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DOI 10.1007/s00415-014-7291-1
REVIEW
Received: 7 January 2014 / Revised: 14 February 2014 / Accepted: 17 February 2014 / Published online: 5 March 2014
The Author(s) 2014. This article is published with open access at Springerlink.com
Abbreviations
CT
Computed tomography
ICH
Intracerebral haemorrhage
CTA
Computed tomography angiography
PET-CT Positron
emission
tomography-computed
tomography
rFVIIa
Recombinant factor VIIa
FFP
Fresh frozen plasma
CEICH
Chronic encapsulated intracerebral haematoma
Introduction
Haemorrhagic stroke, which accounts for 1020 % of all of
the new strokes that occur every year [78], has a 1-month
mortality rate of approximately 40 % [164]. Although it
has drawn the attention of researchers because of the high
rates of morbidity and mortality, the outcomes and prognosis of intracranial haemorrhage have not improved significantly during the last several decades [142, 164].
Progressing stroke, also known as progressive stroke,
stroke-in-progression, stroke-in-evolution, and deteriorating
stroke, has been a clinical concept for a long time [27, 54].
Progressing stroke happens often within 3672 h, with marked
deterioration in clinical manifestations measured by the
Scandinavian Stroke Scale or the Canadian Stroke Scale [83,
117, 154]. This concept was traditionally limited to ischaemic
stroke [116], and haemorrhagic stroke was often ruled out in
the initial studies of progressing stroke [84]. However, evidence has shown that a progression also exists in the haemorrhagic stroke [27, 54, 113]. Several researchers have shown
that primary haemorrhagic stroke is more often associated with
progression than ischaemic stroke [18] and that early deterioration is associated with a poorer outcome [93].
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Early neurological deterioration of intracerebral haemorrhage has been recognised in many patients with haemorrhagic stroke [30, 46, 93, 100, 113]. As with progressing
ischemic stroke, a deterioration of clinical signs and
symptoms often happens within 2472 h with intracerebral
haemorrhage and is associated with haematoma expansion
[30], perihaematomal oedema [46], intraventricular haemorrhage [100], and inflammation [155]. The expansion of
haematoma may account for most of the progression [100,
113, 150]. Additionally, in the second to third weeks after
the onset of intracerebral haemorrhage, many patients may
undergo a deterioration of symptoms after the initial alleviation by conservative management, which indicates a
subacute progression [171, 182]. Furthermore, the progression of haemorrhage may appear to be a chronic form,
in which the gradual formation of an encapsulated intracerebral haematoma may cause progressive neurologic
deficits over weeks or months [64, 69, 133]. Therefore, the
concept of progressing haemorrhagic stroke should be
separated from the progressing ischaemic stroke, because
the causes, pathogenesis, mechanisms, manifestations and
management of the former all differ from the latter.
In this review article, we proposed the concept of progressing haemorrhagic stroke and summarised the three
categories of progressing haemorrhagic stroke, which are
as follows: acute progressing haemorrhagic stroke, subacute progressing haemorrhagic stroke and chronic encapsulated intracerebral haematoma. We explored several
aspects of their causes, mechanisms and management.
123
Intraventricular extension of haemorrhage is another deteriorating factor of early ICH [100, 155]. Intraventricular
extension may occur simultaneously with ICH or within
2472 h after the onset of initial ICH, in 2055 % of all
ICH patients [106, 152]. Steiner et al. [152] and Bhattathiri
et al. [16] all showed that ICH patients with intraventricular haemorrhage had a worse functional outcome compared to those without intraventricular hemorrhage.
Adjusting for the ICH score and haematoma expansion,
intraventricular haemorrhage is still associated with a
higher mortality rate within the patients hospitalisation
stay [106].
Perihaematomal oedema
Perihaematomal oedema volume increases significantly
after onset within the first 24 h after spontaneous ICH [56].
The chronological CT images showed that perihaematomal
oedema increased rapidly within 3 days after onset and
reached its initial peak in the fourth or fifth day [79, 165].
The highly evident initial mass effect could also contribute
2063
References
Type of
study
Mayer
et al.
[113]
Prospective
Cases
END occur
in
46
15 (33 %)
Flemming
et al. [46]
Retrospective
Leira et al.
[100]
Prospective
61
16 (26 %)
Predictive factors:
Glasgow Coma Scale score \14, Imaging
characteristics such as haemorrhage volume
[60 mL; shift of the septum pellucidum;
effacement of the contralateral ambient cistern;
widening of the contralateral temporal horn;
Causes:
Haematoma enlargement, perihaematomal oedema
266
61 (22.9 %)
Predictive factors:
On admission: Body temperature of 37.5 C,
neutrophil count, serum fibrinogen levels of
523 mg/dL;
At 48 h: early ICH growth, intraventricular bleeding,
highest systolic blood pressure
Sorimachi
et al.
[150]
Retrospective
Sun et al.
[155]
Retrospective
184
19 (10 %)
Causes:
Haematoma enlargement; hydrocephalus; convulsion;
pneumonia
83
31 (37 %)
Predictive factors:
Midline shift on imaging; ICH score; white blood cell
count [10,000/mL3
associated with liver disease [87] and the amount of alcohol consumption [50], and negatively associated with the
level of fibrinogen [50]. Warfarin use was associated with
both haematoma expansion and intraventricular haemorrhage [17, 45, 47]. Broderick et al. and Yildiz et al. found a
correlation between antiplatelet therapy and haematoma
expansion [19, 180]. The low serum LDL cholesterol level
was also reported to be associated with a higher haematoma expansion rate; researchers think that this association
is related to the function of LDL to maintain vascular
integrity [144].
Hypertension
Kazui et al. [87] showed that an interaction of hyperglycaemia and hypertension on hospital admission was
associated with haematoma expansion. Takeda et al. [159]
showed that blood pressure of [160 mmHg measured at
1.5 h after admission was significantly associated with
haematoma expansion. Steiner et al. [152] also showed that
increased baseline blood pressure was associated with
intraventricular haemorrhage growth. Sykora et al. [156]
showed that decreased baroreflex sensitivity was significantly correlated with increased blood pressure fluctuation
and was an independent predictor of relative oedema. The
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sign [40, 65]. Furthermore, Almandoz et al. have developed a spot sign score system, involving spot sign numbers, maximal axial dimension and maximal attenuation.
The higher scores are associated with higher in-hospital
mortality and poor outcome [33, 34]. A clinical trial is
being conducted to test its predicting value in early
haematoma growth [59] (Fig. 2).
However, although ASA/AHA recommended CTA or
contrast CT to identify the patients at risk for haematoma
expansion [122], neither of them is a routinely performed
examination at the time of hospital admission in many
institutions. Haematoma density heterogeneity could be a
substitute for the prediction of haematoma expansion.
Haematoma heterogeneity refers to the irregularity of
shape and density of the initial haematoma on the CT scan,
and researchers have found an association between
haematoma heterogeneity and haematoma expansion [13,
81]. Takeda et al. [159] concluded that the presence of
haematoma volume above 16 mL, haematoma heterogeneity and 1.5 h of a systolic blood pressure above
160 mmHg together increased the likelihood of haematoma expansion to approximately 59 %. Although its definition was traditionally arbitrary, Ji et al. [81] defined the
haematoma heterogeneity as a difference of over 20 HU in
CT value between two regions exceeding 10 mm2 in area.
Barras et al. used quantitative CT densitometry to measure
mean attenuation, square root of variance, coefficient of
variation, skewness and kurtosis of the attenuation distribution of the haematoma; they found that the coefficient of
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Fig. 2 Patient with spot sign, demonstrating extravasation and haematoma expansion [166]. Reproduced from Wolters Kluwer Health with
permission
123
basal ganglia/thalamic bleeding with continuous hypertonic saline infusion within 72 h, and the relative oedema
volume and the occurrence of intracranial pressure crisis
had significantly decreased.
Blood pressure control
The protective effect of anti-hypertensive therapy in ICH
has been broadly explored. A retrospective series of 76
patients by Ohwaki et al. showed that systolic blood
pressure (SBP) of C160 mmHg was significantly associated with haematoma enlargement compared to those
of B150 mmHg, and efforts to lower SBP below
150 mmHg may prevent this risk [130]. Also, several
clinical trials have been conducted. The Intensive Blood
Pressure Reduction in Acute Cerebral Hemorrhage Trial
(INTERACT) randomised 404 patients to receive either
standard blood pressure management (SBP \180 mmHg)
or more aggressive blood pressure management (SBP
\140 mmHg); the results showed a decrease in
haematoma expansion by 2.80 mL, with no significant
difference in perihaematomal oedema [8]. The results of
the INTERACT phase 2 trail, performed on 2,839
patients, showed no significant reduction of haematoma
expansion but significant improved functional outcome
in the intensive blood pressure lowering group compared
to the control group [7]. The Antihypertensive Treatment
of Acute Cerebral Hemorrhage (ATACH) study randomised 60 patients to receive intravenous nicardipine
hydrochloride to three systolic blood pressure reduction
goals: 170199, 140169, or 110139 mmHg. The post
hoc analysis results showed that patients with a lower
blood pressure were less likely to have haematoma
expansion, perihaematomal oedema, and a poor 3-month
outcome [137].
Presently, based on the existing incomplete evidence,
AHA/ASA guidelines recommend that for patients with
SBP of [200 mmHg or MAP of [150 mmHg, continuous
intravenous infusion to reduce the BP should be applied,
with BP monitoring every 5 min. For SBP of [180 mmHg
or MAP of [130 mmHg in patients with a likelihood of
ICP elevation, reducing BP while simultaneously maintaining a cerebral perfusion pressure of C60 mmHg is
recommended. If there is no evidence of elevated ICP, then
a modest reduction of BP (e.g., MAP of 110 mmHg or a
target BP of 160/90 mmHg) with a re-examination every
15 min is recommended [121].
Coagulopathy reversal
Because coagulopathy contributes to the early progression
of haemorrhagic stroke, ultra-early haemostatic therapies
2067
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2068
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2069
Stroke unit
Tension haematoma
Clinical features
Mechanisms
Causes
Delayed perihaematomal oedema
Inaji et al. [79] investigated the chronological changes of
perihaematomal oedema in 14 patients with CT scan and
found that its volume increased rapidly within 3 days after
haemorrhage, subsequently increased slowly until day 14,
and decreased thereafter. Consistently, Venkatasubramanian et al. [165] investigated 27 patients prospectively with
MR imaging and found that oedema volume growth was
fastest in the first 2 days, and continued until 12 3 days.
By 2 weeks, the haemorrhage volume decreased, whereas
oedema and haemorrhage plus oedema volumes significantly increased [11, 52]. A retrospective study involving
490 patients revealed that after admission to the hospital,
the perihaematomal oedema increased, whereas the
haematoma volume decreased, and the mass effect almost
doubled between 7 and 11 days, which could cause an
increase in ICP and secondary clinical deterioration [151].
Different from the initial oedema, the delayed perihaematomal oedema is mainly caused by erythrocyte lysis [72,
177]. It has been observed in ICH patients that during the
second week, the perihaematomal oedema increases in size
simultaneously with the lysis of the clot [173]. In several
animal experiments, the intracerebral infusion of packed
erythrocytes to the ICH rats caused oedema 3 days later
[176], whereas the intracerebral infusion of lysed erythrocytes caused oedema within 24 h [175, 176], similar to the
infusion of haemoglobin [174]. Furthermore, the upregulation of the primary heme degradation enzyme, heme
oxygenase-1 (HO-1), has been observed in experimental
ICH [169], simultaneously inhibiting HO-1 attenuated the
brain oedema [174]. The infusion of haemoglobin degradation products, such as heme and Fe2?, could also induce
brain oedema, whereas the oedema caused by the haemoglobin infusion could be attenuated by the infusion of iron
chelator deferoxamine, indicating that iron degraded from
haemoglobin is the primary cytotoxic factor that contributed to the delayed brain oedema [74].
Granulation tissue formation
Formation of tension haematoma is related to the granulation tissue around the initial haematoma. During the
absorption of a haematoma, granulation tissues form
around it, which can be seen on contrast CT as ringenhancement [172]. The granulation tissue is capsule-like
which limits the absorption of haematomas. Subsequently,
the oncotic pressure inside the haematoma increases and
the infiltration of plasma increases the tension inside the
capsule progressively [162]. Additionally, blood may leak
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Managements
Osmotherapy
When a sudden deterioration of clinical signs and symptoms occur during the conservative treatment process, a
subacute progression of ICH should be suspected. A
repeated CT at this time is necessary to determine whether
there is increased mass effect or re-bleeding. The priority is
to control the ICP, and a more intensive osmotherapy
should be applied. Placement of an ICP monitor is recommended, especially in patients with a Glasgow Coma
Scale score of less than eight and those with transtentorial
herniation [122]. Several researchers have recommended
an early and continuous infusion of hypertonic saline to
reduce the impending perihaematomal oedema and progression of mass effect [167]. However, osmotherapy
might not be beneficial for certain patients; therefore,
surgery would be the best recommendation for these
patients.
Surgeries
As previously described, minimally invasive surgery is
more applicable in reducing the perihaematomal oedema
progression [124]. For the patients with tension
123
2071
Fig. 5 Management of
subacute progressing stroke
Causes
Radiosurgery
Etiology
Hypertension
References
Yashon et al. [179]
Lin et al. [102]
Arteriovenous malformation
Cavernoma
For the encapsulated haematoma or CEICH, occult vascular malformations are often the underlying cause. Arteriovenous malformations [133], cavernomas [64, 120],
microaneurysms, vascular amyloidosis or atherosclerosis
are the common underlying causes [108, 133, 147]. CEICH
also occurs after radiosurgeries [92] or trauma [25, 181].
Several causes remain unknown [147].
Whether hypertension contributes to the causes of
CEICH is controversial. Most of the cases reported do not
have a history of hypertension [64, 120], whereas several
cases have been reported to be likely caused by hypertension [102]. Liquified chronic intracerebral haematomas is
often secondary to hypertension [179] (Table 2).
Unknown
Mechanisms
The mechanism of the progression of CEICH has not been
established, and it is hard to predict whether CEICH will
affect certain patients. On histological examination,
CEICH consists of central haematoma and peripheral thick
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2072
123
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