions at
1 month, there may be a period of thrombotic or inflammatory activation that leads to subclinical and clinical events
soon after ICH, like in other acute brain injury states. In
animal models of subarachnoid hemorrhage44 and traumatic
brain injury,45 platelets have been shown to aggregate and
cause mircrovascular occlusion due to an inflammatory prothrombotic environment.

Impact on Long-Term Outcomes

Given the data on the prevalence of ischemic lesions after
ICH, the next logical question is: do they matter? Silent brain
infarcts are frequently observed on brain imaging of elderly
individuals, serve as markers for the extent or severity of
cerebrovascular disease, and predict subsequent risk of stroke
and vascular dementia.46 48 Early subclinical DWI lesions
after acute ischemic stroke also increase the subsequent risk
of recurrent ischemic stroke, transient ischemic attack, and
vascular death.49 Silent infarcts may also interact with the
index infarct volume and worsen the degree of motor impairment in patients with stroke.50
Two longitudinal studies have evaluated the influence of
DWI lesions on subsequent functional outcomes after ICH.
At 3 months, those with DWI lesions were 5-fold more likely
to have poor functional outcomes (defined as modified
Rankin Scale score 4 6 indicating dependence or death)
adjusting for known predictors (age, initial stroke severity,
and ICH score).10 Another single-center study evaluated
outcomes at 1 year and noted that those with DWI lesions
were 6-fold more likely to have poor outcomes at follow-up
than those without, independent of stroke severity.51 A third
prospective study of 97 patients with ICH followed for
median 42 months demonstrated that DWI lesions signifi-

Acute Ischemic Infarcts After ICH

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cantly increased risks of ischemic stroke and combined

ischemic stroke, ICH, and vascular death.28
The mechanisms by which small ischemic lesions worsen
outcome after ICH are uncertain. These may reduce neuroplasticity and retard restorative ipsi- and contralesional synaptic networks. Some lesions may be strategically symptomatic but only become recognized after the initial clinical
presentation, influenced mostly by the hematoma itself,
recedes in the subacute period. Lastly, DWI lesions in ICH
may simply be markers for frail patients who are destined
for poor recovery and elevated risk of recurrent stroke.

Implications for Current Practice

These studies cumulatively support (1) a considerable (approximately 25%) prevalence of DWI lesions; (2) a strong
correlation with BP-lowering; and (3) a negative impact of
DWI lesions on functional outcomes after ICH. Thus, it may
be time to reconsider our approach to this disease and to
re-evaluate ongoing clinical trials aimed at BP-lowering after
ICH. Aggressive BP-lowering has become standard practice
at many centers at the time the pivotal clinical trials to
determine its clinical impact are still underway; a more
refined approach with careful titration of antihypertensive
therapy and using individualized targets may be necessary.
Randomized clinical trials of BP-lowering should incorporate
MRI to evaluate for secondary ischemic lesions and assess
their influence on functional outcomes. We postulate that
DWI lesions may modify the effect of BP-lowering on
functional outcomes after ICH such that it may be hazardous
in those with DWI lesions and beneficial in those without.

Future Directions
Given these potential implications and yet many open questions, it is imperative that research in this area continue. First,
imaging techniques including perfusion and functional imaging may help quantify the hemodynamic effects of acute
BP-lowering after ICH and evaluate the impact of silent
lesions on functional recovery. Second, serial MRI studies are
needed to define the timing of ischemic lesions because
subacute infarcts may be amenable to prevention. Third,
detailed outcomes assessments are currently lacking but
would provide insights into subtle cognitive or quality-of-life
effects not appreciated by crude outcome measures such as
the Rankin Scale. Fourth, pilot studies should assess the
prevalence of DWI lesions at different target BP levels and
the safety of ischemic stroke prevention strategies such as
aspirin and statin therapy after ICH.
New targets for therapeutic intervention in ICH are sorely
needed. Current guidelines for BP reduction and hemostatic
therapy to limit hematoma growth at the possible expense of
cerebral hypoperfusion and arterial thrombosis, respectively,
may be doing more harm than good. If an active biological
link between hemorrhagic and ischemic brain disease exists
and imaging-based techniques can identify those at risk for
either or both conditions, then the relative value of secondary
prevention strategies such as lipid-lowering, long-term BP
control, glycemic regulation, and antithrombotic agents gains
even greater importance for individualized application in
vulnerable patients. Early use of antiplatelet and statin ther-

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apies to prevent secondary neuronal injury during a proinflammatory, stroke-prone period even at the expense of
hemorrhage growth or recurrent hemorrhage may be more
beneficial than currently believed. Furthermore, risk factors
such as carotid artery stenosis, atrial fibrillation, and underlying hypercoagulable states may need to be considered in the
diagnostic evaluation of ICH. In summary, the emerging data
on secondary brain ischemia after ICH may offer a novel
therapeutic target for this deadly disease.

Source of Funding
Supported by American Heart Association Midwest Affiliate Grant
11CRP7520073 (S.P.).

Disclosures
None.

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KEY WORDS: blood pressure

weighted imaging

cerebral hematoma

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