PIS

66
Intracerebral Hemorrhage
Carlos S. Kase, Ashkan Shoamanesh
CHAPTER OUTLINE
MECHANISMS OF INTRACEREBRAL HEMORRHAGE
Hypertension
Vascular Malformations
Intracranial Tumors
Bleeding Disorders, Anticoagulants, and Fibrinolytic
Treatment
Cerebral Amyloid Angiopathy
Granulomatous Angiitis of the Central Nervous System
and Other Vasculitides
Sympathomimetic Agents
Hemorrhagic Infarction
Head Trauma
CLINICAL FEATURES OF INTRACEREBRAL HEMORRHAGE
Putaminal Hemorrhage
Caudate Hemorrhage
Thalamic Hemorrhage
Lobar Hemorrhage
Cerebellar Hemorrhage
Pontine Hemorrhage
Mesencephalic Hemorrhage
Medullary Hemorrhage
Intraventricular Hemorrhage
TREATMENT OF INTRACEREBRAL HEMORRHAGE
General Management of Intracerebral Hemorrhage
Choice Between Medical and Surgical Therapy in
Intracerebral Hemorrhage
Hemostatic Therapy of Intracerebral Hemorrhage
Intracerebral hemorrhage (ICH) accounts for approximately
10%–20% of strokes (O’Donnell et al., 2010). Its clinical
importance derives from its high frequency and 30-day mortality, which is close to 50%. The incidence of ICH has
remained stable in the past 3 decades (van Asch et al., 2010),
despite a gradually improved level of detection and treatment
of hypertension, suggesting that ICH due to other mechanisms, such as anticoagulant use, has become more frequent
(Flaherty et al., 2007). ICH continues to be a major public
health problem, especially in populations at high risk such as
young and middle-aged blacks and Hispanics, in whom ICH
occurs more frequently than in whites, the medically indigent
who lack hypertension treatment, and the elderly on antithrombotic therapy. A growing body of evidence suggests that
genetic factors such as possessing the ε2 and ε4 alleles of the
apolipoprotein E gene play an important role in the occurrence of certain forms of ICH such as lobar hemorrhages
(Greenberg et al., 2004). Novel potential genetic factors predisposing to ICH continue to be added by experimental, clinical, and genome-wide association studies (Gould et al., 2006).
Finally, the management of ICH is controversial as the assessment of various interventions awaits the completion of prospective clinical trials.
MECHANISMS OF INTRACEREBRAL
HEMORRHAGE
Hypertension
The main cause of ICH is hypertension. The primary role of
hypertension in ICH is supported by a high frequency (72%–
81%) of history of hypertension, significantly higher blood
pressure measurements at admission in comparison with
patients with other stroke subtypes, high frequency of left
ventricular hypertrophy, and over-representation of common
genetic variants associated with hypertension (Falcone et al.,
2012).
In one study of 188 patients with primary ICH (i.e., excluding patients with hemorrhage associated with ruptured arteriovenous malformations [AVMs], tumor, anticoagulant and
thrombolytic therapy, and cocaine ingestion), it was determined that the cause was hypertension in 72% of patients.
Similarly, a multicenter international study determined hypertension as the strongest risk factor for ICH, accounting for
74% of the population-attributable risk (O’Donnell et al.,
2010). Other modifiable risk factors for ICH included excessive smoking, alcohol intake, central obesity, low cholesterol
levels, unhealthy diet, and sedentary lifestyle. Further support
for the importance of hypertension in the pathogenesis of ICH
is the steady increase in ICH incidence with advancing age,
which is also associated with an increase in the prevalence of
hypertension. Furthermore, mean systolic pressure increases
steeply in the days leading to an ICH (Fischer et al., 2014).
The vascular lesion produced by chronic hypertension that
leads to arterial rupture and ICH is probably lipohyalinosis of
small intraparenchymal arteries. The role of microaneurysms
of Charcot and Bouchard is uncertain, although their anatomical location at sites preferentially affected by ICH supports their causal importance. The nonhypertensive causes of
ICH are listed in Box 66.1.
Vascular Malformations
Because a detailed discussion of intracranial aneurysms and
AVMs is provided elsewhere (see Chapter 67), the analysis is
limited here to the role of small vascular malformations in the
pathogenesis of ICH. These lesions are often documented by
magnetic resonance imaging (MRI), by pathological examination of specimens obtained at the time of surgical drainage of
ICHs, or at autopsy. However, cerebral angiography also plays
an important role in the diagnosis of these lesions.
ICHs caused by small AVMs or cavernous angiomas are
frequently located in the subcortical white matter of the cerebral hemispheres. The clinical presentation of the ICH in this
setting has a few distinctive characteristics: the hematoma is
generally smaller, and symptoms develop more slowly than
with hypertensive ICH; the presence of associated subarachnoid hemorrhage on CT scan suggests an aneurysm or AVM
as the cause of a lobar ICH; and ICHs associated with small
vascular malformations generally tend to occur in younger
patients than those with hypertensive ICH, and have a female
preponderance.
Cavernous angiomas are often recognized by MRI as a
cause of ICH in the subcortical portions of the cerebral
968
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Intracerebral Hemorrhage
BOX 66.1 Nonhypertensive Causes of
Intracerebral Hemorrhage
Vascular malformations (saccular or mycotic aneurysms,
arteriovenous malformations, cavernous angiomas)
Intracranial tumors
Bleeding disorders, anticoagulant and fibrinolytic treatment
Cerebral amyloid angiopathy
Granulomatous angiitis of the central nervous system and other
vasculitides, such as polyarteritis nodosa
Sympathomimetic agents (including amphetamine and cocaine)
Hemorrhagic infarction
Head trauma
Miscellaneous: other vasculopathies (e.g., moyamoya disease,
reversible cerebral vasoconstriction syndrome, cerebral
autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy [rarely]), and septic emboli/arteritis in the
setting of infective endocarditis (all discussed elsewhere)
969
individuals of Mexican descent, in whom cavernous angiomas
are inherited in an autosomal dominant pattern linked to a
mutation in gene CCM1 in chromosome 7q (Gault et al.,
2006). Cavernous angiomas manifest with seizures (27%–
70%), ICH (10%–30%), or focal neurological deficits (29%–
35%). ICH occurs in both the supratentorial and infratentorial
varieties. A progressive course due to recurrent small hemorrhages within and around the malformation is occasionally
seen in posterior fossa (especially pontine) lesions, and the
deficits can evolve over protracted periods, at times suggesting
a diagnosis of multiple sclerosis or a slowly growing brainstem
tumor.
A clinical profile thus can be suggested for cases of ICH due
to small vascular malformations. These occur in generally
young, predominantly female patients who present with a
syndrome of lobar ICH in which CT may document a superficial lobar hematoma with adjacent local subarachnoid hemorrhage, or MRI demonstrates the characteristic features of a
small AVM or cavernous angioma. Lack of documentation of
the vascular malformation on angiography is the rule—
especially in the slow-flow cavernous angiomas—and definite
diagnosis requires either MRI or the histological examination
of a sample of the hematoma and its wall.
The overall annual rate of ICH in persons with cavernous
angiomas is 0.15–6%, with higher rates reported in persons
initially manifesting with hemorrhage and lower rates in incidental cases found on neuroimaging (Al-Shahi Salman et al.,
2012; Flemming et al., 2012). The risk of recurrent hemorrhage
is highest in the first 2 years following initial ICH and occurs
more frequently in women.
Intracranial Tumors
Fig. 66.1 Magnetic resonance imaging (proton density) of large
cavernous angioma of the midpons in axial view, showing mixedsignal central nidus with peripheral hemosiderin ring.
hemispheres and in the pons. This technique demonstrates
a characteristic pattern on T2-weighted images, with a central
nidus of irregular bright signal intensity mixed with mottled
hypointensity (the “popcorn” pattern), surrounded by a peripheral hypointense ring corresponding to hemosiderin deposits
(Fig. 66.1), reflecting previous episodes of blood leakage at
the edges of the malformation. These lesions are predominantly supratentorial, favoring the temporal, frontal, and
parietal lobes, whereas the less frequent infratentorial locations favor the pons. They are generally single lesions, but
multiplicity is not rare, especially in patients with familial
cavernous angiomas. Familial clustering is common among
Bleeding into an underlying brain tumor is relatively rare in
series of patients presenting with ICH, accounting for less than
10% of the cases. The tumor types most likely to lead to this
rare complication are glioblastoma multiforme or metastases
from melanoma, bronchogenic carcinoma, choriocarcinoma,
or renal cell carcinoma (Fig. 66.2). The ICHs produced in this
setting may have clinical and imaging characteristics that
should suggest an underlying brain tumor, including: (1) the
presence of papilledema on presentation, (2) the location of
ICH in sites that are rarely affected in hypertensive ICH, such
as the corpus callosum, which in turn is commonly involved
in malignant gliomas (Fig. 66.3), (3) the presence of ICH in
multiple sites simultaneously, (4) a CT scan characterized by
a ring of high-density hemorrhage surrounding a low-density
center in a noncontrast study, (5) enhancing nodules adjacent
to the hemorrhage on contrast CT or MRI, and (6) a disproportionate amount of surrounding edema and mass effect
associated with the acute hematoma. In these circumstances,
a search for a primary or metastatic brain tumor should follow
and include evaluation for systemic malignancy; if there is
none, cerebral angiography and eventually craniotomy for
biopsy of the wall of the hematoma cavity should be considered. Confirmation of the diagnosis of ICH secondary to
malignant brain tumor carries a dismal prognosis, with a
30-day mortality rate in the 90% range.
Bleeding Disorders, Anticoagulants, and
Fibrinolytic Treatment
Bleeding disorders due to abnormalities of coagulation are
rare causes of ICH. Hemophilia caused by factor VIII deficiency leads to ICH in approximately 2.5% to 6.0% of
patients, half with ICH and half with subdural hematomas.
The majority of these hemorrhages occur in young patients,
generally younger than age 18, and their mortality is high,
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66
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PART III Neurological Diseases and Their Treatment
A
B
C
Fig. 66.2 Computed tomography scan (A) and magnetic resonance imaging FLAIR sequence (B) of hemorrhage in left cerebellar hemisphere,
showing moderate amount of surrounding edema in patient with history of lung cancer. C, Highly cellular pleomorphic metastatic tumor with
multiple mitoses documented in biopsy of residual cavity after drainage of intracranial hemorrhage (H&E, ×20).
B
A
C
Fig. 66.3 Noncontrast CT scan of acute hemorrhage into the deep white matter of the left parietal lobe with extension into the corpus callosum
and across the midline (A), due to glioblastoma multiforme with high cellularity, pleomorphism, and endothelial proliferation (B, H&E, ×20), as
well as giant cells with atypical mitoses (C, H&E, ×100).
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Intracerebral Hemorrhage
about 10% for subdural hematomas and 65% for ICH.
Immune-mediated thrombocytopenia, especially idiopathic
thrombocytopenic purpura, is associated with life-threatening
ICH in approximately 1% of patients. Bleeding occurs when
the platelet count drops below 10,000/µL, and the hemorrhages may occur anywhere in the brain. Acute leukemia,
especially the acute lymphocytic variety, is a common cause
of ICH that favors the lobar white matter of the cerebral
hemispheres. The occurrence of ICH frequently coincides
with systemic bleeding, mostly mucocutaneous and gastrointestinal. These bleeding complications of acute lymphocytic
leukemia are often accompanied by both thrombocytopenia
(platelet counts of 50,000/µL or less) and rapidly increasing
numbers of abnormal circulating leukocytes of 300,000/µL
or more (blastic crisis). Acute promyelocytic leukemia, a
variant of acute myelogenous leukemia, has a particular propensity to produce ICH secondary to disseminated intravascular coagulation.
Treatment with oral anticoagulants increases the risk of
ICH by 8- to 11-fold compared with individuals with otherwise similar risk factors for ICH who are not receiving anticoagulants. Anticoagulant-related cases account for 9% to 14%
of ICH (Pezzini et al., 2014). Potential risk factors for intra­
cranial bleeding in patients receiving anticoagulants include
advanced age, hypertension, preceding cerebral infarction,
head trauma, and excessive prolongation of the International
Normalized Ratio (INR). The last factor plays a major role in
the pathogenesis of ICH in patients receiving vitamin K antagonists. In the secondary stroke prevention trial SPIRIT (Stroke
Prevention in Reversible Ischemia Trial), 651 patients assigned
to warfarin treatment were maintained at an INR of 3.0 to 4.5,
resulting in 24 instances of ICH (14 fatal), in comparison with
3 ICHs (1 fatal) in the group of 665 patients treated daily with
30 mg of aspirin (SPIRIT Study Group, 1997). These data
further support the recommendation that oral anticoagulation
in patients with cerebrovascular disease should aim at an INR
of 2 to 3 to reduce the frequency of this complication. The
presence of severe leukoaraiosis and cerebral microbleeds
(CMBs) on neuroimaging are additional factors that independently increase the risk of ICH in patients on vitamin K
antagonists (Lovelock et al., 2010).
These hemorrhages have certain distinctive clinical characteristics: they tend to present with a slowly progressive
course, at times over periods as long as 48 to 72 hours, in
contrast with the usually more rapidly evolving presentation
of hypertensive ICH; hematomas in patients receiving anticoagulants expand and reach volumes that are, on average,
larger than those occurring in hypertensive ICH, in turn
resulting in the higher mortality rate of approximately 65%;
signs of systemic bleeding rarely accompany ICH in this
setting. Anticoagulant-related ICH may represent bleeding
from vessels different from those involved in ICH of hypertensive origin. Certain angiopathies with bleeding potential,
such as cerebral amyloid angiopathy (CAA), may play a
causal role in the ICHs that occur in patients treated with
anticoagulants (Falcone et al., 2014; Lovelock et al., 2010).
The available data largely pertain to oral anticoagulation
with warfarin and it is uncertain whether the recently
approved novel oral anticoagulants (NOACs; direct thrombin
or factor Xa inhibitors) will have similar or more favorable
profiles. Randomized controlled trials have shown lower ICH
rates amongst the NOACs in comparison to warfarin therapy
in the management of nonvalvular atrial fibrillation. The
specific targeting of the novel agents of a single factor within
the coagulation cascade (factor Xa or IIa [thrombin]), rather
than the inhibition of four vitamin K-dependent factors (II,
VII, IX, and X) by warfarin, has been speculated to account
for these differences.
971
In addition to the anticoagulants, other substances with the
potential for altering clot formation mechanisms are occasionally associated with ICH. These include drugs with fibrinolytic
properties, such as streptokinase and tissue plasminogen activator (tPA). There is evidence to suggest that this complication
of thrombolytic therapy may be favored by pre-existing vasculopathies with bleeding potential such as CAA. Recombinant
tPA for the treatment of acute ischemic stroke was complicated
by ICH in 6.4% of cases (NINDS rtPA Stroke Study Group,
1995), which is 10 times the rate found in the placebo group.
Risk factors for ICH in this setting include a severe neurological deficit at presentation and documentation of hypodensity
or mass effect on CT before treatment (NINDS tPA Stroke
Study Group, 1997). Intra-arterial thrombolysis with prouro­
kinase for middle cerebral artery occlusion leads to improved
clinical outcomes but is associated with an 11% rate of early
symptomatic ICH (Furlan et al., 1999). These hemorrhages
occur at the site of the preceding cerebral infarct, are generally
large (Fig. 66.4), and carry a dismal prognosis (Kase et al.,
2001). Hyperglycemia at pretreatment baseline has been identified as a potential risk factor for ICH in patients treated with
either intra-arterial prourokinase (Kase et al., 2001) or intravenous (IV) tPA (Poppe et al., 2009) for acute ischemic stroke.
Additional risk factors for post-thrombolysis ICH include
post-thrombolysis elevated blood pressure (Butcher et al.,
2010), baseline dual antiplatelet therapy with aspirin and
clopidogrel (Diedler et al., 2010), and the presence of
leuko­araiosis.
Another potential risk factor for ICH after thrombolysis is
the presence of incidental CMBs, which can be easily detected
with gradient echo or susceptibility-weighted MRI sequences
(Fig. 66.5). A recent study showed that acute stroke patients
with multiple CMBs (greater than 2) have higher ICH rates and
worse outcomes following IV tPA (Dannenberg et al., 2014).
These findings are in keeping with a previous systematic review
where pooled analysis of 790 patients suggested that individuals with CMBs are at higher risk of post-thrombolysis ICH,
particularly those with higher lesion burden (Shoamanesh
et al., 2013).
CMBs are characterized pathologically by small areas of
previous bleeding, in the form of hemosiderin-laden macrophages, and often represent the presence of a bleeding-prone
microangiopathy, most commonly hypertensive arteriopathy
or CAA (Shoamanesh et al., 2011). The role of CMBs in predicting ICH after use of anticoagulants, antiplatelet agents,
and thrombolytics has, however, yet to be clearly defined by
prospectively collected data. As a result, no firm recommendations can be given at present for using or withholding these
treatment options based solely on the presence of these often
incidentally detected lesions (Charidimou et al., 2012b).
Cerebral Amyloid Angiopathy
CAA is characterized by selective deposition of β-amyloid in
the walls of cerebral vessels, primarily small and mediumsized arteries of the cortex and leptomeninges. Because the
frequency of CAA increases steadily with age, reaching 60% in
unselected autopsies of individuals older than 90 years, it
characteristically causes ICH in the elderly and is rarely documented before the age of 55 years. In addition, the superficial
location of the affected vessels in the cortex and leptomeninges is responsible for a predominantly lobar location of ICH.
The widespread character of the angiopathy is responsible for
the observation of both recurrent and multiple simultaneous,
predominantly lobar, hemorrhages in elderly patients. An
additional characteristic of CAA is its association with histopathological features of Alzheimer disease. There is clinical
and progressive dementia in 10% to 30% of patients with CAA
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66
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PART III Neurological Diseases and Their Treatment
Controls
Fig. 66.4 Symptomatic intracerebral hemorrhages after intra-arterial thrombolysis of middle cerebral artery occlusion with prourokinase.
(Reprinted with permission from Kase, C.S., Furlan, A.J., Wechsler, L.R., et al., 2001. Cerebral hemorrhage after intra-arterial thrombolysis for
ischemic stroke: the PROACT II Trial. Neurology 57, 1603–1610.)
and neuritic plaques in approximately 50% of cases. CAA may
present with features other than ICH, such as episodes of
transient focal neurological deficit clinically suggestive of
either transient ischemic attacks or partial seizures. These
often occur days, weeks, or months before an episode of major
lobar ICH and may correlate with convexal subarachnoid
hemorrhage, cortical superficial siderosis (Fig. 66.6), or possibly CMBs (Charidimou et al., 2012a).
The histological lesion in CAA is deposition of Congo redpositive, birefringent amyloid material in the media and
adventitia of small cortical and leptomeningeal arteries. The
actual mechanism of rupture of an affected artery may be
either a weakening of the wall or formation of microaneurysms at sites of amyloid deposition, particularly in advanced
cases with fibrinoid necrosis and concentric splitting of the
vessel with the characteristic “double-barrel” appearance.
Other conditions may combine with CAA to produce rupture
of affected vessels, including head trauma, neurosurgical
procedures, concomitant granulomatous angiitis of the central
nervous system (CNS), and use of antithrombotic and fibrinolytic agents.
Granulomatous Angiitis of the Central Nervous
System and Other Vasculitides
Granulomatous angiitis of the CNS, also referred to as isolated
angiitis of the CNS, is characterized by mononuclear inflammation with giant cell formation in the media and adventitia
of small and medium-sized intracranial arteries and veins (see
Chapter 70). An associated element of intimal hyperplasia
leads frequently to cerebral infarcts and occasionally to ICH.
Among the vasculitides, the other variety that is known to
present with ICH is polyarteritis nodosa. As opposed to granulomatous angiitis of the CNS, this form of necrotizing vasculitis depicts prominent signs of systemic involvement including
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Intracerebral Hemorrhage
973
66
A
B
C
D
Fig. 66.5 Magnetic resonance imaging T2* susceptibility-weighted sequence with multiple, strictly lobar, CMBs in subject with cerebral amyloid
angiopathy (A and B), and multiple predominantly deep CMBs in a subject with hypertensive arteriopathy (C and D).
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974
PART III Neurological Diseases and Their Treatment
*
*
*
B
A
*
*
*
*
C
fever, malaise, weight loss, anemia, elevated erythrocyte sedimentation rate, and renal impairment with hypertension (see
Chapter 58).
Sympathomimetic Agents
Sympathomimetic agents can cause ICH after IV, oral, or intranasal use (see Chapter 86). The hemorrhages usually occur
within minutes to a few hours after drug use, and the majority
Fig. 66.6 Magnetic resonance imaging in an 84-year-old woman
presenting with confusion and word finding difficulty. FLAIR
sequence (A) demonstrates bihemispheric convexal subarachnoid hemorrhage (asterisks) and susceptibility-weighted imaging (B, C) shows
multiple cortical cerebral microbleeds (arrows, B), and areas of cortical
superficial siderosis (asterisks, C) suggestive of prior occult convexal
subarachnoid hemorrhage. This constellation of findings is highly suggestive of cerebral amyloid angiopathy.
are located in the subcortical white matter of the cerebral
hemispheres. In approximately half of reported cases, transient hypertension has been documented, as well as multifocal
areas of spasm and dilatation (“beading”) of intracranial arteries on angiography. Although the latter is frequently referred
to as a vasculitis or arteritis, histological proof is lacking, and
this angiographic picture probably represents multifocal
spasm secondary to the drug. The decongestant and appetitesuppressant, phenylpropanolamine, has been associated with
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Intracerebral Hemorrhage
ICH in young patients (median age in the early 30s), predominantly women (Kernan et al., 2000), usually without a history
of hypertension but with acute hypertension on admission in
a third of patients. Beading of intracranial arteries is frequent
on angiography.
Cocaine (see Chapter 86) has become the most common
sympathomimetic agent associated with ICH. Both ICH and
subarachnoid hemorrhage can occur within short periods
(generally minutes) of the use of both the alkaloid (free-base)
form of cocaine and its precipitate form, known as crack. The
ICHs favor the subcortical white matter but occasionally occur
in the deep portions of the hemispheres (Fig. 66.7). There may
be multiple simultaneous ICHs, both deep and superficial, the
mechanism of which remains unknown. In some instances,
975
the origin of the ICH can be traced to a coexistent AVM or
aneurysm, whereas the remainder are probably associated
with either cocaine-induced vasoconstriction followed by
reperfusion, concomitant heavy alcohol intake, or (rarely) a
drug-induced cerebral vasculitis.
Hemorrhagic Infarction
Hemorrhagic infarction is pathologically and pathogenically
different from ICH in that it results from restoration of blood
flow to infarcted tissue that had previously ensued from arterial or venous occlusion. As a result, its pathological aspect is
one of multifocal petechial hemorrhagic staining of an area of
the brain primarily affected by ischemic necrosis (i.e., infarction) (Fig. 66.8). Hemorrhagic infarction characteristically
occurs in the setting of cerebral embolism, or rarely following
restoration of cerebral perfusion to borderzone infarcts that
had resulted from global hypoperfusion, such as in the case
of cardiac arrest. Cerebral infarction secondary to venous
occlusion (e.g., thrombosis of superior sagittal sinus or cortical veins) is also frequently hemorrhagic as a result of venous
stasis in the necrotic area. In all these instances of hemorrhagic
infarction, the bleeding reflects the mechanism of the infarct
and is not due to therapeutic measures such as use of anticoagulant drugs.
Clinical differences between hemorrhagic infarction and
ICH usually permit their clear distinction (Table 66.1), but
severe and confluent foci of hemorrhagic infarction may at
times be difficult to distinguish from foci of primary ICH.
Head Trauma
ICH caused by cerebral contusion characteristically occurs in
the surface of the brain, because its mechanism is one of direct
brain trauma against its bony covering at the time of an
acceleration–deceleration head injury (see Chapter 62). This
explains the sites of predilection for traumatic brain hemorrhages in the basal frontal, anterior temporal, and occipital
areas, resulting from the coup and contrecoup mechanisms of
injury. Thus, traumatic brain hemorrhages are frequently
multiple.
CLINICAL FEATURES OF INTRACEREBRAL
HEMORRHAGE
Fig. 66.7 Left putaminal hemorrhage after use of crack cocaine.
(Courtesy Susan S. Pansing, MD.)
A
B
The clinical presentation of ICH has two main elements:
symptoms that reflect the effects of intracranial hypertension
and those that are specific for the location of the hematoma.
C
Fig. 66.8 A, Left hemispheric hemorrhagic infarction in the territory of the middle cerebral and anterior cerebral arteries as a result of intracranial
internal carotid artery embolic occlusion. B, Left anterior cerebral artery distribution hemorrhagic infarction. C, Small hemorrhagic infarction in the
left medial occipital (calcarine) cortex due to embolic occlusion of distal branch of the posterior cerebral artery.
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66
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PART III Neurological Diseases and Their Treatment
TABLE 66.1 Differences between Intracerebral Hemorrhage and
Hemorrhagic Infarction
Intracerebral
hemorrhage
Hemorrhagic
infarction (embolic)
Onset of deficit
Sudden, followed
by progression
Maximal from onset
Raised intracranial
pressure
Prominent
Absent
Embolic source
No
Yes
Dense,
homogeneous
Spotted, mottled
CLINICAL
COMPUTED TOMOGRAPHY
High attenuation
Mass effect
Prominent
Absent or mild
Location
Subcortical, deep
(gray nuclei)
Cortex more than
subcortical white
matter
Distribution
Beyond arterial
territories
Along branch
distribution
Late enhancement
Ring-type
Gyral-type
Ventricular blood
Yes
No
MAGNETIC RESONANCE IMAGING*
Hypointense blood (T2)
Homogeneous
Patchy, mottled
Hyperintense edema
(T2)
Thin peripheral
halo
Extensive, in vascular
territory
ANGIOGRAM/MAGNETIC RESONANCE ANGIOGRAPHY
Characteristics
Mass effect
(avascular)
Branch occlusion
*Magnetic resonance imaging (MRI) depicts the same features as
computed tomography (CT) in regard to mass effect, location,
distribution, late enhancement, and ventricular blood. This table
lists only the features MRI adds to those of CT.
Reprinted with permission from Kase, C.S., Mohr, J.P., Caplan, L.R.,
2004. Intracerebral hemorrhage. In: Mohr, J.P., Choi, D.W., Grotta,
J.C., et al. (Eds), Stroke: Pathophysiology, Diagnosis, and
Management, fourth edn. Churchill Livingstone, Philadelphia.
A
The general clinical manifestations of ICH related to increased
intracranial pressure (ICP) (headache, vomiting, and depressed
level of consciousness) vary in their frequency at onset of
ICH. The correlation of these symptoms (especially abnormal
level of consciousness) with hematoma size applies to all
anatomical varieties of ICH, which in turn relates directly to
mortality.
A characteristic of ICH at presentation is the frequent progression of focal neurological deficits over periods of hours.
This early course reflects progressive enlargement of the
hematoma (Fig. 66.9), which at times amounts to volume
increments of more than 300% as measured by serial CT scans
(Demchuk et al., 2012). The presence of small foci of contrast
extravasation, referred to as the spot sign, during CT angiography (CTA) in patients with acute ICH is predictive of hematoma
enlargement (Goldstein et al., 2007; Wada et al., 2007). When
CTA is performed within the first few hours post ICH onset,
the presence of the spot sign (Fig. 66.10) correlates with a
frequency of hematoma enlargement in up to 77% of patients,
compared to only 4%–22% in patients without the sign
(Demchuk et al., 2012; Wada et al., 2007). Further data have
shown that features such as number of spot signs (>3),
maximal diameter (>5 mm), and maximal attenuation (>180
Hounsfield units) are independent predictors of hematoma
expansion (Thompson et al., 2009).
MRI adds further precision to the diagnosis of ICH, especially in determining the time elapsed between onset and time
of MRI examination. The type of signal intensity change
depicted by T1- and T2-weighted MRI sequences can be correlated with the hyperacute, acute, subacute, and chronic
stages of evolution of an intracerebral hematoma (Table 66.2).
Physical examination findings that relate to the different
anatomical locations of ICH are summarized in Table 66.3.
Putaminal Hemorrhage
The most common variety of ICH, putaminal hemorrhage,
represents approximately 35% of cases (Kase et al., 2011)
(eFig. 66.11). A wide spectrum of clinical severity relates to
hematoma size, from minimally symptomatic cases presenting with pure motor hemiparesis or slight hemiparesis and
B
Fig. 66.9 A, Basal-tegmental pontine hemorrhage at the time of admission. B, Massive enlargement of hemorrhage with extension into the fourth
ventricle and hydrocephalus of temporal horns, 6 hours later.
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Intracerebral Hemorrhage
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eFig. 66.11 Right putaminal hemorrhage.
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Intracerebral Hemorrhage
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66
A
B
C
Fig. 66.10 “Spot sign” in intracerebral hemorrhage. Baseline (A) and 24-hour (C) noncontrast CT scans show expansion of a right caudate
hemorrhage with ventricular extension. CT angiography at baseline (B) shows an area of contrast extravasation (“spot sign”) suggestive of ongoing
bleeding (arrow). (From Demchuk, A.M., Dowlatshahi, D., Rodriguez-Luna, D., et al., 2012. Prediction of haematoma growth and outcome in
patients with intracerebral haemorrhage using the CT-angiography spot sign (PREDICT): a prospective observational study. Lancet Neurol
11, 309.)
TABLE 66.2 Temporal Changes in Magnetic Resonance Imaging
Features of Intracerebral Hemorrhage
Stage of
intracerebral
hemorrhage
Magnetic resonance imaging signal intensity
Type of Hemoglobin
T1Weighted
T2Weighted
First hours
Oxyhemoglobin
Same or ↓
↑
Hours to days
Deoxyhemoglobin
Same or ↓
↓↓
First days
Methemoglobin,
intracellular
↑
Several days to
months
Methemoglobin,
extracellular
↑↑
↑↑
Several days to
indefinitely
Ferritin/hemosiderin
Same or ↓
↓↓
↓
Same, Equal signal with surrounding brain; ↓, hypointense to brain;
↑, hyperintense to brain; ↓↓, marked hypointensity; ↑↑, marked
hyperintensity.
absent. At times, the main manifestations of caudate ICH are
neuropsychological deficits including abulia, disorientation,
and memory disturbances, occasionally accompanied by language disturbances (Kase, 2010). The main differential diagnosis of caudate ICH is ruptured anterior communicating
artery aneurysm with bleeding through the septum pellucidum into the ventricular system. In this instance, CT shows
blood in the interhemispheric fissure and in the lowermost
frontal cuts, as opposed to the higher location of the unilateral
clot in the head of one caudate nucleus in primary caudate
ICH. Ventricular extension of the hemorrhage is a regular
feature in caudate ICH, and hydrocephalus is usually present.
Nevertheless, the outcome is generally good. The majority of
patients recover without neurological sequelae, although at
times neuropsychological deficits persist.
Thalamic Hemorrhage
dysarthria, to the extreme of coma with decerebrate rigidity in
instances of massive hematomas with rupture into the ventricles. Modern CT series of putaminal hemorrhage document a
mortality rate of 37%, in contrast to 65% to 75% from pre-CT
data. This difference reflects the description of the full spectrum of hematoma size in recent reports, including smaller
hematomas with benign outcomes, which were misdiagnosed
as infarcts in the pre-CT era. Ventricular extension carries an
invariably poor prognosis in putaminal hemorrhage.
Thalamic hemorrhage represents 10% to 15% of ICH cases
(Kase et al., 2011) (eFig. 66.13). Its onset tends to be more
abrupt than that of putaminal hemorrhage, and slow progression of deficits is less common. These features may reflect early
communication of the medially located hematoma with the
third ventricle. The prognosis in thalamic hemorrhage relates
to hematoma size and level of consciousness at presentation
(Kase, 2010). Another reliable sign of poor prognosis in thalamic ICH is the presence of hydrocephalus, an occasional
complication that can occur abruptly secondary to aqueductal
obstruction by an intraventricular clot, with potential for a
reversal of symptoms by ventriculostomy.
Caudate Hemorrhage
Lobar Hemorrhage
Caudate hemorrhage is a rare variety of ICH that accounts for
only approximately 5% of cases (Kase et al., 2011) (Fig. 66.12).
It results from rupture of penetrating arteries from the anterior
and middle cerebral arteries, and its most common cause is
hypertension. Presentation is similar to that of subarachnoid
hemorrhage in that the clinical picture is dominated by signs
of intracranial hypertension and meningeal irritation, with
focal neurological deficits (hemiparesis, horizontal gaze palsy,
Horner syndrome) being minimal and transient or altogether
Lobar hemorrhage is second to putaminal hemorrhage in frequency, accounting for approximately 25% of ICH cases (Kase
et al., 2011) (eFig. 66.14). Nonhypertensive mechanisms
including AVMs, sympathomimetic agents (in young patients),
and CAA (in elderly patients) are frequent causes. The peripheral (subcortical) location of these hematomas explains the
lower frequency of coma at onset, as compared with the deep
ganglionic forms of supratentorial ICH. Although seizures at
the time of presentation of ICH are rare, they occur in as many
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Intracerebral Hemorrhage
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eFig. 66.13 Right
extension.
thalamic
hemorrhage
with
ventricular
eFig. 66.14 Right parieto-occipital lobar hemorrhage.
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Hemiplegia
Generally dense
Absent or mild,
transient
Generally dense
Prominent in
frontoparietal
location
Absent
Variable, usually
bilateral
Variable, usually
present
Generally absent
Generally absent
Type of
intracerebral
hemorrhage
Putaminal
Caudate
Thalamic
Lobar
Cerebellar
Pontine
Mesencephalic
Medullary
Intraventricular
Rare
Occasional
Rare
Variable,
usually
bilateral
Absent
Prominent in
frontoparietal
location
Frequent,
prominent
Absent
Frequent
Hemisensory
syndrome
No
No
No
No
No
In dominant
temporoparietal
location
Occasional, thalamic
variety
No
Global>motor>conduction
Aphasia
TABLE 66.3 Clinical Features of Anatomic Forms of Intracerebral Hemorrhage
No
No
No
No
No
In occipital
hematomas
In large
hematomas
No
In large
hematomas
Homonymous
Visual Defects
Occasional
No
No
Bilateral
Ipsilateral
Contralateral in frontal
hematomas
Contralateral, occasionally
ipsilateral
Generally absent
Contralateral
Horizontal
Occasional
No
Occasional, upward
No
No
No
Yes, upward
No
No
Vertical
Gaze palsy
Rare (decerebrate rigidity)
Nystagmus, ataxia,
hiccups, facial
hypesthesia, dysarthria,
dysphagia, twelfth nerve
palsy, Horner syndrome
Unilateral or bilateral third
nerve palsy
Pinpoint reactive pupils,
ocular “bobbing,”
decerebrate rigidity,
respiratory rhythm
abnormalities
Ipsilateral fifth through
seventh nerve palsy,
Horner syndrome
No (only present with
herniation)
Skew deviation, Horner
syndrome, Parinaud
syndrome
No
No (only present with
herniation)
Brainstem Signs
978
PART III Neurological Diseases and Their Treatment
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Intracerebral Hemorrhage
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66
Fig. 66.16 Large tegmental basal pontine hemorrhage with
hydrocephalus of temporal horns.
Fig. 66.12 Left caudate hemorrhage with extension into the
lateral ventricles.
features of hydrocephalus, hematomas of 3 cm or more in
diameter, and effacement of the quadrigeminal cistern.
Pontine Hemorrhage
as 28% of patients with lobar ICH. The clinical features reflect
location: hemiparesis of upper limb predominance in frontal
hematomas, sensorimotor deficit and hemianopia in parietal
hemorrhages, fluent aphasia with relatively preserved repetition in dominant temporal hematomas, and homonymous
hemianopia in occipital lobe hemorrhages. The mortality rate
in individuals with lobar ICH is lower than in those with
hematomas in other locations, and the long-term functional
outcome may also be better.
Cerebellar Hemorrhage
Cerebellar hemorrhage represents approximately 5% to 10%
of ICH cases (Kase et al., 2011) (eFig. 66.15). Its clinical presentation is characteristic, with abrupt onset of vertigo, headache, vomiting, and inability to stand and walk, but absence
of hemiparesis or hemiplegia. The physical findings that allow
its clinical diagnosis are the triad of appendicular ataxia, horizontal gaze palsy, and peripheral facial palsy, all ipsilateral to
the hemorrhage.
The clinical course in cerebellar hemorrhage can be difficult to predict at onset. There is a notorious tendency for
abrupt deterioration to coma and death after a period of clinical stability under hospital observation. This unpredictable
course has stimulated a search for early clinical or CT signs
that may separate patients with benign outcome from those
who deteriorate clinically with the onset of brainstem compression and a high likelihood of mortality. These include
clinical evidence of compromise of brainstem function, CT
Pontine hemorrhage represents approximately 5% of ICH
cases (Kase et al., 2011) (Fig. 66.16). The massive bilateral
basal-tegmental variety produces the classic picture of coma,
quadriplegia, decerebrate posturing, horizontal ophthalmoplegia, ocular bobbing, pinpoint reactive pupils, abnormalities of respiratory rhythm, and preterminal hyperthermia.
Since the introduction of CT and MRI, less severe forms
of pontine hemorrhage that are compatible with survival
are recognized. These hemorrhages are frequently located in
the tegmentum, lateral to the midline, and thus produce
syndromes of predominantly unilateral dorsal pontine involvement (“one-and-a-half” syndrome [see Chapter 21], internuclear ophthalmoplegia, fifth and seventh nerve palsies), with
variable degrees of long-tract interruption. These hematomas
result from rupture of distal tegmental branches of a long
circumferential artery originating from the basilar trunk.
Mesencephalic Hemorrhage
Mesencephalic hemorrhage is exceptionally rare (Kase et al.,
2011). The causal mechanism was hypertension or ruptured
AVM in half of the reported cases, the others being of
undetermined cause. Occasional unilateral hematomas (eFig.
66.17) can present with ipsilateral third nerve palsy, cerebellar
ataxia, and contralateral hemiparesis. Bilateral cases frequently
have prominent tectal-tegmental signs, with bilateral ptosis,
paralysis of upward gaze, and small pupils with light-near
dissociation (see Chapter 21). Often patients survive without
surgical treatment, but with persistent sequelae.
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Intracerebral Hemorrhage
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eFig. 66.15 Large midline and left-sided hemispheric cerebellar
hemorrhage.
eFig. 66.17 Gradient echo (T2) magnetic resonance image of left
tegmental midbrain hemorrhage.
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980
PART III Neurological Diseases and Their Treatment
Medullary Hemorrhage
TREATMENT OF INTRACEREBRAL HEMORRHAGE
Examples of pure primary ICH involving the medulla alone
(eFig. 66.18) are rare, with most reported cases representing
medullary extension of caudal pontine hematomas. The clinical presentation of primary medullary hemorrhage reflects the
location of the lesion on one-half of the medulla, generally
extending beyond the dorsolateral region, both medially
(resulting in ipsilateral hypoglossal nerve palsy) and ventrally
(resulting in contralateral hemiparesis). These two features
distinguish most examples of medullary hemorrhage from the
classical presentations of Wallenberg lateral medullary syndrome, caused by infarction rather than hemorrhage (see
Chapter 21).
Issues related to treatment of ICH have been dominated by
two main considerations: (1) the type and intensity of medical
interventions required to improve the functional and vital
prognosis and (2) the choice between medical and surgical
therapy. These two issues are discussed separately.
Intraventricular Hemorrhage
Extension of hemorrhage into the ventricular system is a
common feature of caudate and thalamic hemorrhages and of
large putaminal and lobar hemorrhages. As a primary form
not associated with a component of intraparenchymal bleeding, intraventricular hemorrhage is rare, accounting for only
about 3% of ICHs. The site of origin of the hemorrhage is
thought to be the vasculature of the subependymal region,
and rarely the source can be identified in the choroid plexus.
The causes of intraventricular hemorrhage are similar to
those of ICH elsewhere, including hypertension, aneurysm,
AVM, coagulation disorders, cerebral tumors, cocaine use,
and rare vasculopathies such as moyamoya disease. Those
from aneurysm rupture are generally due to an anterior communicating artery aneurysm that ruptures in an upward direction, bleeding directly into one of the lateral ventricles; in
these instances, basal frontal subarachnoid hemorrhage and
interhemispheric hemorrhage accompany the intraventricular
hemorrhage and should always suggest a ruptured aneurysm.
AVMs that cause purely intraventricular hemorrhage are generally small and located in the medial aspect of the basal
ganglia or thalamus. Rarely, an intraventricular AVM or
cavernous angioma may cause a primary intraventricular
hemorrhage.
The clinical presentation of intraventricular hemorrhage is
with acute onset of headache, nausea, vomiting, and decreased
level of consciousness, with focal neurological deficits either
minimal or altogether absent (Flint et al., 2008). This presentation is identical to that of subarachnoid hemorrhage from
ruptured aneurysm or AVM. If focal deficits such as hemiparesis or ocular motor disturbances are prominent, the picture is
not strictly that of a pure intraventricular hemorrhage but
rather one of primary ICH with ventricular extension.
Intraventricular hemorrhage can be diagnosed reliably with
CT and MRI, the latter being more sensitive in detecting a
small component of subependymal intraparenchymal hemorrhage. Also, MRI can suggest a diagnosis of aneurysm, AVM,
or cavernous angioma as the mechanism of hemorrhage. Even
after extensive testing, the cause of many intraventricular hemorrhages remains unknown.
The prognosis of intraventricular hemorrhage is strongly
dependent on the severity of the initial manifestation and its
mechanism. Patients who are comatose as a result of the
initial hemorrhage generally succumb, especially if they have
early signs of brainstem involvement (ophthalmoparesis,
loss of pupillary reflexes, decerebrate rigidity). Those who
remain alert or obtunded without signs of parenchymal
involvement tend to recover without neurological sequelae,
although memory disturbances may be a relatively frequent
residual deficit (Flint et al., 2008). Patients with the idiopathic form of intraventricular hemorrhage have the best
prognosis.
General Management of Intracerebral
Hemorrhage
Because ICH is frequently associated with increased ICP, most
of the therapies used in this setting are directed at lowering
the ICP or preventing hematoma expansion, which occurs in
28%–38% of ICH presenting within 3 hours of symptom
onset. Among the many medications and procedures available, a small group has come into customary use in most
institutions, despite their value not being proven in properly
controlled studies.
Initial Evaluation
On arrival in the emergency department, patients with ICH
need to be immediately evaluated for stabilization of vital
signs and airway protection. If the patient has a depressed level
of consciousness and a Glasgow Coma Scale score of 8 or less,
endotracheal intubation should follow. This is best performed
with the administration of short-acting IV agents such as
thiopental (1–5 mg/kg) or lidocaine (1 mg/kg) to block the
increases in ICP that result from tracheal stimulation.
Following emergent evaluation of vital signs and laboratory studies, clinical examination and CT are needed to establish the topography and size of the ICH, which determine the
plan for further management. These decisions are made in
conjunction with a neurosurgical consultant.
Laboratory testing in cases suggestive of ICH should include
complete blood count for hematologic disorders, a toxicology
screen for sympathomimetic drug use, and serum glucose, as
elevated levels have been associated with hematoma expansion and worse outcomes. Coagulation studies are essential,
especially in instances of hemorrhage in patients receiving
anticoagulants, those previously treated with thrombolytic
agents, or patients with liver disease. Coagulation abnormalities in patients receiving anticoagulants should be treated
emergently because if anticoagulation is not reversed, it can
lead to progressive enlargement of the hematoma. Patients
with ICH in the setting of heparin anticoagulation should be
treated with protamine sulfate, 1 mg per 100 units of heparin
estimated in plasma, whereas those on warfarin should receive
5 to 25 mg of IV vitamin K1 and, most important, fresh frozen
plasma (10–20 mL/kg) or prothrombin complex concentrate
(PCC). In view of the expected delays in having fresh frozen
plasma immediately ready in these instances, the availability
of PCC seems to offer the option of a more rapid reversal of
abnormally prolonged INR. The direct benefits of PCC over
fresh frozen plasma in cases of warfarin-related ICH are currently under investigation (Steiner et al., 2011). Recombinant
factor VIIa is also available for rapid IV injection; however,
there are limited data supporting its use in warfarin-related
ICH (Freeman et al., 2004). As factor VIIa replaces only one
of the four deficient vitamin K-dependent factors, anticoagulation may not be completely reversed in vivo despite rapid
normalization of the INR, which is heavily dependent on
factor VIIa activity. Accordingly, factor VIIa is currently not
recommended as a first-line treatment for warfarin-related
ICH (Morgenstern et al., 2010).
In the absence of consensus guidelines for how best to
manage their reversal, the rapid increase in the use of NOACs
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Intracerebral Hemorrhage
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eFig. 66.18 Noncontrast computed tomography study with
primary right dorsolateral medullary hemorrhage.
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Intracerebral Hemorrhage
will pose a clinical challenge when faced with the management of patients with ICH in the setting of NOAC use. Of the
three currently approved NOACs (dabigatran, apixaban, and
rivaroxaban), the clearance of dabigatran, which has low
plasma protein binding, can be effectively accelerated through
hemodialysis. Activated charcoal may also be used to reduce
the absorption of recently ingested capsules. While awaiting
drug-specific antidotes, currently in development, limited data
suggest that PCC may offer some benefit in reversing NOACrelated hemorrhage (Jackson and Becker, 2014).
Instances of ICH after thrombolytic therapy are best treated
with 4 to 6 units of cryoprecipitate or fresh frozen plasma, as
well as single-donor platelets.
General Measures for Prevention of Further Elevation of
Intracranial Pressure
General measures include control of hypertension and treatment of seizures. The former can be necessary because persistent hypertension, by causing increased cerebral perfusion
pressure, may produce an increase in cerebral edema around
the ICH, with further elevation of ICP. However, this potential
benefit of antihypertensive therapy must be balanced against
the possible harmful effects of drug-induced hypotension,
with resulting cerebral ischemia and further neurological deterioration. This difficult clinical problem is compounded
by the lack of knowledge concerning optimal balance
between adequate cerebral perfusion and control of ICP. Reassuringly, the rapid lowering of blood pressure does not seem
to have a significant effect on perihematomal cerebral perfusion in moderate-sized ICH (Butcher et al., 2013). Pharmacological correction of severe hypertension (blood pressure
>180/105 mm Hg) is recommended in the acute phases of
ICH, with the goal being maintenance of normal cerebral
perfusion pressure levels on the order of 50 to 70 mm Hg, and
aiming at a blood pressure of 160/90 mm Hg (Morgenstern
et al., 2010). In cases presenting with systolic blood pressure
between 150 and 220 mm Hg, further reduction of systolic
blood pressure to 140 mm Hg is safe and may improve clinical
outcome (Anderson et al., 2013). The antihypertensive agent
of choice in this setting is the IV beta- and alpha-blocking
agent labetalol, often used in combination with loop diuretics. The use of the IV calcium channel blocker nicardipine is
an equally appropriate choice in this setting in view of its lack
of cerebral vasodilatory effect. These IV agents have the advantage of being rapidly effective and easy to titrate.
Seizures, a feature of the lobar rather than deep ganglionic
varieties of ICH, typically occur at onset. In patients who did
not have early seizures, there is a negligible risk of late epilepsy. Thus the routine prophylactic use of anticonvulsants in
patients with ICH is not justified. Early tonic-clonic convulsions need immediate control because they can contribute to
increased ICP. The major anticonvulsants are of comparable
value in this situation. EEG for the diagnosis of nonconvulsive
status epilepticus should be considered in patients with
depressed level of consciousness that is out of proportion to
the size and location of ICH.
Specific Treatment of Increased Intracranial Pressure
The mainstays of treatment of intracranial hypertension have
been hyperventilation, osmotic diuretic therapy, and cortico­
steroids. Hyperventilation is most effective in rapidly lowering
intracranial hypertension, usually within minutes of achieving
levels of hypocapnia in the range of 25 to 30 mm Hg. Intravenous mannitol (0.25–1 g/kg), a rapid and reliable way of
lowering ICP, may be used along with hyperventilation in situations of neurological deterioration with impending hernia-
981
tion. Although dexamethasone is frequently given with the
purpose of decreasing intracranial hypertension by reducing
cerebral edema, its use is not supported by data from a single
controlled clinical trial (Broderick et al., 2007).
Intensive monitoring of ICP together with aggressive
medical treatment of intracranial hypertension appears to
improve the outcome of comatose patients with ICH. Failure
to control raised ICP with these measures can be used as an
objective indicator that surgical evacuation of the hematoma
may be required, because persistently elevated ICP in these
circumstances invariably results in progression to coma and
death.
Choice between Medical and Surgical Therapy in
Intracerebral Hemorrhage
A direct surgical approach is considered frequently in patients
with superficial (lobar) hematomas of the cerebral hemispheres or with cerebellar hemorrhage, whereas patients with
deep hemorrhages (caudate, thalamic, pontine, mesencephalic, and medullary in location) are rarely if ever surgical
candidates. Putaminal hemorrhage occupies an intermediate
position and is most controversial. Few scientific data are
available to assist the clinician in this therapeutic choice.
Several randomized clinical trials compared surgical with
nonsurgical treatment of ICH, and the results were generally
inconclusive, mostly because of methodological issues. Mendelow and associates (2005) reported the results of a prospective international multicenter clinical trial comparing surgical
and nonsurgical treatment of ICH. The international STICH
(Surgical Trial of Intracerebral Haemorrhage) randomized
1033 patients into each treatment arm, with the surgery for
hematoma evacuation being performed within 4 days of ICH
onset. The primary trial outcome, death or disability (measured with the extended Glasgow Outcome Scale) at 6 months,
was virtually identical in the two groups: 74% in the surgical
group and 76% in the nonsurgical group. Similarly, mortality
at 6 months was 36% and 37%, respectively. Prespecified
subgroup analyses showed no superiority of one treatment
modality over the other, with the only exception being that
hematomas located at a depth of less than 1 cm from the cortical surface fared better with surgical treatment. Based on this
observation, the subsequent STICH II examined the benefit of
initial conservative management versus surgical therapy within
this particular subgroup and there were no significant differences found (Mendelow et al., 2013). These well-conducted
prospective studies have added to the mounting evidence of a
lack of benefit of surgical treatment for most varieties of
supratentorial ICH. However, prior studies largely utilized conventional craniotomy as the predominant mode of surgical
therapy, and currently ongoing trials are assessing the benefit
of promising minimally invasive procedures for hematoma
evacuation in patients with ICH (Mould et al., 2013).
In view of these data, most patients are currently treated
nonsurgically, with the exception of those with lobar hemorrhage with progressive deterioration in the level of consciousness, and most instances of cerebellar hemorrhage. In addition,
the presence of a lesion with potential for causing recurrence
of ICH, such as an AVM, aneurysm, or cavernous angioma, is
another indication for surgical therapy. Patients with putaminal and lobar ICH who undergo a steady decline in level of
consciousness, with onset of coma, have a mortality of 100%
with medical therapy. On the basis of this consideration, occasional patients with putaminal ICH are treated surgically, with
a slight improvement in survival rates but without any demonstrated improvement in functional outcome. This raises a
difficult ethical dilemma contrasting improved survival rates
with poor quality of life in patients with massive basal
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66
982
PART III Neurological Diseases and Their Treatment
ganglionic ICHs, in whom severe hemiplegia, hemisensory
loss, and aphasia or hemi-inattention syndromes are the
expected permanent sequelae.
The other group for whom surgery is frequently considered
includes patients with cerebellar hemorrhage. Although a
benign outcome without surgical evacuation is well documented in small cerebellar hemorrhages, the potential for
sudden deterioration to coma and death, not infrequently
after a clinically stable course under hospital observation, is
well recognized. CT criteria for early selection of candidates
for surgical therapy are large hematomas (diameter of 3 cm or
more), presence of hydrocephalus, and obliteration of the
quadrigeminal cistern (eFig. 66.19). In addition to these CT
features, early signs of pontine tegmental compression, such
as ipsilateral gaze and facial palsy, and development of obtundation and extensor plantar responses constitute indications
for emergency surgical therapy, because otherwise the outcome
is often fatal.
In addition to direct evacuation of a hematoma, there is
the option of ventricular drainage for the relief of hydrocephalus and increased ICP in cases of cerebellar, thalamic, and
caudate ICH. In cerebellar hemorrhage, massive hydrocephalus can be a major cause of clinical deterioration, and ventriculostomy may provide dramatic improvement, serving as a
bridge to surgical evacuation rather than a substitute, since
ventricular drainage does not diminish compression of the
brainstem, and may exacerbate the potential for upward trans­
tentorial cerebellar herniation due to decompression of the
supratentorial ventricular system. Patients with thalamic hemorrhage occasionally show a dramatic reversal of oculomotor
signs, coma, or both, after ventricular drainage. Patients with
primary intraventricular hemorrhage and hydrocephalus
benefit from ventricular drainage as well. Preliminary data
suggest that ventricular drainage facilitated by local intraventricular instillation of tPA achieves a more rapid and efficient
removal of the intraventricular blood, without an increase in
the risk of rebleeding. This approach is currently being evaluated in a prospective randomized clinical trial that is correlating the removal of blood from the ventricular system with
clinical outcomes.
Hemostatic Therapy of Intracerebral Hemorrhage
The general scarcity of effective surgical therapies for ICH, plus
the documented tendency of hematomas to enlarge after
onset, have stimulated an interest in developing treatments
aimed at retarding this process. Mayer and colleagues (2005)
tested the procoagulant agent, recombinant activated factor
VII (rFVIIa), in 399 patients with ICH within 4 hours from
symptom onset and documented a significant reduction in
hematoma growth with three dosages of rFVIIa (40, 80,
160 µg/kg) in comparison with placebo. This was also associated with a significant trend in favor of rFVIIa when clinical
outcomes and mortality were compared at 90 days. Thromboembolic complications were more frequent in the rFVIIa
groups (7%) than in the placebo group (2%). These encouraging preliminary results were tested in the phase III FAST (rFVIIa
in Acute Haemorrhagic Stroke Treatment) trial. This study
compared rFVIIa in two dosages (20 and 80 µg/kg) with
placebo in patients with ICH treated within 4 hours from
onset. Although the subjects treated with 80 µg/kg of rFVIIa
had a significantly smaller increase in hematoma volume at
24 hours post treatment, this was not translated into clinical
benefit: mortality and severe disability at 90 days occurred
with essentially the same frequency in the three treatment
groups (Mayer et al., 2008). In addition, the rate of arterial
thromboembolic complications was significantly higher
(10%) in the group that received rFVIIa at a dose of 80 µg/kg
than in the group that received placebo (5%). Further testing
of this agent is likely to be limited to specific patient subpopulations. One such group is that of patients at high risk of
hematoma expansion, with a positive “spot sign” detected on
CTA early after presentation with ICH. The NINDS-sponsored
STOP-IT trial is testing rFVIIa against placebo in this setting.
Alternative hemostatic therapies in ICH, such as tranexamic
acid, are also being tested in ongoing clinical trials.
REFERENCES
The complete reference list is available online at https://expertconsult
.inkling.com/.
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Intracerebral Hemorrhage
982.e1
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A
B
eFig. 66.19 Midline cerebellar hemorrhage with brainstem distortion, obliteration of quadrigeminal cistern (arrows) (A), and supratentorial hydrocephalus (B).
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982.e2
PART III Neurological Diseases and Their Treatment
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