Research

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Location-specific differences ! 2019 World Stroke Organization
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in hematoma volume predict sagepub.com/journals-permissions
DOI: 10.1177/1747493019830589

outcomes in patients with journals.sagepub.com/home/wso

spontaneous intracerebral hemorrhage

Natasha Ironside1 , Ching-Jen Chen2, Victoria Dreyer1,

Brandon Christophe1, Thomas J Buell2 and
Edward Sander Connolly1

Abstract
Background and objective: Functional outcome after spontaneous intracerebral hemorrhage (ICH) may vary depend-
ing on hematoma volume and location. We assessed the interaction between hematoma volume and location, and
modified the original ICH score to include such an interaction.
Methods: Consecutive ICH patients were enrolled in the Intracerebral Hemorrhage Outcomes Project from 2009 to
2017. Inclusion criteria were age18 years, baseline modified Rankin Scale (mRS) score 0–2, neuroimaging, and follow-up.
Functional dependence and mortality were defined as 90-day mRS>2 and death, respectively. A location ICH score was
developed using multivariable regression and area under the receiver operator characteristic curve (AUROC) analyses.
Results: The study cohort comprised 311 patients, and the derivation and validation cohorts comprised 209 and 102
patients, respectively. Interactions between hematoma volume and location predicted functional dependence (p ¼ 0.008)
and mortality (p ¼ 0.025). The location ICH score comprised age80 years (1 point), Glasgow Coma Scale score
(3–9 ¼ 2 points; 10–13 ¼ 1 point), volume–location (lobar:24 mL¼2 points, 21–24 mL¼1 point; deep:8 mL¼2
points, 7–8 mL¼1 point; brainstem:6 mL¼2 points, 3–6 mL¼1 point; cerebellum:24 mL¼2 points, 12–24 mL¼1
point), and intraventricular hemorrhage (1 point). AUROC of the location ICH score was higher in functional depend-
ence (0.883 vs. 0.770, p ¼ 0.002) but not mortality (0.838 vs. 0.841, p ¼ 0.918) discrimination compared to the original
ICH score.
Conclusions: The interaction between hematoma volume and location exerted an independent effect on outcomes.
Excellent discrimination of functional dependence and mortality was observed with incorporation of location-specific
volume thresholds into a prediction model. Therefore, the volume–location relationship plays an important role in ICH
outcome prediction.

Keywords
Intracerebral hemorrhage, hematoma volume, functional outcome, location, morbidity, mortality

Received: 7 October 2018; accepted: 23 January 2019

Introduction
Background and objectives
Spontaneous intracerebral hemorrhage (ICH) has an
approximate annual incidence of 15 to 25 per 100,000
persons, and it is associated with significant mortality
and functional disability.1–3 Hematoma volume is an
important predictor of morbidity and mortality that
has been consistently identified in these patients.4–7
Local mass effect of the hematoma on the adjacent
1
Department of Neurological Surgery, Columbia University College of
Physicians and Surgeons, New York, NY, USA
2
Department of Neurological Surgery, University of Virginia Health
System, Charlottesville, VA, USA
Corresponding author:
Natasha Ironside, Department of Neurological Surgery, Columbia
University Medical Center, 710 W. 168th St., New York 10032, NY, USA.
Email: ironsidenatasha@gmail.com

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2 International Journal of Stroke 0(0)
neuronal tissue results in primary injury, while subse-
quent perihematomal edema and inflammatory reac-
tions cause further disruption and damage to these
surrounding tissues.8 As a result, patient outcome is
contingent upon the normal function and eloquence
of the tissue found within or adjacent to the hema-
toma.9,10 Furthermore, the severity of neurological def-
icits and subsequent functional outcomes may vary
with different hematoma volumes at each location.5,9–14
A number of clinical and research tools exist for the
grading of ICH severity.15 Although the ICH score,
the most commonly utilized grading tool, accounts
for hematoma volume (30 mL) and infratentorial
ICH location as independent predictors of 30-day mor-
tality, it does not incorporate the potential importance
of the relationship between differences in initial hema-
toma volume and location.5 In this study, we aim to
assess the interaction between hematoma volume and
location, and to modify the original ICH score to
include such an interaction, if found.
Methods
Study design and setting
Between February 2009 and November 2017, consecu-
tive patients presenting with spontaneous
ICH at our institution were prospectively enrolled
in the Intracerebral Hemorrhage Outcomes Project
(ICHOP). The ICHOP study methods have been previ-
ously described in detail.16,17 The study was approved
by the Institutional Review Board (IRB) committee at
our institution, and written informed consent was
obtained from all patients (or respective legal guard-
ians) participating in the study. All participants or
designated proxies underwent a standardized data col-
lection protocol, which included a personal interview
and medical chart abstraction. The study was reported
in accordance with the STROBE statement.18
Participants
ICH was defined as an acute (<24 h) neurological def-
icit with evidence of intraparenchymal bleeding on neu-
roimaging. The inclusion criteria for this study were (1)
age  18 years; (2) baseline modified Rankin Scale
(mRS) score of 0–2 prior to ICH;19 (3) initial computed
tomography (CT) neuroimaging within 72 h of symp-
tom onset and (4) available 90-day follow-up functional
outcomes data. Primary intraventricular hemorrhage
(IVH) and ICH related to trauma, brain tumor, hem-
orrhagic transformation of cerebral infarction, vascular
abnormality, or any other suspected secondary causes
were excluded from the study.
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Variables
Baseline demographic and medical history data
included age, sex, ethnicity, history of atrial fibrillation
(AF), coronary artery disease (CAD), hyperlipidemia,
hypertension (HTN) and diabetes mellitus. Medication
history data included antiplatelet and/or anticoagulant
use prior to admission. Anticoagulant types included
heparin (comprising unfractionated and low-molecular
weight heparin) and warfarin. Use of novel oral anti-
coagulants was not recorded for any of the ICHOP
study patients. Clinical and laboratory data included
admission systolic blood pressure (SBP), blood glucose
and Glasgow coma scale (GCS) score.20 Outcome
measures included death at 90 days and functional
dependence, defined as a mRS score of >2 at 90 days.
Imaging analysis
Assignment of ICH location and volumetric analyses
were based upon the first available CT scan, and were
performed by neuroradiologists or neurologists blinded
to clinical data. Deep ICH was defined as hematoma
exclusively involving the thalamus or basal ganglia,
lobar ICH was defined as hematoma originating in
the cortex and/or cortical-subcortical junction.
Infratentorial hematomas were divided into two sub-
groups, defined by their site of origin in the cerebellum
or brainstem. Subjects with ICH involving more than
one territory were excluded from the analysis. ICH
location was adjudicated by prospective weekly consen-
sus meetings among ICHOP study neurologists.
MIPAV software (Version 4.3, NIH, MD) was uti-
lized to perform semi-automated hematoma volumetric
analysis. These methods have previously been described
in detail.21,22 Briefly, the center-point of the region of
interest (ROI) was manually identified from each two-
dimensional (2D) slice and level-set contouring was
applied. Thresholds of between 40 and 140 Hounsfield
Units (HU) were utilized for hematoma definition, and
segmentation accuracy was then confirmed by visual
inspection.23 In cases of erroneous results, manual edit-
ing of the ROI was performed by the user. The number
of segmented voxels and calculation of blood quantity
(in mL) was executed by the software and verified by
study staff.
Statistical methods
Statistical analyses were performed using SPSS
Statistics (version 25.0; IBM Corp, Armonk, NY,
USA). Univariable logistic regression analyses of base-
line data dichotomized by outcome measures were per-
formed. Normality was assessed using histogram plots
and the Shapiro-Wilk test. To evaluate the interaction
Ironside et al.
between hematoma volume and location, a derivation
sample comprising two-thirds of the patient cohort
were randomly selected. Multivariable logistic regres-
sion analyses, initially including all potential predictor
variables, with stepwise backward elimination of non-
contributory variables (p > 0.10), to identify independ-
ent predictors of mortality and functional dependence,
were performed on the derivation sample. Non-normal
variables were log-transformed prior to inclusion in the
regression analyses. The first-order interaction between
hematoma volume and location was tested in the final
model. Statistical models were assessed for goodness-
of-fit using the Hosmer–Lemeshow test and covariates
were tested for multicollinearity using tolerance and
variance inflation factor. Area under the receiver oper-
ator characteristic curve (AUROC) analysis was per-
formed to assess the discrimination of independent
variables included in the logistic regression models.
Cut-off points for location-specific hematoma volumes
were calculated using the Youden’s Index (YI) and
accuracy was assessed using sensitivity, specificity, posi-
tive predictive value (PPV) and negative predictive
value (NPV).24 An outcome risk stratification score,
the location ICH score, was derived from the cut-off
location-specific hematoma volume threshold values.
Additional components were added in a stepwise fashion
based upon the strength of their independent association
with the outcome measures. Models were compared
using AUROC analysis in order to select the optimal
scoring criteria. The accuracy of the location-specific
hematoma volume thresholds and the discriminative
ability of the location ICH score in predicting each of
the outcome measures were subsequently tested in the
validation sample comprising the remaining one-third of
the patient cohort. Sensitivity analyses were performed
to assess the discriminative ability of the location ICH
score after excluding patients with do not resuscitate
(DNR) or withdrawal of care status. Statistical signifi-
cance was defined as p < 0.05, and all tests were two-
tailed. Missing data were not imputed.
Results
Participants
Of the 664 enrolled patients, 352 patients were
excluded from the present study (51 patients for sec-
ondary cause of ICH, 183 patients for pre-admission
mRS > 2, 98 patients for lack of appropriate head CT
scan, 17 patients for primary IVH and 4 patients for
multiple ICH location) (Supplementary Figure 1,
Supplementary Table 1). The remaining 311 patients
(mean age 63  14 years; 39% (n ¼ 121) female) com-
prised 85 (27.2%) lobar, 180 (57.7%) deep, 28 (9.0%)
3
cerebellar and 18 (5.8%) brainstem ICH locations. The
median hematoma volumes were 24 mL (11–52 mL),
10 mL (3–28 mL), 14 mL (4–27 mL), and 4 mL
(2–10 mL) for lobar, deep, cerebellar, and brainstem
ICHs, respectively. Intraventricular extension was pre-
sent in 183 (47.5%) of cases, including 40/85 (47.1%)
lobar, 125/180 (69.4%) deep, 12/28 (42.9%) cerebellum
and 6/18 (33.3%) brainstem ICH locations.
Determinants of functional and survival outcomes
Univariable predictors of 90-day functional dependence
and mortality for the derivation cohort are presented in
Tables 1 and 2. At 90 days, functional dependence was
observed in 249/311 (80.0%) and mortality in 103/311
(33.1%) of all included patients. Among the derivation
cohort, functional dependence was observed in 168/209
(80.4%) and mortality in 70/209 (33.5%) of patients.
Independent predictors of 90-day functional depend-
ence were older age (OR¼1.074 [1.033–1.116],
p < 0.001), lower GCS score on admission (OR¼0.667
[0.548–0.812], p < 0.001), hematoma location
(Thalamus/ Basal ganglia: OR¼0.934 [0.307–2.842],
p ¼ 0.90; Cerebellar: OR¼0.039 [0.005–0.286],
p ¼ 0.001; Brainstem: OR¼1.837 [0.216–15.594],
p ¼ 0.58; with lobar as the reference category) and asso-
ciated IVH (OR¼2.921 [1.076–7.930], p ¼ 0.04). There
was a significant interaction between hematoma volume
and location in the model (OR¼1.375 [1.085–1.743],
p ¼ 0.008) (Table 3). Independent predictors of 90-day
mortality were older age (OR¼1.205 [1.013–1.075],
p ¼ 0.004) and lower GCS score on admission
(OR¼0.696 [0.620–0.782], p < 0.001). There was a sig-
nificant interaction between hematoma volume and
location in the model (OR¼1.205 [1.024–1.417],
p ¼ 0.025) (Table 4).
Location-specific hematoma volumes
Table 5 outlines the AUROC analyses for the associ-
ation between hematoma volume and the outcome
measures, stratified by location. The optimal cut-off
values to predict functional dependence were 21.0 mL
(YI¼0.374), 7.0 mL (YI¼0.578), 12.0 mL (YI¼0.525)
and 2.0 mL (YI¼0.833) for lobar, deep, cerebellum
and brainstem locations, respectively. The optimal
cut-off values to predict mortality were 24.0 mL
(YI¼0.357), 8.0 mL (YI¼0.408), 24.0 mL (YI¼0.623)
and 6.0 mL (YI¼0.800) for lobar, deep, cerebellum
and brainstem locations, respectively. The discrimina-
tive ability of the location-specific hematoma volume
cut-points in predicting functional dependence and
mortality for the validation cohort is summarized in
Supplementary Table 2.
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4 International Journal of Stroke 0(0)

Table 1. Univariable predictors of 90-day functional dependence (mRS 3–6) in patients admitted with spontaneous intracerebral
hemorrhage

Derivation cohort All patients

(n ¼ 209) (n ¼ 311)

mRS 0–2 mRS 3–6

(n ¼ 41) (n ¼ 168) OR 95% C.I. p-value

Demographics

Age, years (mean  S.D.) 56.3  11.4 63.79  14.4 1.038 1.011–1.065 0.005 62.6  14.7

Female, n (%) 10/41 (24.3) 69/168 (41.1) 2.161 0.994–4.696 0.052 121/311 (38.9)

Ethnicity, n (%)

White 8/41 (19.5) 37/168 (22.0) 70/311 (22.5)

Black 15/41 (36.6) 50/168 (29.8) 0.721 0.277–1.878 0.503 99/311 (31.8)

Asian 2/41 (4.9) 9/168 (5.4) 0.973 0.176–5.391 0.975 17/311 (5.5)

Hispanic 15/41 (36.6) 65/168 (38.7) 0.937 0.363–2.418 0.893 115/311 (37.0)

Other 2/41 (4.9) 5/168 (3.0) 1.514 0.162–14.080 0.716 10/311 (3.2)

Co-morbidities, n (%)

AF 1/41 (2.4) 16/168 (9.5) 4.211 0.541–32.710 0.169 25/311 (8.0)

CAD 7/41 (17.0) 19/168 (11.3) 0.619 0.241–1.591 0.320 39/311 (12.5)

Hyperlipidemia 11/41 (26.8) 40/168 (23.8) 0.853 0.392–1.853 0.687 82/311 (26.4)

HTN 32/41 (78.0) 133/168 (79.2) 1.069 0.467–2.446 0.875 243/311 (78.1)

Diabetes mellitus 11/41 (26.8) 39/168 (23.2) 0.825 0.379–1.795 0.627 74/311 (23.8)

Medications

Antiplatelets 16/41 (39.0) 56/168 (33.3) 0.781 0.386–1.581 0.492 112/311 (36.0)

Anticoagulants 3/41 (7.3) 20/168 (11.9) – – – 32/311 (10.3)

Heparin 1/41 (2.4) 3/168 (1.8) 0.770 0.077–7.614 0.823 6/311 (2.0)

Warfarin 2/41 (4.9) 17/168 (10.1) 2.182 0.483–9.858 0.310 26/311 (8.4)

Clinical variables

SBPa, mean mmHg  SD 192.9  40.3 186.1  45.0 0.996 0.989–1.005 0.390 186.6  41.8

Glucosea, mean mmol/L  SD 154.9  84.5 156.4  67.7 1.000 0.995–1.005 0.905 156.0  70.6

GCSa, median [IQR] 15 [14–15] 8 [5–14] 0.639 0.537–0.759 <0.001 11 [6–15]

Hematoma volume, 4 [2–11] 14 [6–39] 1.057 1.025–1.090 <0.001 22.5  26.1

median mL [IQR]

Hematoma location

Lobar 10/41 (24.4) 45/168 (26.8) – – – 85/311 (27.3)

(continued)

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Ironside et al. 5

Table 1. Continued

Derivation cohort All patients

(n ¼ 209) (n ¼ 311)

mRS 0–2 mRS 3–6

(n ¼ 41) (n ¼ 168) OR 95% C.I. p-value

Basal Ganglia/Thalamus 21/41 (51.2) 100/168 (59.5) 1.058 0.461–2.430 0.894 180/311 (57.9)

Cerebellum 8/41 (19.5) 10/168 (6.0) 0.278 0.088–0.882 0.030 28/311 (9.0)

Brainstem 2/41 (4.9) 13/168 (7.7) 1.444 0.281–7.438 0.660 18/311 (5.8)

Infratentorial, n (%) 10/41 (24.3) 23/168 (13.7) 0.491 0.212–1.136 0.097 46/311 (14.8)

IVH present, n (%) 19/41 (46.3) 113/168 (67.3) 2.379 1.189–4.759 0.014 183/311 (58.9)
AF: atrial fibrillation; CAD: coronary artery disease; CHF: congestive heart failure; HTN: hypertension; SBP: systolic blood pressure; DBP: diastolic
blood pressure; GCS: Glasgow Coma Scale; NIHSS: National Institutes of Health Stroke Severity Scale score; IVH: intraventricular hemorrhage; C.I.:
confidence interval; OR: odds ratio; S.D.: standard deviation; p-value: probability value. Bold values indicate statistical significance.
a
On admission.

Location ICH score
An outcome risk stratification scale was developed
from categorized hematoma volume data, to which
points were assigned on the basis of location.
Location-specific hematoma volume thresholds most
predictive of functional dependence were assigned one
point, whereas those most predictive of mortality were
assigned two points. AUROC analyses and optimal
cut-off values for the remaining continuous independ-
ent outcome predictors are presented in Supplementary
Table 3. The location ICH score components are pre-
sented in Table 6. The AUROC for the location ICH
score in predicting 90-day functional dependence
was 0.859, which was significantly higher than
that of the original ICH score (0.859 vs. 0.806,
p ¼ 0.03) (Supplementary Table 4). AUROC for the
location ICH score in predicting 90-day mortality was
0.831, and this was similar to that of the original
ICH score (0.831 vs. 0.826, p ¼ 0.60) (Supplementary
Table 4).
Validation of the location ICH score
The AUROC for the location ICH score in predicting
90-day functional dependence among the validation
cohort was 0.883, which was significantly higher than
that of the original ICH score (0.883 vs. 0.770,
p ¼ 0.002; Figure 1, Table 7). Distributions of patients
with functional dependence at 90 days among the ori-
ginal ICH and modified ICH scores are presented in
Figure 2. The AUROC for the location ICH score in
predicting 90-day functional dependence was signifi-
cantly higher than that of the modified ICH score
(0.883 vs. 0.783; p ¼ 0.05), the ICH-GS score (0.883
vs. 0.585; p < 0.001) and the FUNC score (0.883 vs.
0.686; p ¼ 0.006).
The AUROC for the location ICH score in predict-
ing 90-day mortality among the validation cohort was
0.838, and this was similar to that of the original ICH
score (0.838 vs. 0.841, p ¼ 0.92; Figure 1, Table 7).
Distributions of patients with mortality at 90 days
among the original ICH and modified ICH scores are
presented in Figure 2. The AUROC for the location
ICH score in predicting 90-day mortality was signifi-
cantly higher than the ICH-GS score (0.838 vs. 0.593;
p < 0.001). It was not significantly different to that of
the modified ICH score (0.838 vs. 0.853; p ¼ 0.96) and
the FUNC score (0.838 vs. 0.812; p ¼ 0.72). Patient
characteristics of the validation cohort are presented
in Supplementary Table 6.
Sensitivity analyses
After exclusion of patients with DNR or withdrawal of
care status (n ¼ 21), the AUROC for the location ICH
score in predicting 90-day functional dependence
among the validation cohort remained significantly
higher than that of the original ICH score (0.847 vs.
0.702; p ¼ 0.002). The AUROC for the location ICH
score in predicting 90-day mortality among the valid-
ation cohort was similar to that of the original ICH
score (0.744 vs. 0.746, p ¼ 0.97).
Discussion
Hematoma volume has been established as the stron-
gest independent predictor of clinical outcome follow-
ing spontaneous ICH and is, therefore, a critical
component of all ICH prognostic scores.4–6,25–29

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6 International Journal of Stroke 0(0)

Table 2. Univariable predictors of 90-day mortality in patients admitted with spontaneous intracerebral hemorrhage

Derivation cohort
(n ¼ 209)

Alive Dead All patients

(n ¼ 139) (n ¼ 70) p-value (n ¼ 311)

Demographics

Age, years (mean  SD) 61.2  13.5 64.5  15.6 1.017 0.997–1.038 0.104 62.6  14.7

Female, n (%) 51/139 (36.7) 28/70 (40.0) 1.087 0.184–1.047 0.781 121/311 (38.9)

Ethnicity, n (%) 0.194

White 30/139 (21.6) 15/70 (21.4) 70/311 (22.5)

Black 45/139 (32.4) 20/70 (28.6) 0.984 0.433–2.349 0.970 99/311 (31.8)

Asian 7/139 (5.0) 4/70 (5.7) 1.265 0.318–50.35 0.738 17/311 (5.5)

Hispanic 55/139 (39.6) 25/70 (35.7) 1.006 0.457–2.214 0.987 115/311 (37.0)

Other 2/139 (1.4) 6/70 (8.6) 6.643 1.189–37.107 0.031 8/311 (2.6)

Co-morbidities, n (%)

AF 9/139 (6.5) 8/70 (10.1) 1.909 0.702–5.187 0.205 25/311 (8.0)

CAD 18/139 (12.9) 8/70 (12.4) 0.889 0.366–2.160 0.795 39/311 (12.5)

Hyperlipidemia 35/139 (25.2) 16/70 (27.9) 0.906 0.460–1.783 0.774 82/311 (26.4)

HTN 111/139 (79.9) 54/70 (77.5) 0.828 0.413–1.660 0.595 243/311 (78.1)

Diabetes mellitus 38/139 (27.3) 12/70 (20.2) 0.565 0.274–1.167 0.123 74/311 (23.8)

Medications

Antiplatelets 46/139 (33.1) 26/70 (37.1) 1.236 0.677–2.254 0.490 112/311 (36.0)

Anticoagulants 13/139 (9.4) 10/70 (14.3) – – – 32/311 (10.3)

Heparin 1/139 (0.7) 3/70 (4.4) 6.458 0.658–63.396 0.109 6/311 (2.0)

Warfarin 12/139 (8.6) 7/70 (10.1) 1.256 0.470–3.352 0.650 26/311 (8.4)

Clinical variables

SBPa, mean mmHg  S.D. 188.3  40.4 185.7  51.1 0.999 0.991–1.005 0.684 186.6  41.8

Glucosea, mean mmol/L  S.D. 146.4  65.3 174.9  78.1 1.006 1.001–1.010 0.011 156.0  70.6

GCSa, median [IQR] 14 [9–15] 6 [3–8] 0.688 0.621–0.763 <0.001 11 [6–15]

Hematoma volume, 8 [3–23] 30 [11–50] 1.030 1.017–1.043 <0.001 22.5  26.1

median mL [IQR]

Hematoma location 0.517

Lobar 41/139 (29.5) 14/70 (20.0) 85/311 (27.3)

Thalamus/Basal ganglia 77/139 (55.4) 44/70 (62.9) 1.673 0.822–3.407 0.156 180/311 (57.9)
(continued)

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Ironside et al. 7

Table 2. Continued

Derivation cohort
(n ¼ 209)

Alive Dead All patients

(n ¼ 139) (n ¼ 70) p-value (n ¼ 311)

Cerebellum 11/139 (7.9) 7/70 (10.0) 1.464 0.462–4.636 0.517 28/311 (9.0)

Brainstem 10/139 (7.2) 5/70 (7.1) 1.464 0.426–5.025 0.544 18/311 (5.8)

Infratentorial, n (%) 21/139 (15.1) 12/70 (17.1) 1.017 0.462–2.239 0.966 46/311 (14.8)

IVH present, n (%) 80/139 (57.6) 52/70 (74.3) 2.064 1.095–3.889 0.025 183/311 (58.9)
AF: atrial fibrillation; CAD: coronary artery disease; HTN: hypertension; SBP: systolic blood pressure; GCS: Glasgow Coma Scale; IVH: intraventricular
hemorrhage; C.I.: confidence interval; S.D.: standard deviation; OR: odds ratio; p-value: probability value. Bold values indicate statistical significance.
a
On admission.

Table 3. Multivariable model of the independent predictors of Table 4. Multivariable model of the independent predictors of
90-day functional dependence 90-day mortality

Odds Odds
mRS 3-6 ratio 95% C.I. p-value Mortality ratio 95% C.I. p-value

Age 1.074 1.033–1.116 <0.001 Age 1.205 1.013–1.075 0.004

GCSa 0.667 0.548–0.812 <0.001 GCSa 0.696 0.620–0.782 <0.001

Location Hematoma 1.205 1.024–1.417 0.025

volume–location
Lobar – – – interaction

Thalamus/Basal 0.934 0.307–2.842 0.904 Note: Hoesmer-Lemeshow goodness of fit test v2(8)¼5.136; p ¼ 0.743.
ganglia GCS: Glasgow Coma Scale; mRS: modified Rankin scale; CI: confidence
interval; p-value: probability value.
a
Cerebellar 0.039 0.005–0.286 0.001 On admission.

Brainstem 1.837 0.216–15.594 0.577

of IVH extension in deep ICH.12,31,32 Finer neuroana-
Hematoma 1.375 1.085–1.743 0.008 tomical distinction (stratification by six location sub-
volume–location groups) has revealed differences in hematoma location
interaction (p < 0.001), higher initial hematoma volume (p < 0.001)
Associated IVH 2.921 1.076–7.930 0.035 and lower admission GCS score (p < 0.001) to be inde-
pendent predictors of 30-day case fatality.11 The ana-
Note: Hoesmer–Lemeshow goodness of fit test v2(8)¼8.843; p ¼ 0.346. lysis of 2066 patients enrolled in the Intensive Blood
GCS: Glasgow Coma Scale; mRS: modified Rankin scale; CI: confidence
interval; p-value: probability value.
Pressure Reduction in Acute Cerebral Hemorrhage
a
On admission. (INTERACT2) trial, further highlighted location-
dependent differences in initial hematoma volume in
addition to a location-dependent risk of death or
Additional associations between hematoma volume major disability (posterior limb of the internal capsule
and hematoma location have been identified.4,11,12,14,30 (OR¼2.10), thalamus (OR¼2.24) and infratentorial
Because lobar ICH has been consistently associated location (OR¼3.04).14 This, in conjunction with obser-
with improved neurologic outcomes upon comparison vations of differences between the risk factors and
to deep ICH, it has been suggested that the higher ini- determinants of hematoma volume among patients
tial hematoma volumes in lobar ICH may be offset by stratified by lobar versus deep ICH location, lends sup-
the poor prognosis associated with increased likelihood port to the hypothesis that location-dependent biologic

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8 International Journal of Stroke 0(0)

Table 5. AUROC analyses identifying the optimal cutoff volumes predictive of poor 90-day functional outcome and mortality for
each hematoma location

Optimal
cut-off Sensitivity Specificity PPV NPV
Location Mean volume  SD (mL) AUROC 95% CI (mL) YI (%) (%) (%) (%)

mRS 0–2 mRS 3–6

(n ¼ 41) (n ¼ 168)

Lobar 19.0  19.9 40.9  19.0 0.695 0.524–0.865 21.0 0.374 67.3 70.0 91.2 31.8
(n ¼ 56)

Basal Ganglia/ 4.1  4.8 22.8  23.4 0.822 0.737–0.907 7.0 0.578 68.0 85.7 95.8 36.0
Thalamus
(n ¼ 121)

Cerebellum 12.5  9.8 22.7  12.1 0.744 0.506–0.982 12.0 0.525 90.0 62.5 75.0 83.3
(n ¼ 18)

Brainstem 1.5  0.7 10.9  11.7 0.854 0.650–1.000 2.0 0.833 83.3 50.0 90.9 33.3
(n ¼ 14)

Alive Dead
(n ¼ 139) (n ¼ 70)

Lobar 29.1  26.4 60.3  45.8 0.723 0.569–0.876 24.0 0.357 78.6 57.1 37.9 88.9
(n ¼ 56)

Basal Ganglia/ 12.5  15.5 32.1  27.2 0.758 0.671–0.846 8.0 0.408 81.8 58.4 52.9 84.9
Thalamus
(n ¼ 121)

Cerebellum 13.3  8.5 25.9  13.3 0.786 0.528–1.000 24.0 0.623 71.4 90.9 83.3 83.3
(n ¼ 18)

Brainstem 5.6  8.9 19.6  11.1 0.900 0.732–1.000 6.0 0.800 100.0 80.0 66.7 100.0
(n ¼ 14)

AUROC: Area under the receiver operator characteristic curve; YI: Youden Index; PPV: positive predictive value; NPV: negative predictive value; CI:
confidence interval; SD: standard deviation; p-value: probability value; mRS: modified Rankin Scale.

pathways responsible for ICH development may deter-
mine both ICH risk and the extent of consequent bleed-
ing.8,31,33 Thus, the severity of neurological deficit and
subsequent functional outcome may vary based upon
differences in hematoma volume and location.
We sought to assess the potential interaction between
hematoma volume and location, and to refine the ori-
ginal ICH score using location-specific hematoma
volume thresholds. In our cohort, the interaction
between ICH location and hematoma volume was a sig-
nificant independent predictor of both functional
dependence (mRS > 2) and mortality. Furthermore,
location-specific differences in the hematoma volumes
that predicted clinical outcomes were observed.
Subsequent analyses revealed that for lobar, cerebellar
and brainstem hematomas, larger hematoma volumes
predicted mortality, upon comparison to the volumes
associated with functional dependence (lobar: 24.0 vs.
21.0 mL, deep: 8.0 vs. 7.0 mL, cerebellar: 24.0 vs.
12.0 mL, brainstem: 6.0 vs. 2.0 mL for mortality and
functional dependence, respectively). While these find-
ings are consistent with consensus evidence associating
higher hematoma volumes with worse clinical outcome,
it appeared that the gradient of the relationship asso-
ciated with increasing hematoma volume and worse clin-
ical outcome may have varied by location.4–6
Additional independent predictors of functional
dependence (age, admission GCS, associated IVH) and
mortality (age, admission GCS) were consistent with
previous reports.4,5,29 Based upon the observed relation-
ship between increasing hematoma volume and worse
clinical outcome for the location sub-groups, we retro-
spectively assigned points to our clinical data for attain-
ment of the location-specific hematoma volume most
predictive of functional outcome (one point) or mortality
(two points). Stepwise addition of independent variables
associated with functional dependence revealed that
inclusion of the following categories—age  80 (one
point), GCS 10–13 (one point), GCS 3–9 (two points)
and associated IVH (one point)—resulted in a

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Ironside et al. 9

Table 6. Components of the location ICH score score and may, in fact, better delineate the likelihood of
90-day functional dependence from mortality in patients
Component Points presenting with spontaneous ICH. However, the fact
Age, yr
that the original ICH score was principally designed to
predict 30-day mortality may have limited the rationale
80 1 of our comparisons at 90 days.5,25,26
Since Hemphill et al. proposed the original ICH
<80 0 score in 2001, a number of modifications have been
GCS scorea
introduced.5,15 The modified ICH score substituted
admission GCS for the National Institutes of Health
3–9 2 Stroke Severity Scale (NIHSS), and was associated
with improved prediction of good functional outcome,
10–13 1 defined as mRS 2, upon comparison to the original
14–15 0
ICH score.29 The ICH-GS score, which incorporated
differences in hematoma volume between infratentorial
Hematoma volume, mLa and supratentorial locations and stratified age into
three subgroups, was associated with a higher sensitiv-
Lobar ity for predicting in-hospital (p < 0.05) and 30-day mor-
24 2
tality (p < 0.05).34 External validation revealed the
ICH-GS score to be superior to the original ICH
21–24 1 score in predicting 90-day favorable functional out-
come, defined as mRS 2 (p ¼ 0.005).35 The FUNC
<21 0 score, designed to predict functional independence
Deep
when defined as a Glasgow Outcome score 4, included
the presence of pre-ICH cognitive impairment as an
8 2 additional score criteria and stratified patients by
three location subgroups.13 Addition of the CT angiog-
7–8 1 raphy spot sign to the original ICH scoring criteria has
<7 0
not been associated with a significant improvement to
the score’s discriminative ability of 90-day poor func-
Brainstem tional outcome (p ¼ 0.14), when defined as mRS 3.28
This highlights the prognostic significance of potential
6 2 interactions between the other independent predictors
2–6 1
of poor functional outcome within the original score.
Throughout the various modifications, the basic archi-
<2 0 tecture of location, hematoma size and admission GCS
score has persisted, which further illustrates the predict-
Cerebellum ive strength of these variables.13,29,34–37
24 2
Utilizing Random Forest machine learning tech-
niques, we have previously attempted to develop a scor-
12–24 1 ing system designed to predict 90-day functional
outcomes among a cohort of 575 patients enrolled in
<12 0 the ICHOP study between 2009 and 2016.38 However,
Associated IVH 1
the derived score was complicated, impractical and did
not assess the prognostic significance of hematoma
GCS: Glasgow Coma Scale, yr: years. location; features that we have attempted to address
a
On admission.
in our current investigation. We acknowledge that the
original ICH score AUROC values of 0.770 and 0.841
significantly higher discriminative ability in predicting for the prediction of functional dependence and mor-
functional dependence (p ¼ 0.002) but not mortality tality, respectively, represent acceptable to excellent dis-
(p ¼ 0.918), upon comparison to the original ICH crimination and thus our results may lack clinical
score. Taken together, these findings suggest that relevance.39 Our analyses revealed the location ICH
combining location-specific hematoma volumes with score to perform better in the discrimination of func-
outcome predictors from previously established prog- tional dependence upon comparison to the various pro-
nostic algorithms performs as well as the original ICH posed modifications, including the modified ICH score

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10 International Journal of Stroke 0(0)

Figure 1. Comparisons of AUROC between the original ICH score and the location ICH score in predicting (a) 90-day poor
functionl outcome (modified Rankin Scale score 3–6) and (b) 90-day mortality.

Table 7. AUROC analyses of the predictive value of the ICH scoring systems

Validation cohort
(n ¼ 102)

Optimal Sensitivity Specificity PPV NPV

AUROC 95% CI cut-off (%) (%) (%) (%)

mRS 3–6

O-ICH score 0.770 0.674–0.865 2 57.7 90.5 95.7 27.3

(0–6)

L-ICH score 0.883 0.819–0.947 2 68.8 100.0 100.0 45.7

(0–6)

Mortality

O-ICH score 0.841 0.756–0.928 3 56.2 92.5 78.3 81.6

(0–6)

L-ICH score 0.838 0.749–0.927 5 53.5 95.7 85.0 81.5

(0–6)
O-ICH: Original intracerebral hemorrhage score; L-ICH: location intracerebral hemorrhage score.

(p ¼ 0.05), the ICH-GS score (p < 0.001) and the FUNC
score (p ¼ 0.002). However, the discriminative ability of
these modified scores, in our cohort, was substantially
lower than previous reports.13,34,35 This highlights the
inherent limitations to deriving a prognostic score from
a single center retrospective cohort, and substantiates
the need for external validation in large, multi-center
studies. Despite this, our primary aim was to analyze
the association between hematoma volume, location
and clinical outcome. We present evidence for location
as a determinant of the initial hematoma volume asso-
ciated with functional dependence. This phenomenon
may occur as a result of divergent pathoetiologies
which determine the extent of the initial hematoma
volume and/or the respective function and eloquence
of the tissue found within or adjacent to the hema-
toma.9,10,29 Interestingly, location has not been demon-
strated to exert an independent influence on hematoma
growth and its associated effect on outcomes.40
Therefore, the proposed relationship between location

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Ironside et al.
Figure 2. Distributions of patients with poor functional outcomes at 90 days among the (a) original ICH and (b) location ICH
scores. Distributions of patient mortality at 90 days among the (c) original ICH and (d) location ICH scores.
and initial hematoma volume, which appears to play an
important role in ICH outcome prediction, may pro-
vide an efficacious and practical means for risk stratifi-
cation in patients with spontaneous ICH.
Our study has several limitations which affect
the validity of our results. Importantly, this study
protocol was not specifically constructed to investigate
the association between location-specific hematoma
volumes and ICH outcomes. Therefore, our retrospect-
ive analysis is subject to confirmation bias in that vari-
ables were chosen based upon data availability and
hypothesis-generation. Specifically, data on hematoma
expansion, IVH volume, IVH expansion and hydro-
cephalus were not presented in this study, all of which
are previously established determinants of ICH out-
come.21,41–43 Further potential limitations include
reporting, recall and missing data biases due to the con-
ditional nature of our results on the accuracy of rec-
orded data. Furthermore, the sourcing of this study
data from a single center is subject to concomitant
selection bias. Our association results should be inter-
preted with caution, given the multitude of factors that
11
influence morbidity and mortality. In conforming
our data to a simplified prognostic model, unmeasured
confounding is likely to have been disregarded. While
our inclusion criteria specified patients who were
functionally independent at baseline (mRS 0–2) in an
attempt to accurately characterize the predictors of 90-
day functional dependence (mRS > 2), our location
ICH score was assigned to a cohort of patients that
were managed with existing outcome prediction
models. Therefore, this may be biased towards a self-
fulfilling prophecy in that patients with early prognos-
tication of a negative outcome may have been subjected
to care limitations. Because the validation sample size
was small and derived from the original patient cohort,
our comparisons between an extensively validated
and a novel prognostic score may lack generalizability.
This has been demonstrated by the presence of baseline
differences between ICHOP patients that were included
and excluded from this study. Therefore, external val-
idation of the location ICH score in a large patient
cohort is necessary, before definite conclusions can be
drawn regarding its scientific and clinical utility.
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12
Conclusions
Hematoma location and volume are significant pre-
dictors of clinical outcome in patients presenting with
ICH. There are significant interactions between hema-
toma location and volume in multivariable models pre-
dicting mortality and functional outcome in ICH
patients. ICH outcomes vary based on location-specific
hematoma volume thresholds. Incorporation of these
thresholds into a modified ICH score demonstrated
excellent discrimination of patients with functional
dependence and mortality. Therefore, the relationship
between hematoma volume and location plays an
important role in ICH outcome prediction.
Additional optimization and prospective validation of
the modified scoring system may be necessary.
Acknowledgements
The authors thank Dr Eric Heyer, MD, PhD and Dr David
Roh, MD, for their critical review of the manuscript.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
ORCID iD
Natasha Ironside http://orcid.org/0000-0002-9390-1574
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