From the Departments of Pathology (M.A., M.R.D.), Radiology (J.P.), and
Pharmacology (J.P.), University of Manitoba, Winnipeg, Canada.
Correspondence to Marc R. Del Bigio, MD, PhD, FRCPC, Department of Pathology, University of Manitoba, D212-770 Bannatyne Ave, Winnipeg, Manitoba R3E 0W3, Canada. E-mail delbigi{at}cc.umanitoba.ca
Methods—Intracerebral hemorrhage was
induced in 2 groups of rats by injection of bacterial
collagenase into the caudate nucleus. In 1 group of rats,
streptokinase was used to lyse the hematoma 4 hours after
hemorrhage induction, and the clot was then aspirated.
Behavioral function was evaluated repeatedly until the rats were killed
7 weeks after collagenase injection. Histology was used to
assess neuronal loss, astroglial proliferation, and overall brain
morphology. In a second experiment, brain water was measured at 24
hours.
Results—The treated rats performed significantly better than
controls on a motor-behavior evaluation on days 1, 2, and 28 after
aspiration. Skilled forelimb testing performed for 3 weeks after the
global behavior evaluations showed a significant deficit of
contralateral forelimb function in both groups, but there was no
significant difference between the 2 groups. Neuronal loss in the
perihematoma striatum was significantly greater in untreated compared
with treated rats. In most rats, structural damage extended into the
internal capsule and thalamus.
Conclusions—Aspiration of the hematoma after
collagenase-induced hemorrhage slightly improved
acute functional outcome and reduced neuronal loss from the striatum.
Further studies are required to delineate the mechanism of the effect.
Current management of ICH includes control of systemic
hypertension and treatment or prevention of raised intracranial
pressure. While most agree that cerebellar and superficial lobar
hematomas should be removed, there is controversy concerning the use of
surgery for deep hematomas in the basal ganglia.8
Different forms of surgical management, for example, open
craniotomy,9 stereotactic
injection of thrombolytic agents to facilitate clot
lysis and removal, or the use of endoscopy,10 have been
described as treatments for ICH. A meta-analysis of randomized
clinical studies in 1997 suggested that immediate surgical removal of
hematomas might improve outcome in noncomatose patients <60 years of
age with a hematoma volume of <50 mL.11 The authors
emphasized that the problem needs to be studied in a randomized
trial.12
The effects of ICH have been studied experimentally using infusion
of autologous blood and implantation of inflatable
balloons.13 14 15 16 To achieve a more reproducible hematoma,
Rosenberg and coworkers17 18 developed a rat model in
which intrastriatal injection of bacterial collagenase was
used to disrupt the basal lamina of cerebral capillaries and cause
bleeding into brain tissue.
The purpose of this study was to test the hypothesis that aspiration of
collagenase-induced hematoma from rat brain is associated
with improved neurological outcome. Detailed histopathological
assessments were correlated with behavioral tests.
Behavioral Testing
Skilled forelimb function was also tested using a staircase
feeding apparatus.19 This required pretraining
before induction of ICH. Rats had free access to food and water during
first 2 days after arrival from the supplier. The rats were housed in
pairs in standard plastic boxes with a 12-hour day/night cycle. During
the following 7 days, the rats were fed 8 to 15 g/d of standard
laboratory chow to reduce their body weight to 85% to 90% of the
initial weight. Hunger was the incentive to perform in the testing
apparatus. The staircase pretraining was performed twice
per day, with a time interval of at least 4 hours between trials. The
rat was placed in a clear plastic box with a food-baited staircase on
either side. Each staircase had 7 steps, each with a well containing 3
45-mg pellets (P.J. Noyes Co Inc). The number of food pellets reached
and eaten in 20 minutes was counted. When a plateau was reached, the
top well was no longer baited with pellets, because these can be
reached with the tongue. An additional 4 to 6 trials were used to
calculate mean pretraining number of pellets eaten from each side. If
the side-to-side difference was >4 on the final trials, the side on
which rat collected more pellets was designated its "preferred"
side. ICH was induced in the dominant brain hemisphere in rats with a
preferred side. After pretraining, the rats were allowed free access to
food for 2 days before surgery and during the 4 weeks after ICH.
Beginning 28 days after ICH, the rats were fed 10 to 12 g/d standard
laboratory chow to decrease the body weight to 90% of the free feeding
level. They were then evaluated daily in the staircase
apparatus for 3 weeks. The top well of the staircase
apparatus was not baited. The number of food pellets eaten
in 20 minutes on each side was counted (maximum possible 18 per
side).
Histological Examination
All sections were inspected macroscopically and microscopically to
determine anatomical structures involved in the hematoma site.
According to the part of striatum involved, hematomas were classified
as being medial, lateral, or whole striatum location. Extension of the
hematoma into the internal capsule was semiquantitatively graded: 0, no
extension; 1, extension in anterior limb; and 2, extension into
posterior limb. Extension of the hematoma into the thalamus was
similarly graded: 0, no extension; 1, focal calcium deposition and cell
loss; and 2, residual cavity.
A "camera lucida" was used to assess the overall brain morphology
on the coronal slice with the maximum hematoma diameter. The
ipsilateral cortical injection site lesion, hematoma cavity, residual
striatum, and ventricle were traced onto a sheet of paper, as were the
contralateral striatum and ventricle. Computerized planimetry was used
to measure the traced areas. Side-to-side differences were compared.
Striatal area loss was calculated as the percentage difference between
contralateral and ipsilateral striatum.
Medium-size striatal neurons were quantified at the coronal level of
the maximum hematoma diameter as previously described.20
With a square ocular graticule and x250 ocular magnification
(objective magnification x20), neurons were counted in three fields
(each area 400x400 µm) immediately adjacent to the hematoma
site; areas with large blood vessels were avoided. Three anatomically
comparable fields in the contralateral caudate nucleus were assessed in
the same manner. The difference between the sums from each side was
used as an index of relative neuronal depletion in striatal tissue
adjacent to the hematoma.
GFAP immunohistochemical labeling was performed on sections at the
coronal level of the maximum hematoma diameter. Sections were incubated
with 20% goat serum for 30 minutes, then the primary polyclonal GFAP
antibody was applied overnight (Dako, dilution 1:400). Secondary
biotinylated goat anti-rabbit antibody (1:300) was applied for 1
hour, followed by streptavidin HRP and DAB. Areas with labeled
astrocytes were compared between ipsilateral and contralateral side in
the cortex and internal capsule and assigned a grade of 0 if the same,
1 if slightly greater, as 2 if much greater on the side of the
hematoma. Reactive gliosis extension beside the residual cavity was
measured with a calibrated ocular graticule.
Water Content
Data Analysis
Motor deficit scores in the first 4 weeks after ICH are shown in the
Figure
In the treated rats, functional performance on day 1 was not
dependent on the location of the hematoma within the striatum, hematoma
extension into the thalamus, hematoma extension into the internal
capsule (see below), or the volume of blood aspirated. However, the
final skilled forelimb performance was dependent to some extent
on the hematoma location within the striatum and extension of injury
into the thalamus. Rats with medially placed hematomas had the least
deficit (Table 2
Localization of the hematomas and anatomical structures damaged by ICH
is shown in Table 2
Striatal tissue surrounding the hematoma in untreated rats exhibited
significantly greater neuronal loss than in treated rats (54±8 versus
16±7, P=0.0014). There was no difference in the absolute
neuronal count in the contralateral striatum between the 2 groups.
Reactive gliosis extended an average of 416±56 µm from the
residual cavity in untreated rats and 296±40 µm in treated rats
(P<0.04; 1-tailed Student's t test). There was
no significant difference in cortical or external capsule gliosis
between the 2 groups.
Brain-water content 24 hours after collagenase injection is
shown in Table 4
Pilot experiments using magnetic resonance imaging before and after
hematoma aspiration showed that the central contiguous portion of the
hematoma could be removed (M.R. Del Bigio, unpublished data, 1997).
Pilot experiments with 10 rats subjected to intrastriatal autologous
blood injection of 40 to 100 µL showed that the resulting hematoma
was very irregular, with extension along the white tracts; the
histological changes adjacent to the hematoma, however,
were almost identical to those seen in the collagenase
model (H.J. Yan and M.R. Del Bigio, unpublished data, 1997). Because we
believed that hematoma removal could be accomplished only in contiguous
regions, we chose the collagenase model for this study. We
wished to determine whether surgical aspiration of
collagenase-induced hematoma could improve the final
outcome in rats.
Intracerebral hemorrhage causes brain damage by
multiple mechanisms. Direct tissue destruction by the hemorrhagic event
and dissection of blood along tissue planes occurs immediately. Damaged
cells and axons in the path are unlikely to be saved by any
intervention. The space-occupying effect of the hematoma compromises
local blood flow in the surrounding tissue. This has been shown by a
variety of experimental methods after inflation of balloons or
injection of autologous blood in the brain24 25 26 27 28 29 and in a
small number of ICH patients by CT scanning combined with xenon
inhalation.30 Our preliminary experiments in this model
using magnetic resonance perfusion imaging31 also indicate
that blood flow is reduced in an area much larger than the hematoma
itself (J. Peeling and M.R. Del Bigio, unpublished data, 1997). These
data suggest that ICH has a penumbral region similar to that adjacent
to ischemic brain damage in which blood flow is reduced and
neuronal function and survival are compromised.32
Important to note is the observation that deflation of a 50-µL
balloon implanted into rat caudate nucleus was associated with recovery
of cerebral blood flow.24 This may explain why we observed
improved neuronal survival and reduced reactive gliosis in the striatum
adjacent to hematomas that had been treated by aspiration.
In this experiment, we observed a significant treatment-related
improvement in motor behavior during the first 2 days after ICH.
Experiments with temporary space-occupying lesion created by balloon
inflation in the caudate nucleus of rats indicate that there is a
significant increase in intracranial pressure.24 28
Intracerebral pressure in pigs with ICH is reduced
after lysis of the clot using tissue plasminogen
activator and aspiration.33 34 Thus, the
improvement we witnessed probably was related to relief of the
space-occupying effect of hematoma, decreased intracranial pressure,
and possibly increased local blood flow. Another postulated effect of
ICH is the release of toxic agents, particularly thrombin, from the
clotting blood.35 36 Aspiration of blood presumably would
reduce the quantity of these agents in the brain. However, we know from
our short-term experiments and the observation of residual
hemosiderin that not all of the blood can be removed.
Without precise information concerning the dose-response curve of these
agents, it is impossible to know whether partial removal of the blood
reduces their effect. A third consideration is a beneficial effect of
the additional 1-hour period of anesthesia. For example,
deep anesthesia induced by 5-hour thiopental infusion is
associated with reduced acute infarct volume after transient middle
cerebral artery occlusion in rats.37 However, this seems
unlikely in the present experiment, because in our previous study
rats that were anesthetized repeatedly with pentobarbital for
the purposes of early sequential MR imaging showed no
benefit.20
The acute motor improvement in this experiment did not appear to be due
to reduction of brain edema, which develops in the first few hours and
peaks at 24 to 48 hours.20 In contrast, Wagner and
coworkers33 documented reduced perihematoma edema in the
pig ICH model after tissue plasminogen
activator–assisted evacuation. The edema associated with
autologous blood injection into the brains of rats and pigs has a
similar time course.29 33 Rosenberg and
coworkers38 39 40 41 have successfully reduced brain water in
rats with collagenase-induced hematomas using a variety of
drugs, but outcomes were measured at 24 hours and behavior was not
assessed in detail.
Despite our documentation of acute motor improvements, reduced neuronal
death in the striatum, and reduced striatal atrophy, surgically treated
rats did not exhibit any late benefit with regard to skilled forelimb
performance. This is likely a function of the brain structures
that were acutely damaged by the hematoma. Most of the hematomas
extended into the thalamus and internal capsule. These provide
assessment of goal-directed movement abilities.19 For
successful reaching and grasping in the staircase test, the
corticospinal tract, the basal ganglia, and the ascending sensory
pathway should be intact.19 42 43 44 Axonal damage in the
internal capsule and thalamic injury would be expected to affect the
outcome of this test, and it is very unlikely that axonal damage would
be amenable to aspiration of blood from the striatum. We must consider
the possibility that the cortical damage caused by repeated needle
insertions was detrimental. It is also worth noting that hematomas
involving either the lateral or entire striatum were associated with
greater disability than those associated with only medial damage. This
has been shown directly in other experiments in which lesions of the
lateral striatum produced severe and chronic impairments of movement
initiation, forelimb-reaching amplitude, and postural synergism but
damage to the medial striatum produced mild or no impairment of
forelimb reaching.45
We conclude that partial surgical aspiration of
collagenase-induced intracerebral hematomas
from rat brains improves the acute functional deficit slightly,
probably through reduction of the space-occupying effect of the
hematoma and consequent reduction of intracranial pressure. Acutely
damaged axons do not benefit by surgical treatment. Late neuronal
survival in the striatum surrounding the hematoma was also improved,
possibly as a result of improved local cerebral blood flow or removal
of potentially toxic blood breakdown products. It appears that
intracerebral hematomas are associated with a penumbra
similar to that surrounding ischemic brain tissue, in which
selective neuronal loss can occur. Further investigations into the
value of drug therapy to treat cerebral edema and neuronal
ischemia combined with surgical treatment are warranted.
Received January 28, 1998;
revision received May 27, 1998;
accepted May 28, 1998.
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Section
of Neurosurgery,
University of Chicago Medical Center,
Chicago, Illinois
The experiment was done to address the clinical question of whether
early hematoma evacuation improves functional outcome. The model used,
however, does not produce clinical differences of the magnitude
observed in humans. None of the rats died from the effects of
intracerebral hemorrhage, unlike the clinical
situation, in which up to 50% of patients with deep
intracerebral hemorrhage die. A 10% to 15%
improvement in motor deficit score was observed and was associated with
a much more marked 70% reduction in neuronal loss. This highlights the
difficulty of using tests of function in rats. Investigators have
relied almost exclusively on histopathological endpoints in the study
of experimental cerebral ischemia. A 70% reduction in infarct
size, if approximately equal to the 70% increase in neuronal survival
noted in this study, would be a marked effect.
The pathogenesis of neurological deficit and death is certainly
multifactorial and includes direct effects of the hematoma causing
direct destruction of brain tissue, destruction by mass effect and
brain shift, ischemia, toxic effects of substances released
from the blood clot, and secondary induction of edema, brain swelling,
increased local pressure, and diffuse intracranial pressure. Broderick
et al1 reported that continued bleeding or rebleeding also
may be a common cause of deterioration and morbidity and mortality. The
rat model reproduces some of these features. It stands to reason that
removing the clot early would prevent or decrease damage due to some of
these mechanisms and therefore have the potential to improve outcome.
The conclusions that are usually drawn from the prior clinical trials
and other pertinent literature are as follows.2 3 4 5 6
Cerebellar and cerebral lobar hemorrhages should be removed
surgically unless the patient is too well to need surgery or does not
need surgery to make a diagnosis or remove the lesion that caused the
hemorrhage, or if the chances of functional outcome are
nonexistent. The following applies to hemorrhage in the pons,
thalamus, and putamen, which are the most common sites for hypertensive
hemorrhage and in general to patients with Glasgow Coma Scale
scores between 7 and 12 or so who are not either very well or very ill.
For patients such as this, with pontine and thalamic
hemorrhage, surgery performed with some delay of hours after
the ictus may increase the survival rate, but those who do survive are
usually severely disabled. The questions to be answered, which apply
more to thalamic than pontine hemorrhage, are whether removing
the hematoma with less disruption of the brain, such as by a
stereotactic method, or doing so sooner after the
hemorrhage, will improve outcome. For putamenal
hemorrhage, surgery decreases mortality but most of the
survivors are disabled. There is more enthusiasm for studying whether
earlier or less "invasive" hematoma evacuation will improve
outcome.
Animal models are important for investigating the pathogenesis of
intracerebral hematoma and the effect of
neuroprotective strategies, but the call for a clinical trial has been
made so many times that the decision does not rest on results of more
experimental data. Experimental studies are unlikely to be able to
answer the question of effect on functional outcome. Answers to
clinical questions such as this one, in which randomization is
difficult, have been sought by prospectively collecting large numbers
of patients.
Received January 28, 1998;
revision received May 27, 1998;
accepted May 28, 1998.
2.
Juvela S, Heiskanen O, Poranen A, Valtonen S, Kuurne T,
Kaste M, Troupp H. The treatment of spontaneous
intracerebral hemorrhage: a prospective
randomized trial of surgical and conservative treatment.
J Neurosurg. 1989;70:755–758.
3.
McKissock W, Richardson A, Taylor J. Primary
intracerebral hemorrhage: a controlled trial of
surgical and conservative treatment in 180 unselected cases.
Lancet. 1961;2:221–226.
4.
Batjer HH, Reisch JS, Allen BC, Plaizier LJ, Su CJ.
Failure of surgery to improve outcome in hypertensive putaminal
hemorrhage: a prospective randomized trial. Arch
Neurol. 1990;47:1103–1106.
5.
Auer LM, Deinsberger W, Niederkorn K, Gell G, Kleinert
R, Schneider G, Holzer P, Bone G, Mokry M, Körner E, Kleinert G,
Hanusch S. Endoscopic surgery versus medical treatment for
spontaneous intracerebral hematoma: a randomized
study. J Neurosurg. 1989;70:530–535.
6.
Unwin DH, Batjer HH, Greenlee RG Jr. Management
controversy: medical versus surgical therapy for spontaneous
intracerebral hemorrhage.
Neurosurg Clin N Am. 1992;3:533–538.[Medline]
[Order article via Infotrieve]
© 1998 American Heart Association, Inc.
Original Contributions
Intracerebral Hemorrhage in the Rat: Effects of Hematoma Aspiration
Abstract
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Introduction
References
Background and Purpose—Deep intracerebral
hemorrhage is associated with considerable mortality and
morbidity, but the value of surgical therapy is debatable. The purpose
of this study was to evaluate whether aspiration of the hematoma in a
rodent model of intracerebral hemorrhage could
improve final neurological outcome.
Key Words: behavior, animal • hematoma • stroke, hemorrhagic • rat • surgery
Introduction
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Introduction
References
Hemorrhagic stroke occurs when a blood vessel or vascular
anomaly ruptures, releasing blood into the surrounding brain tissue.
Spontaneous intracerebral hemorrhage (ICH)
represents one of the most devastating types of
stroke,1 occurring annually in 12 to 35 persons per
100 000 population, and accounting for 8% to 14% of all
strokes.2 3 Most clinical cases are associated with
hypertension, and the most common sites of ICH are striatum,
cerebellum, and pons.4 The 30-day mortality rate is 43%
to 51%, and most survivors are left with a neurological
disability.5 6 7
Materials and Methods
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
Introduction
References
Intracerebral Hemorrhage
All experimental procedures were done in accordance with the
guidelines of the Canadian Council on Animal Care. Protocols were
approved by the local experimental ethics committee. Sixty-six young
adult male Sprague-Dawley rats weighing 175 to 250 g were used.
Forty-four rats were underwent behavior testing followed by
pathological exam 7 weeks after hemorrhage. Fourteen rats were
killed 24 hours after ICH for brain-water determinations. Eight rats
were used for assessment of streptokinase injection. For induction of
hemorrhage, each rat was anesthetized with
pentobarbital (50 mg/kg IP) and placed in a stereotactic
frame (David Kopf Instruments). Through a hole drilled in the skull, a
30-gauge needle was introduced into the caudate nucleus (3 mm
lateral to midline, 0.02 mm anterior to coronal suture, depth
6 mm below the surface of the skull), and 1.4 µL of saline
containing 0.3 U collagenase (Type IV, Sigma Chemical Co)
was infused over 7 minutes. After the infusion, the needle was left in
the place for 3 minutes and then removed.
Physiological parameters were not
monitored during the procedure. The bone hole was sealed with bone wax,
the scalp wound was sutured, and the animal was placed in a box with
free access to food and water. Every second rat with
collagenase injection was selected for aspiration of the
hematoma. Four hours after collagenase injection, the rat
was reanesthetized with pentobarbital (50 mg/kg IP) and again
placed in the stereotactic frame. Using the same
stereotactic coordinates, streptokinase (3 µL; 1000
U/µL, Sigma) was injected by a 27-gauge needle into the hematoma
center. One hour later, aspiration was accomplished by application of
gentle suction with a syringe attached to a 25-gauge needle placed at
the same stereotactic coordinates.
Physiological parameters were not
monitored in this experiment. The volume of aspirated blood was
measured. Eight rats without ICH were injected with the same quantity
of streptokinase in 1 side and an equal volume of saline in the
contralateral striatum and were killed 1, 3, 7, or 11 days later for
histological assessment.
All testing was done by a single observer without knowledge of
the treatment group. Motor behavior was evaluated using 4 tests in each
rat 1, 3, 5, 7, 11, 14, 17, 21, and 28 days after
collagenase injection. The specific tests included (1)
observation of spontaneous ipsilateral circling, graded from 0 (no
circling) to 3 (continuous circling); (2) contralateral hindlimb
retraction, which measured the ability of the animal to replace the
hindlimb after it was displaced laterally by 2 to 3 cm, graded from 0
(immediate replacement) to 3 (replacement after minutes or no
replacement); (3) beam walking ability, graded 0 for a rat that readily
traverses a 2.4-cm-wide, 80-cm-long beam to 3 for a rat unable to stay
on the beam for 10 seconds; and (4) bilateral forepaw grasp, which
measures the ability to hold onto a 2-mm-diameter steel rod, graded 0
for a rat with normal forepaw grasping behavior to 3 for a rat unable
to grasp with the forepaws. The scores from all 4 tests, which were
done over a period of about 15 minutes on each assessment day, were
added to give a motor deficit score (maximum possible score, 12).
Seven weeks after collagenase injection, each rat
was reanesthetized and perfused through the heart with 300 mL
cold 4% paraformaldehyde in 0.1 mol/L
phosphate-buffered saline. The brain was removed and stored in the same
fixative. Fixed brains were cut coronally through the needle entry site
(identifiable on the brain surface), as well as 2 mm anterior and
2 mm posterior to that plane. Brain slices were dehydrated and
embedded in paraffin. Sections (5 µm) were cut, and each 10th
section from the rostral to the caudal portion of the residual hematoma
cavity was stained with hematoxylin and eosin.
Fourteen rats were used for this experiment. Six rats had
collagenase-induced hemorrhage, and 8 had
collagenase-induced hemorrhage followed by
aspiration as described above. Twenty-four hours after ICH, the
motor-behavior tests were done, then each rat was killed by
pentobarbital overdose. The brain was quickly removed and placed on a
cooled surface, and the cerebellum and brain stem were removed. The
cerebrum was divided into hemispheres, and each hemisphere was
coronally cut into 3 parts; the first cut was through the needle entry
site and the second through the midpoint of the posterior remnant. Each
section was weighed, wrapped in preweighed aluminum foil, dried for 3
days in an oven at 110°C, and weighed again. Water content was
calculated as the percentage change between wet weight and dry
weight.
All data are presented as mean±SEM. Data were
analyzed using StatView version 4.1 (Abacus Concepts, Inc).
Z-score histograms were used to determine whether the data were
distributed normally. For the skilled forelimb test, the mean
posthematoma value was calculated for each week (5 trials) for each
side separately. The means before and after hematoma were compared.
Normally distributed data (behavior, areas of residual cavity,
ventricle, striatum, cortical damage, neuronal count, and water
content) were analyzed by Student's t test to
compare the hematoma and aspiration groups. Correlation coefficient or
regression analysis was used to assess the relationship between
morphologic features and behavioral outcomes. The Kruskal-Wallis test
was used to assess relationship between hematoma location or extension
into internal capsule and the functional deficit.
Results
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
Introduction
References
Six rats were excluded before surgery because they refused to eat
in the staircase apparatus during the pretraining period.
No rats died immediately after surgery. Two rats were euthanized 4 to 5
weeks after ICH because of unexpected weight loss.
Histological analysis showed large abscesses in
the cortex and striatal region of each rat. One rat was excluded after
histological analysis because the bacterial
collagenase had been injected into the septal region. For
final analysis, there were 18 control rats with naturally
evolving hematomas and 17 treated rats with aspirated hematomas. The
volume of aspirated blood ranged 20 to 100 µL. Streptokinase
injection into the striatum of rats without ICH was associated with no
inflammation, no neuronal changes, and minimal hemorrhage 1 to
11 days later. The changes were similar to those seen on the
contralateral side that received injection of saline alone. 
. The scores were significantly
better in the treated group on days 1, 2, and 28 (P<0.03;
1-tailed t test). Results of the skilled forelimb testing
are shown in Table 1. The number of food
pellets eaten reached a plateau after 8 to 10 trials in the pretraining
period. Four rats constantly preferred the right side, 5 preferred the
left side. The plateau was reached in 5 trials during post-ICH testing.
There were no differences in performance between the groups
before ICH. The limb ipsilateral to the hematoma exhibited no loss in
performance after ICH. There was a significant decline in
function of the forelimb contralateral to the hematoma, but there was
no difference between the treated and untreated rats.
View larger version (16K):
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Figure 1. Line graph showing motor deficit scores (mean±SEM) in
untreated rats with naturally evolving hematoma ( 
) and treated
rats whose hematoma was aspirated (
). The treated group had
significantly better scores (*) on days 1, 2, and 28
(P<0.03; 1-tailed Student's t test).
View this table:
[in a new window]
Table 1. Skilled Forelimb Testing in Rats With
Intracerebral Hematoma ). By regression
analysis, in the treated rats there were no significant
relationships between the final skilled forelimb performance
and the area of cortical damage, the size of the residual striatal
cavity, or the volume of blood aspirated.
View this table:
[in a new window]
Table 2. Brain Structures Damaged by
Intracerebral Hematoma and Relationship to Skilled
Forelimb Performance 
. The anterior limb of the internal capsule and
portions of the ventroposterior and ventrolateral thalamic nuclei
sustained some damage in most rats. The pattern of damage was the same
in the 2 groups. The relative sizes of the residual damage are shown in
Table 3. The ipsilateral ventricle was
less enlarged in the rats treated with aspiration, suggesting that
there may have been less striatal atrophy. The cortical lesion at the
needle entry site was larger in the treated group, probably as a result
of repeated needle insertions.
View this table:
[in a new window]
Table 3. Relative Size of Brain Structures and Damaged
Areas . Water content was
significantly increased in the cerebrum ipsilateral to the hematoma
compared to the contralateral side in both animal groups. However,
there was no difference in water content between the treated and
untreated groups.
View this table:
[in a new window]
Table 4. Water Content in Brain Slices 24 Hours After
Intracerebral Hemorrhage
Discussion
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
Introduction
References
There is considerable controversy regarding the value of surgical
therapy over conservative therapy for spontaneous
intracerebral hemorrhage. Although many studies
have been reported, most are considered inadequate to quantify reliably
the risk and benefit of surgical treatment. Two recent independent
reviews of the literature with meta-analysis
assessment11 21 determined that there are only 4
randomized trials of surgical treatment worth
considering.9 10 22 23 Both groups of authors concluded
that there was insufficient information on the safety and efficacy of
surgery and that more information was needed from a multicenter
randomized trial to determine whether some patients with ICH would
benefit from surgery.
Acknowledgments
This work was funded by The Heart and Stroke Foundation of
Manitoba. Dr Del Bigio is in receipt of a scholarship from the Manitoba
Health Research Council. We thank Dr H. J. Yan for advice concerning
the animal model and Dr D. Corbett for advice concerning the behavioral
testing. We thank Cathy Crook for technical assistance.
References
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Introduction
References
1.
Ducker TB. Spontaneous
intracerebral hemorrhage. In: Wilkins
RH, Rengachary SS, eds. Neurosurgery. Vol 2. New York,
NY: McGraw-Hill;1985:1510–1517.
Editorial Comment
Introduction
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Introduction
References
In the article published above, Altumbabic and colleagues
induced deep intracerebral hemorrhage in rats
by injection of bacterial collagenase. Every second rat was
reanesthetized 4 hours later, streptokinase was injected, and
the hematoma was aspirated. The groups were compared on "behavioral
function," histopathology, and brain edema. Hematoma aspiration
resulted in a small improvement in "motor deficit score" 1, 2, and
28 days after hemorrhage, which was determined by assessing a
combination of 4 specific tests. On another test of skilled forelimb
function, no differences could be detected between groups. Hematoma
aspiration reduced neuronal loss and reactive gliosis but not edema.
The authors argue that the additional anesthesia time in
the clot removal group did not favorably affect outcome, but this
remains a possible explanation for the improvements observed,
particularly in the absence of measurements of vital signs, including
brain temperature.
References
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Introduction
References
1.
Broderick JP, Brott TG, Tomsick T, Barsan W, Spilker
J. Ultra-early evaluation of intracerebral
hemorrhage. J Neurosurg. 1990;72:195–199.[Medline]
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