Stroke

CLINICAL AND POPULATION SCIENCES

Location-Specific Hematoma Volume Cutoff and

Clinical Outcomes in Intracerebral Hemorrhage
Kay-Cheong Teo , MBBS, FHKAM; Sze-Man Fong , MBBS; William C.Y. Leung , MBBS; Ian Y.H. Leung, MBBS,
FHKAM; Yuen-Kwun Wong , PhD; Olivia M.Y. Choi , MPsych; Ka-Keung Yam, MBBS, FHKAM; Rachel C.N. Lo , BSc;
Raymond T.F. Cheung, MD, PhD; Shu-Leong Ho, MD; Anderson C.O. Tsang , MS; Gilberto K.K. Leung , MS,
PhD; Koon-Ho Chan , MD, PhD*; Kui-Kai Lau , DPhil*

BACKGROUND: Major intracerebral hemorrhage (ICH) trials have largely been unable to demonstrate therapeutic benefit in
improving functional outcomes. This may be partly due to the heterogeneity of ICH outcomes based on their location, where
a small strategic ICH could be debilitating, thus confounding therapeutic effects. We aimed to determine the ideal hematoma
volume cutoff for different ICH locations in predicting ICH outcomes.
METHODS: We retrospectively analyzed consecutive ICH patients enrolled in the University of Hong Kong prospective stroke
registry from January 2011 to December 2018. Patients with premorbid modified Rankin Scale score >2 or who underwent
neurosurgical intervention were excluded. ICH volume cutoff, sensitivity, and specificity in predicting respective 6-month
neurological outcomes (good [modified Rankin Scale score 0–2], poor [modified Rankin Scale score 4–6], and mortality) for
specific ICH locations were determined using receiver operating characteristic curves. Separate multivariate logistic regression
models were also conducted for each location-specific volume cutoff to determine whether these cutoffs were independently
associated with respective outcomes.
RESULTS: Among 533 ICHs, the volume cutoff for good outcome according to ICH location was 40.5 mL for lobar, 32.5 mL
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for putamen/external capsule, 5.5 mL for internal capsule/globus pallidus, 6.5 mL for thalamus, 17 mL for cerebellum, and
3 mL for brainstem. ICH smaller than the cutoff for all supratentorial sites had higher odds of good outcomes (all P<0.05).
Volumes exceeding 48 mL for lobar, 41 mL for putamen/external capsule, 6 mL for internal capsule/globus pallidus, 9.5
mL for thalamus, 22 mL for cerebellum, and 7.5 mL for brainstem were at greater risk of poor outcomes (all P<0.05).
Mortality risks were significantly higher for volumes that exceeded 89.5 mL for lobar, 42 mL for putamen/external capsule,
and 21 mL for internal capsule/globus pallidus (all P<0.001). All receiver operating characteristic models for location-
specific cutoffs had good discriminant values (area under the curve >0.8), except in predicting good outcome for
cerebellum.
CONCLUSIONS: ICH outcomes differed with location-specific hematoma size. Location-specific volume cutoff should be
considered in patient selection for ICH trials.
GRAPHIC ABSTRACT: A graphic abstract is available for this article.

Key Words: cutoff ◼ hematoma location ◼ intracerebral hemorrhage ◼ stroke outcome

See related article, p 1558

ntracerebral hemorrhage (ICH) is a deadly and debilitat-

I
ing form of stroke. Despite relentless efforts, effective
treatment to improve functional outcomes following ICH
has remained elusive.1–7 With the exception of the INTER-
ACT-2 trial (The Second Intensive Blood Pressure
Reduc- tion in Acute Cerebral Hemorrhage Trial), where a
significant

Correspondence to: Kui-Kau Lau, DPhil, Department of Medicine, Queen Mary Hospital, Room 405B, 4/F, Professorial Block, 102 Pok Fu Lam Rd, Hong Kong,
Email gkklau@hku.hk or Koon-Ho Chan, MD, PhD, Department of Medicine, Queen Mary Hospital, Room 405B, 4/F, Professorial Block, 102 Pok Fu Lam Rd, Hong
Kong, Email koonho@hku.hk
*K.-H. Chan and K.-K. Lau contributed equally.
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.122.041246.
For Sources of Funding and Disclosures, see page 1556.

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Stroke. June DOI: Stroke. 2023;54:1548–1557. DOI: June 2023
© 2023 The Authors. Stroke is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the
terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
Stroke is available at www.ahajournals.org/journal/str

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 Teo et
Nonstandard Abbreviations and Acronyms
aOR adjusted odds ratio
BP blood pressure
CT computed tomography
EC external capsule
HE hematoma expansion
IC internal capsule
ICH intracerebral hemorrhage
IVH intraventricular hemorrhage
LSW last seen well
mRS modified Rankin Scale
OR odds ratio
ROC receiver operating characteristic
positive shift in the modified Rankin Scale (mRS) was
demonstrated with acute blood pressure (BP) lowering,1
acute therapeutic trials for ICH, which include BP
lowering or hemostatic drugs administration to reduce
hematoma expansion (HE) and surgical evacuation of
hematoma, had failed to convincingly yield positive
results.1–7 A possible explanation for these treatments’
lack of therapeutic ben- efit is the heterogeneity of ICH
outcomes based on their location, where a small strategic
ICH could be debilitating, thus confounding therapeutic
effects.
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It is well recognized that ICH outcomes differ
significantly depending on their location.8–20 Traditionally,
ICH prognosti- cation based on location is separated
crudely into infraten- torial and supratentorial.21 However,
recent studies have demonstrated that the
prognostication of ICH outcomes should be classified
into more specific anatomic sites.8–20
Although studies have produced inconsistent results, for
supratentorial ICH, the prognosis is generally better for
lobar ICH8–11 but worse for thalamic.12,13 Importantly, since
ICH volume is also another crucial modifier of ICH
outcomes,22 it is becoming more evident that a location-
specific ICH vol- ume would better predict ICH
outcomes.19,20 A small stra- tegic bleed affecting the
thalamus may have devastating neurological deficits,
while a similar-sized ICH at the frontal lobe could have a
more favorable neurological outcome.
Therefore, as the interaction between ICH location
and volume significantly impacts neurological outcomes,
using location-specific hematoma volumes for patient
selection could, in theory, better guide the selection of
patients who may best benefit from treatment. Herein,
we aimed to determine the ideal location-specific volume
cutoffs in predicting ICH outcomes at different ICH sites.
METHODS
Data Availability Statement
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Stroke. June DOI:
Location-Specific ICH Volume
Study Design and Participants
CLINICAL AND
We retrospectively analyzed consecutive ICH patients enrolled
in the University of Hong Kong prospective stroke registry from
January 2011 to December 2018. We included all primary ICH
POPULATION
patients aged ≥18 who presented to Queen Mary Hospital,
Hong Kong, within 48 hours of symptom onset or last seen
well (LSW) time. ICH diagnosis was confirmed by computed
tomography (CT) scan of the brain. Individuals who underwent
neurosurgical intervention, with premorbid mRS score of >2,
secondary ICH, multiple ICH locations, or had a recurrent ICH/
stroke within 6 months of index ICH were excluded. The study
protocol was approved by the institutional review boards of
our institution. Written informed consent was obtained from all
patients, or their next of kin for patients who could not con-
sent during enrollment into the stroke registry. The study was
reported in accordance with the STROBE (Strengthening the
Reporting of Observational Studies in Epidemiology) reporting
guidelines.
Management of ICH
All patients were managed according to our hospital’s estab-
lished stroke pathway, which is regularly updated in line with
the American Heart Association ICH guidelines.23,24 In brief,
the stroke pathway is activated, and our stroke team is notified
by the Accident and Emergency Department for all patients
with suspected stroke. An urgent CT brain is performed, and
neurosurgery will be consulted in cases of ICH. The decision
to proceed with surgery is at the discretion of the neurosur-
geon on-call after discussion with the patient or next of kin.
Indications for surgical treatment include ICH within 1 cm of
the surface with obtunded Glasgow Coma Scale or significant
mass effect, hydrocephalus, and cerebellar ICH with brainstem
compression or hydrocephalus. Patients deemed unsuitable
for surgery are transferred to our high-dependency stroke unit
under the care of a multidisciplinary team. A standardized man-
agement protocol with a BP reduction target of systolic BP
140 mm Hg is adopted. Upon stabilization, patients who require
further rehabilitation are transferred to a designated stroke
rehabilitation unit at Tung Wah Hospital, Hong Kong.
Variables and Outcomes
Demographic data, social, and medical histories were collected
by trained study staff through in-person interviews of patients
(and reliable informants) and a review of electronic medi-
cal records at the time of enrollment. Clinical data captured
included Glasgow Coma Scale and BP on admission.
Six-month mRS scores were determined based on elec-
tronic records of clinic or rehabilitation visits at 6 months (±1
month) after index ICH. We defined good outcome as mRS
score 0 to 2 and poor outcome as mRS score 4 to 6.
Imaging Analysis
All CT brain images were reviewed blinded to clinical outcomes.
CT scans were analyzed to determine ICH location, hematoma
Anonymized data pertaining to the research presented will be made available
from the corresponding author upon reasonable request.
Stroke. 2023;54:1548–1557. DOI: June 2023
 Teo et Location-Specific ICH Volume

volume, and the presence of intraventricular

hemorrhage (IVH). ICH location was classified as
lobar, external capsule (EC), putamen, globus
pallidus (GP), internal capsule (IC), thalamus,
caudate head, cerebellum, or brainstem. For large
ICH with over- lapping sites, the CT images were
reviewed by 2 experienced

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 Teo et
stroke neurologists (K.C.T. and K.K.L.) to determine the exact
ICH location. However, as it is often difficult to differentiate EC
from putamen, and GP from IC due to the close proximity of
these structures, we grouped EC and putamen, and GP and IC
POPULATION
together. Hematoma volume was determined using the ABC/2
formula.25 If multiple CTs were performed within 48 hours of
CLINICAL AND
admission, the largest ICH volume was recorded for analysis.
The severity of IVH was scored based on the Graeb score.26
The Graeb score is a semiquantitative measure of IVH, ranging
from 0 to 12 points, with the higher scores indicating increased
IVH volumes.
Statistical Methods
Statistical analyses were performed using SPSS version 28.0
and Prism version 6.0. Descriptive statistics are presented
either as mean and SD, or median with interquartile range for
continuous variables, and number and percentage of the sub-
total for categorical variables. Categorical variables were com-
pared using χ2 or Fisher exact tests, and continuous variables
using the Kruskal-Wallis or Student t test. Patients with caudate
head ICH were excluded due to their small number (n=17).
Multivariate logistic regression analysis was performed to
determine the association of ICH location with poor outcome
and mortality. Each individual ICH location (lobar, thalamus, IC/
GP, putamen/EC, brainstem, and cerebellum) was entered into
separate multivariate logistic regression models to determine
the association between different locations and outcomes. The
multivariate regression models included age, ICH volume (log-
transformed), and covariates with P<0.2 in univariable analy-
ses with backward elimination to arrive at a minimal model
that included only variables associated at P<0.1. Glasgow
Coma Scale was classed as ≥9 or <9 based on the FUNC
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score,18 while the Graeb score was categorized as ≥5 or <5
since the former was associated with poor outcomes in ICH.27
An inter- action term was next added to the regression
model to test whether there was a significant interaction
between ICH loca- tion and volume. As outcomes differ
between lobar, deep, and infratentorial ICH, additional
multivariate logistic regression models were performed
specifically for deep and infratento- rial ICH.
The optimal ICH volume cutoff (to the closest 0.5 mL), sen-
sitivity, and specificity in predicting the different outcomes of
interest (good outcome [mRS score 0–2], poor outcome [mRS
score 4–6], and mortality at 6 months) for different ICH loca-
tions were determined using receiver operating characteristic
(ROC) curves. Separate multivariate logistic regression models
were conducted for each location-specific hematoma volume
cutoff with the respective outcome of interest (good outcome
versus mRS score 3–6; poor outcome versus mRS score 0–3;
mortality versus mRS score 0–5). We included age and covari-
ates with P<0.2 from the univariable analyses into the
multivari- ate regression model with backward elimination to
arrive at a final model including only the location-specific
cutoff and vari- ables associated at P<0.1. All significance
tests were 2-tailed, and significance was set at P<0.05. Data
were reported with odds ratio (OR) and 95% CI.
Sensitivity Analyses
Separate ROC analyses were performed for symptoms onset/
LSW to CT time ≤6 and >6 hours for each ICH location to
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Location-Specific ICH Volume
determine whether the cutoffs varied according to time win-
dows. The ROC curves based on the time windows for each
location were compared using the DeLong test to evaluate
whether they differed significantly.
We also performed sensitivity analyses to assess how the
sensitivity and specificity of each location-specific volume cut-
off based on the primary analysis varied after including patients
who underwent surgery, and to determine whether these cut-
offs remained independently associated with outcomes after
including these patients. The sensitivity and specificity of all
location-specific cutoffs were calculated using the ROC curve,
and multivariate logistic regression analyses were performed
on each location-specific volume cutoff. Similarly, for respec-
tive location and outcome of interest, covariates with P<0.2
from the univariable analyses were entered into a multivariate
regression model with backward elimination to arrive at a final
model including only the location-specific cutoff and variables
associated at P<0.1.
RESULTS
Of 861 consecutive ICH patients included in the stroke
registry during the study period, 533 were eligible to the
current analysis (Figure 1). As expected, compared with
patients with mRS score ≥3 at 6 months, those with good
outcomes were younger, had higher admission Glasgow
Coma Scale score, smaller ICH volume and IVH score,
longer symptom onset/LSW to CT time and were less
likely to have infratentorial ICH. They were also more
likely to present with an ICH located at the putamen/
EC (Table 1). There were no significant differences in
the clinical or outcome measures between patients with
ICHs presumably located at the IC and GP (Table S1) or
between putamen and EC (Table S2).
Clinical Characteristics and Outcomes Based
on ICH Location
The clinical characteristics and outcomes differed sig-
nificantly according to ICH location (Table 2). Notably,
patients with lobar ICH were older, had larger ICH vol-
umes, and were less likely to have an IVH. Patients with
IC/GP ICHs and putamen/EC ICHs also significantly
differ, where IC/GP ICHs had smaller hematoma vol-
umes and were more likely to have IVH. Poor outcome
and mortality at 6 months were the highest for infraten-
torial-located ICHs.
Analyses of ICH Location and 6-Month
Outcomes
Lobar ICH was associated with a significantly lower risk
of poor outcome (adjusted odds ratio [aOR], 0.13 [95%
CI, 0.06–0.29]). The risk of poor outcome was highest
for thalamic (aOR, 2.66 [95% CI, 1.17–6.08]) and brain-
stem ICH (aOR, 8.87 [95% CI, 2.38–33.06]). In a sub-
group analysis of only deep ICH, the risk of poor outcome
Stroke. 2023;54:1548–1557. DOI: June 2023
 Teo et
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remained the greatest for thalamic ICH but was reduced
for putamen/EC ICH (aOR, 0.18 [95% CI, 0.06–0.48];
Table 3).
For mortality, patients with putamen/EC ICH had a
lower risk (aOR, 0.42 [95% CI, 0.20–0.91]), while the
risk was increased for brainstem ICH (aOR, 33.11 [95%
CI, 8.05–136.11]; Table 3).
Interaction analysis demonstrated a significant inter-
action between ICH volume and location for both poor
<
There was otherwise no association of laterality with
outcome in univariate analysis (all P>0.80), so this was
not entered into the multivariate regression model.
Location-Specific Hematoma Volume Cutoff
and the Association With Clinical Outcomes
The respective location-specific volume cutoffs, sensitiv-
ity, and specificity in predicting different clinical
outcomes are presented in Table 4. All area under the
curves of the location-specific cutoff for good outcome,
poor outcome, and mortality were >0.8, except for
good outcome for cerebellum (area under the curve,
0.623).
The odds for good outcomes were significantly higher
for ICH with volume smaller than the location-specific
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Location-Specific ICH Volume
CLINICAL AND
POPULATION
Figure 1. Flow diagram of study
inclusion and exclusion criteria.
CT indicates computed tomography; ICH,
intracerebral hemorrhage; and mRS,
modified Rankin Scale.
cutoff for all supratentorial ICH locations (all P<0.05;
Figure 2). For poor outcome, the risk for all ICH locations
were greater when ICH volumes exceeded the cutoffs
(all P<0.05; Figure 2). Mortality risks were significantly
higher for volumes that exceeded 89.5 mL for lobar, 42
mL for putamen/EC, 21 mL for IC/GP, and 22 mL for
cerebellum (all P<0.001; Figure 2).
Sensitivity Analyses for Location-Specific
Hematoma Volume Cutoff
Table S4 shows the respective location-specific volume
cutoffs, sensitivity, and specificity in predicting clinical
outcome, stratified by symptom onset/LSW to CT time
of ≤6 versus >6 hours. There was no significant differ-
ence between the ROC curves of both time windows for
all locations (all P>0.05 for DeLong test). Patients pre-
senting >6 hours after symptom onset/LSW tended to
have smaller ICH (median volume 10.7 versus 21.8 mL;
P<0.001)
After including the 77 patients who had undergone
surgery, the sensitivity and specificity for respective loca-
tion-specific cutoffs are presented in Table S5. These
cut- offs remained significantly associated with
outcomes of interest when compared to the primary
analysis (Table S6).
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 Teo et Location-Specific ICH Volume

Table 1. Study Participants’ Characteristics According to the 6-Month Modified Rankin Scale

Variables mRS score ≤2 (n=197) mRS score 3–5 (n=192) mRS score 6 (n=144) P value
POPULATION

Demographics
Age, y (mean, SD) 58.6±11.8 72.2±11.8 75.1±15.4 <0.001
CLINICAL AND

Male sex 143 (72.6) 103 (53.6) 82 (56.9) <0.001

Race/ethnicity 0.138
Han Chinese 191 (97.0) 188 (97.9) 135 (93.8)
White 0 (0) 2 (1.0) 2 (1.4)
Others 6 (3.0) 2 (1.0) 7 (4.9)
Medical history
Hypertension 108 (54.8) 116 (60.4) 75 (52.1) 0.283
Diabetes 24 (12.2) 47 (24.5) 32 (22.2) 0.005
Ischemic stroke 13 (6.6) 16 (8.3) 15 (10.4) 0.449
ICH 10 (5.1) 10 (5.2) 5 (3.5) 0.719
Ischemic heart disease 8 (4.1) 18 (9.4) 27 (18.8) <0.001

Prior antiplatelet use 19 (9.6) 34 (17.7) 56 (38.9) <0.001

Prior anticoagulant use 10 (5.1) 15 (7.8) 20 (13.9) 0.014

Admission data
Systolic BP, mm Hg (mean, SD)* 187.5±35.8 181.5±31.9 189.3±38.2 0.101
Diastolic BP, mm Hg (mean, SD)* 108.5±23.6 100.1±22.2 100.1±23.0 <0.001

GCS (median, IQR)† 15 (15–15) 15 (13–15) 7 (3–10) <0.001

CT brain findings
Onset/LSW to CT time, h (median, IQR) 4.5 (1.4–15.9) 2.9 (1.2–8.2) 1.8 (1.1–4.9) <0.001

Onset/LSW to CT time within 6 h 114 (57.9) 133 (69.3) 114 (79.2) <0.001

ICH volume, mL (median, IQR) 9.6 (3.4–17.1) 15.8 (7.0–36.5) 55.6 (25.2–135.4) <0.001

IVH 26 (13.2) 67 (34.9) 110 (76.4) <0.001

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IVH Graeb score (median, IQR) 3 (2–5) 3 (2–5) 7 (3–9) <0.001

ICH location <0.001

Lobar 36 (18.3) 45 (23.4) 46 (31.9)

Putamen/external capsule 86 (43.7) 65 (33.9) 33 (22.9)
Internal capsule/globus pallidus 41 (20.8) 28 (14.6) 19 (13.2)
Thalamus 19 (9.6) 33 (17.2) 15 (10.4)
Cerebellum 7 (3.6) 13 (6.8) 12 (8.3)
Brainstem 8 (4.1) 8 (4.2) 19 (13.2)
BP indicates blood pressure; CT, computer tomography; GCS, Glasgow Coma Scale; ICH, intracerebral hemorrhage; IVH, intraventricular hemor-
rhage; LSW, last seen well; and mRS, modified Rankin Scale.
*Missing data in 13 subjects.
†Missing data in 10 subjects.

ICH location.1–5 The interaction between ICH location and

DISCUSSION
Our study has demonstrated the critical interaction
between ICH location and volume with neurological
outcomes. The varying location-specific volume cutoffs
in predicting neurological outcomes for different ICH
sites reflect the heterogeneity of ICH outcomes based
on location. The prognosis of a small ICH at the thalamus
or IC/GP is much worse than that for a similar-sized ICH
at the putamen/EC or lobar region. These findings may
have important implica- tions in patient selection for future
ICH trials.
One of the important caveats of previous therapeu-
tic trials for acute ICH treatment is that most have not
accounted for the heterogeneity of outcomes based on
volume with outcome could be more crucial in acute
thera- peutic trials for ICH than those for ischemic stroke,
as the therapeutic benefit of acute treatment of ICH is not
as pro- found as that of reperfusion therapies for ischemic
stroke. Successful reperfusion therapy for ischemic
stroke may completely reverse brain injury. On the
contrary, acute treat- ment of ICH, either by reducing HE
or surgical evacuation, will not reverse brain injury but only
prevent further damage. Hence, the interaction between
ICH location and volume with neurological outcomes will
drastically confound treat- ment effects. For HE reduction
trials, most trials including ATACH-2 (Antihypertensive
Treatment of Acute Cerebral Hemorrhage II), TICH-2
(Tranexamic Acid for Hyperacute

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 Teo et Location-Specific ICH Volume

Table 2. Clinical Characteristics and Outcomes Based on ICH Location

CLINICAL AND
Lobar Putamen/EC IC/GP Thalamus Cerebellum Brainstem
Variable (n=127) (n=184) (n=88) (n=67) (n=32) (n=35) P value

POPULATION
Age, y (mean, SD) 74.4±12.4 62.9±14.6 68.7±14.8 70.9±12.9 75.4±10.9 57.3±14.5 <0.001

Male sex 65 (51.2) 124 (67.4) 59 (67.0) 38 (56.7) 19 (59.4) 23 (65.7) 0.063
Admission SBP, mm Hg (mean, SD)* 179.5±38.8 188.2±30.4 185.4±34.1 182.1±32.9 182.2±37.8 205.8±42.7 0.004
Admission DBP, mm Hg (mean, SD)* 97.8±25.0 107.4±20.5 103.1±24.5 98.5±22.6 97.5±19.5 115.4±24.2 <0.001

GCS (median, IQR)† 14 (10–15) 15 (11–15) 15 (13–15) 15 (13–15) 15 (5–15) 9 (4–15) <0.001

GCS ≥9† 99 (78.6) 160 (87.4) 73 (85.9) 54 (85.7) 24 (75.0) 18 (52.9) <0.001

ICH volume, mL (median, IQR) 48.4 (16.3–110.9) 23.0 (11.5–46.3) 6.2 (2.2–22.2) 9.2 (3.4–14.2) 10.8 (4.3–38.1) 8.0 (2.5–21.6) <0.001

IVH 45 (35.4) 39 (21.2) 43 (48.9) 45 (67.2) 16 (50.0) 15 (42.9) <0.001

IVH Graeb score ≥5 21 (16.5) 27 (14.7) 22 (25.0) 22 (32.8) 7 (21.9) 6 (17.1) 0.025
Poor outcome at 6 mo 59 (46.5) 63 (34.2) 28 (31.8) 31 (46.3) 16 (50.0) 20 (57.1) 0.017
Mortality at 6 mo 46 (36.2) 33 (17.9) 19 (21.6) 15 (22.4) 12 (37.5) 19 (54.3) <0.001

BP indicates blood pressure; EC, external capsule; GCS, Glasgow Coma Scale; GP, globus pallidus; IC, internal capsule; ICH, intracerebral hemorrhage; IQR, inter-
quartile range; and IVH, intraventricular hemorrhage.
*Missing data in 13 subjects.
†Missing data in 10 subjects.

Primary Intracerebral Haemorrhage), and SPOTLIGHT/
STOP-IT (“Spot Sign” Selection of Intracerebral Hemor-
rhage to Guide Hemostatic Therapy/The Spot Sign for
Predicting and Treating ICH Growth Study) were
success- ful in reducing hematoma expansion but failed
to demon- strate outcome benefit.2–5 Our study may
provide some valuable insight into these findings. Based
on our results, a patient with thalamic ICH >9.5 mL
volume would be highly unlikely to achieve a good
neurological outcome, even with the best trial drug that
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to reduce the rate of poor outcome, patients with ICH
vol- umes smaller than the location-specific volume
cutoffs for poor outcome will be ideal study candidates
(48.0 mL for lobar, 41 mL for putamen/EC, 6 mL for
IC/GP, and 9.5 mL for thalamus), in which prevention of
HE beyond these cut- offs would likely translate to clinical
benefit. ICH located at the putamen/EC or lobar region
would be the ideal site for these trials as there is a larger
volume difference between good, poor outcomes and
mortality, allowing more flexibility for patient selection and

could stop HE immediately. In com- parison, a good
outcome would be expected for a 20 mL putaminal ICH
regardless of any treatment effect. Hence, location-
specific volume cutoffs should be applied based on the
primary outcome of interest for patient selection in
clinical trials. For example, in an HE reduction trial that
aims
reducing the confounding effect of unaccounted
hematoma expansion between the time of brain imaging
and study drug administration on neurologi- cal outcome.
These areas are also less likely to have IVH and brain
stem injury,28 which also would affect neurologi- cal
outcomes of ICH.

Table 3. Multivariate Analyses of ICH Locations and 6-Month Outcomes

Poor outcome* Mortality†

Variables Adjusted OR (95% CI) P value Adjusted OR (95% CI) P va
All locations
Lobar 0.13 (0.06–0.29) <0.001 0.48 (0.21–1.10) 0.08
Putamen/external capsule 1.10 (0.60–2.01) 0.755 0.42 (0.20–0.91) 0.02
Internal capsule/globus pallidus 1.71 (0.74–3.95) 0.209 1.47 (0.52–4.13) 0.46
Thalamus 2.66 (1.17–6.08) 0.020 1.34 (0.46–3.90) 0.59
Cerebellum 1.77 (0.62–5.07) 0.290 2.13 (0.60–7.56) 0.24
Brainstem 8.87 (2.38–33.06) 0.001 33.11 (8.05–136.11) <0.0

Deep ICH
Putamen/external capsule 0.18 (0.06–0.48) <0.001 0.16 (0.04–0.63) 0.00
Internal capsule/globus pallidus 1.96 (0.74–5.21) 0.178 2.11 (0.67–6.64) 0.20
Thalamus 3.23 (1.18–8.79) 0.022 2.27 (0.69–7.45) 0.17
Infratentorial ICH
Brainstem 3.26 (0.46–23.05) 0.237 6.93 (0.85–56.51) 0.07
GCS indicates Glasgow Coma Scale; ICH, intracerebral hemorrhage; and OR, odds ratio.
*Adjusted for age, ICH volume (log-transformed), GCS, Graeb Score, diabetes.
†Adjusted for age, ICH volume (log-transformed), GCS, Graeb Score, prior antiplatelet use.

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 Teo et Location-Specific ICH Volume

Table 4. ICH Volume Cutoffs for Specific Outcome of Interest Based on ICH Location

Outcome of Cutoff volume, Number with outcome of interest Area under the Sensitivity Specificity
POPULATION

Location interest mL below or above cutoff curve (95% CI) (95% CI)
Lobar Good <40.5 36/127 (28.3) 0.808 86 (71–95) 70 (60–79)
CLINICAL AND

Poor >48.0 59/127 (46.5) 0.928 88 (77–95) 82 (71–90)

Mortality >89.5 46/127 (36.2) 0.935 83 (69–92) 94 (86–98)
Putamen/external Good <32.5 86/184 (46.7) 0.823 90 (81–95) 64 (54–74)
capsule
Poor >41.0 63/184 (34.2) 0.877 75 (62–85) 92 (85–96)
Mortality >42.0 33/184 (17.9) 0.926 91 (76–98) 84 (77–90)
Internal capsule/ Good <5.5 41/88 (46.6) 0.850 80 (65–91) 81 (67–91)
globus pallidus
Poor >6.0 28/88 (31.8) 0.921 96 (82–100) 72 (59–83)
Mortality >21.0 19/88 (21.6) 0.928 84 (60–97) 90 (80–96)
Thalamus Good <6.5 19/67 (28.4) 0.806 74 (49–91) 77 (63–88)
Poor >9.5 31/67 (46.3) 0.848 77 (59–90) 81 (64–92)
Mortality >10.5 15/67 (22.4) 0.839 87 (60–98) 69 (55–81)
Cerebellum Good <17.0 7/32 (21.9) 0.623 86 (42–100) 48 (28–69)
Poor >22.0 16/32 (50.0) 0.844 69 (41–89) 94 (70–100)
Mortality >22.0 12/32 (37.5) 0.863 83 (52–98) 90 (68–99)
Brainstem Good <3.0 8/35 (22.9) 0.912 88 (47–100) 89 (71–98)
Poor >7.5 20/35 (57.1) 0.957 90 (68–99) 87 (60–98)
Mortality >10.5 19/35 (54.3) 0.947 74 (49–91) 100 (79–
100)
ICH indicates intracerebral hemorrhage.

Similarly, location-specific volume cutoff can be Our findings are consistent with previously published
applied in patient selection for surgical evacuation. literature on location-specific ICH outcomes.8–13 In a
Surgical evacuation theoretically improves neurologi- recently published article from the ERICH and ATACH-2
Downloaded from http://ahajournals.org by on August 28,

cal outcomes by reducing secondary brain injury due
to the inflammatory response driven by the hematoma,
mass effect, and elevated intracranial pressure.29,30 The
STICH-II trial (Surgical Trial in Lobar Intracerebral Haem-
orrhage) included only lobar ICHs,6 while deep ICHs
(mainly putamen/EC) were also included in the MISTIE
III trial (Minimally Invasive Surgery With Thrombolysis in
Intracerebral Hemorrhage Evacuation Phase III).7 The
median ICH volume was around 40 mL for both of these
studies. Around 40% to 50% of study subjects in the
nonsurgical arm had favorable neurological outcomes
(mRS score 0–3).6,7 These findings were compatible with
our results, where the odds of poor outcome (mRS score
4–6 in the current study) were lower for lobar ICH with
hematoma volume ≤48 mL, and ≤41 mL for putamen/
EC ICH. Since increasing hematoma size augments sec-
ondary brain injury in ICH,29,30 we postulate that there
may be a critical hematoma volume associated with
maximal secondary brain injury and consequent poor
outcome. Applying a volume cutoff >48 mL for lobar
and >41 mL for putamen/EC for patient selection for
hematoma evacuation may capture patients who will best
benefit from surgery. In the exploratory secondary
results of MISTIE III, a favorable outcome in clot size
reduction to 15 mL or less in the MISTIE group was
predominantly seen in patients with initial ICH >45 mL.7
cohort on deep ICH, hematoma volume cutoff for poor
outcome for thalamic ICH was 8 mL (9.5 mL in our
study) and 18 mL for basal ganglia ICH.19 We provided
2 separate cutoff volumes for basal ganglia ICH, IC/
GP, and putamen/EC, respectively, as the latter tend to
have larger ICH volume (median volume 23.0 versus 6.2
mL; P<0.001). Another important finding is that lobar
ICH was associated with favorable outcomes despite its
larger volume. Since motor impairment is one of the most
crucial factors for stroke recovery,31 a plausible explana-
tion for the favorable outcome noted in lobar ICH is that
the predilection for motor pathway involvement is less
compared with other ICH locations due to its large area.
We postulate that the location-specific volume cutoff
would differ further for different ICH sites in the lobar
region (frontal, parietal, temporal, occipital), as there is
a rostrocaudal gradient in functional outcome for lobar
ICH, in which occipital ICH has the best outcome.32
Nonetheless, we could not perform such an analysis due
to the limited numbers.
Our study has several limitations. First, this was a
retrospective analysis of a prospective stroke cohort.
However, as we recruited consecutive ICH patients
treated in a single center, selection and outcome bias
were limited. Second, our cohort size is limited, espe-
cially for infratentorial and caudate ICH. Our preliminary

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 Teo et Location-Specific ICH Volume

CLINICAL AND
POPULATION
Figure 2. Location-specific hematoma volume cutoff and neurological outcome.
The location-specific volume cutoff for predicting neurological outcomes of different intracerebral hemorrhage (ICH) locations are shown. Green
Downloaded from http://ahajournals.org by on August 28,

represents good outcome (modified Rankin Scale [mRS] score 0–2), yellow represents poor outcome (mRS score 4–6), and mortality is colored
red. The odds for good outcomes were significantly higher when ICH volumes were smaller than the location-specific cutoffs for all supratentorial
ICH sites (all P<0.05). For poor outcome, the risk for all ICH locations was greater when volumes exceeded the respective cutoffs (all P<0.05).
Mortality risks were also higher for volumes larger than cutoffs for lobar, putamen/external capsule (EC), internal capsule (IC)/globus pallidus
(GP), and cerebellum (all P<0.001). *Multivariate regression analysis of respective outcome and location is available in Table S3. †Regression
analysis cannot be performed as all brainstem ICH patients with volume >10.5 mL died at 6 mo.
analysis demonstrated that caudate ICH is a distinct rather than the volume from the first brain CT. Finally,
ICH site with definite IVH, which was usually severe and our results are derived from a single center, where the
with high mortality, but the small sample size (n=17) predominant ethnicity was Han Chinese. Further studies
lim- ited further analysis of this site. For infratentorial are required to verify the generalizability of our results to
ICH, the small numbers led to a wide 95% CI for ROC other populations.
and regression analyses. Third, we employed the Our study displays numerous strengths. First, we
ABC/2 formula to calculate ICH volume rather than present a novel idea for patient selection based on
planimet- ric analysis. However, the formula is a well- location-specific ICH volume cutoff due to the signifi-
established method to calculate ICH volume and is more cant heterogeneity of ICH outcomes based on location.
practical for patient selection for trials.33 Forth, the This may be why ICH trials have repeatedly failed to
symptom onset/ LSW to CT time may affect the demonstrate therapeutic benefit in improving functional
location-specific cutoff values, as early-presenting outcomes. Importantly, all the ROC models for location-
patients tend to have hema- toma expansion, and late- specific cutoffs had good discriminant values, especially
arriving patients tend to have smaller ICH. Inherently, for supratentorial ICH, where these cutoffs were inde-
the cutoff values for late-arriving patients tended to be pendently associated with different outcomes of interest.
smaller. However, the potential confounding effect of Finally, our patients were treated under a standardized
the time window on the relation- ship between stroke pathway from a single center, reducing the treat-
location-specific hematoma volume and outcome was ment and outcome bias.
likely minimized as we utilized the larg- est ICH In summary, we demonstrate significant heterogeneity
volume recorded for all patients (for those with in ICH outcomes based on location-specific hematoma
hematoma expansion, the largest ICH volume was used),

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 Teo et
volume and present location-specific volume cutoffs for
different neurological outcomes of interest. Patient selec-
tion based on location-specific volume cutoff should be
POPULATION
considered in future ICH trials.
CLINICAL AND
ARTICLE INFORMATION
Received September 13, 2022; final revision received March 5, 2023; accepted
March 17, 2023.
Affiliations
Division of Neurology, Department of Medicine, Queen Mary Hospital (K.-C.T.,
S.-M.F., W.C.Y.L., I.Y.H.L., Y.-K.W., K.-K.Y., R.C.N.L., R.T.F.C., S.-L.H., K.-H.C., K.-K.L.),
Research Center of Heart, Brain, Hormone and Healthy Aging (R.T.F.C., S.-
L.H., K.-H.C., K.-K.L.), and Division of Neurosurgery, Department of Surgery,
Queen Mary Hospital (O.M.Y.C., A.C.O.T., G.K.K.L.), LKS Faculty of Medicine,
The Uni- versity of Hong Kong, Hong Kong SAR. The State Key Laboratory of
Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong SAR
(R.T.F.C., K.- H.C., K.-K.L.).
Acknowledgments
Drs Teo, Chan, and Lau performed concept and design. All authors performed
ac- quisition, analysis, or interpretation of data. Drs Teo and Fong performed
drafting of the article. All authors performed critical revision of the article for
important intellec- tual content. Drs Teo and Wong performed statistical analysis.
Drs Teo, Chan, A.C.O. Tsang, and Lau obtained funding. Choi and Dr Wong
provided administrative, tech- nical, or material support. Dr Teo had full access to
all of the data in the study and take responsibility for the integrity of the data and
the accuracy of the data analysis.
Sources of Funding
The authors’ work on this study was supported by funding from the Research
Fund Secretariat of the Food and Health Bureau, The Government of the Hong
Kong SAR. The funding entities had no role in the design or conduct of the study;
collection, management, analysis, or interpretation of the data; preparation, review,
or approval of the article; and decision to submit the article for publication.
Disclosures
Downloaded from http://ahajournals.org by on August 28,
Dr Teo is supported by the Hong Kong Neurological Society Scholarship for
Young Neurologist. Dr Lau is supported by the Innovation and Technology
Bureau, Re- search Grants Council, The Government of the Hong Kong SAR,
Amgen, Boehring- er Ingelheim, Eisai and Pfizer; and has consulted for Amgen,
Boehringer Ingelheim, Daiichi Sankyo and Sanofi; all of whom are unrelated to the
current work.
Supplemental Material
STROBE checklist
Tables S1–S6
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