1069203 WSO International Journal of Stroke X(X)Editorial

Research

International Journal of Stroke

2022, Vol. 17(1) 109­–119
Intravenous thrombolysis in stroke https://doi.org/10.1177/1747493021991969
© 2021 World Stroke Organization
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DOI: 10.1177/1747493021991969
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Marek Sykora1,2 , Stefan Krebs2, Florentina Simader1,

Thomas Gattringer3 , Stefan Greisenegger4, Julia Ferrari2,
Alexandra Bernegger2, Alexandra Posekany5 and
Wilfried Lang1,2; on behalf of the Austrian Stroke Unit
Registry Collaborators*

Abstract
Background: Up to 30% of stroke patients initially presenting with non-disabling or mild deficits may experience poor
functional outcome. Despite, intravenous thrombolysis remains controversial in this subgroup of stroke patients due to
its uncertain risk benefit ratio.
Aim: We aimed to analyze the real-world experience with intravenous thrombolysis in stroke patients presenting with
very low NIHSS.
Methods: Data of stroke patients presenting with mild initial stroke severity (NIHSS 0–5) including vascular risk factors,
stroke syndrome and etiology, early neurological deterioration, symptomatic intracerebral haemorrhage (sICH), and
functional outcome by modified Rankin Scale were extracted from a large nationwide stroke registry and analysed.
Patients were categorized and compared according to admission severity NIHSS 0–1 versus NIHSS 2–5 and intravenous
thrombolysis use.
Results: Seven hundred and three (2%) of 35,113 patients presenting with NIHSS 0–1 and 6316 (13.9%) of 45,521 of
patients presenting with NIHSS 2–5 underwent intravenous thrombolysis. In the NIHSS 0–1 group, intravenous thromb-
olysis was associated with early neurological deterioration (adjusted OR 8.84, CI 6.61–11.83), sICH (adjusted OR 9.32,
CI 4.53–19.15) and lower rate of excellent outcome (mRS 0–1) at three months (adjusted OR 0.67, CI 0.5–0.9). In stroke
patients with NIHSS 2–5, intravenous thrombolysis was associated with early neurological deterioration (adjusted OR
1.7, 1.47–1.98), sICH (adjusted OR 5.75, CI 4.45–7.45), and higher rate of excellent outcome (mRS 0–1) at three months
(adjusted OR 1.21, CI 1.08–1.34).
Conclusions: Among patients with NIHSS 0–1, intravenous thrombolysis did not increase the likelihood of excellent
outcome. Moreover, potential signals of harm were observed. Further research seems to be warranted.

Keywords
Low NIHSS, mild, minor, stroke, thrombolysis, harm, safety, efficacy, outcome

Received: 22 July 2020; accepted: 3 December 2020

Introduction
Up to 50% of strokes present with mild neurological
deficits (NIHSS score  5) on admission.1 Patients
with mild stroke symptoms are traditionally excluded
from intravenous thrombolysis (IVT) due to safety
concerns potentially outweighing the putative benefits
of recanalization therapy. Yet, up to 30% of minor
stroke patients may end up with relevant functional
deficits.2–4 Large non-randomized series suggested
benefit of IVT in mild stroke patients presenting
with NIHSS  5.5,6 However, the recent randomized
1
Medical Faculty, Sigmund Freud University Vienna, Austria
2
Department of Neurology, St John’s Hospital, Vienna, Austria
3
Department of Neurology, Medical University of Graz, Austria
4
Department of Neurology, Medical University Vienna, Austria
5
Research Unit of Computational Statistics, University of Technology,
Vienna
The first two authors contributed equally.
*A list of all national collaborators is provided in the Appendix 1
Corresponding author:
Marek Sykora, Krankenhaus Barmherzige Bruder Wien, Johannes von
Gott Platz 1, 1020 Vienna, Austria.
Email: marek.sykora@med.sfu.ac.at

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PRISMS study did not prove functional outcome
benefits in IVT-treated patients with non-disabling
stroke as compared to aspirin therapy.7 On the con-
trary, the study suggested harm due to an increased
rate of symptomatic intracerebral hemorrhage in the
IVT group. IVT in stroke with minor and non-dis-
abling symptoms remains thus highly controversial.
Here, we aimed to analyze the real-world experience
with IVT in stroke patients with admission NIHSS
score 0–1 in a large nationwide cohort.
Methods
Study design and population
The Austrian Unit Stroke Registry is a nationwide
prospective registry of the Austrian stroke unit network
founded by the Federal Ministry of Health. Anonymized
data on baseline characteristics, risk factors and eti-
ology, acute management, and functional outcome at
discharge and at three months are registered for all
patients admitted to one of currently 39 stroke units in
Austria. Data collection and clinical ratings are per-
formed by experienced stroke neurologists using stan-
dardized definitions of variables and scores. To ensure
high data quality, immediate electronic data entry is
obligatory. The web-based database includes online
plausibility checks and help. Biannual educational meet-
ings serve to guarantee uniform data documentation.
Clinical stroke syndrome is classified according to the
Oxfordshire Stroke Classification Project Criteria,8 and
cause is determined according to the Trial of Org 10172
in Acute Stroke Treatment criteria.9 More details on the
Austrian stroke unit registry and the definition of vari-
ables and ratings have been described previously.10 The
Austrian stroke unit registry is part of a governmental
quality assessment program for nationwide stroke care
and is financed by the Federal Ministry of Health. All
data are anonymized and centrally administered by the
Gesundheit Oesterreich GmbH—the national research
and planning institute for health care, a competence
and funding center of health promotion. All scientific
analyses included in this study were approved and super-
vised by a national academic review board.11 No
informed consent was obtained.
Data of patients coded as ‘‘ischemic stroke,’’ aged
>18 years, with admission NIHSS 0–5 and not
undergoing mechanical thrombectomy were extracted
from the Austrian Stroke Unit Registry. All partici-
pating centers used both CT and MR imaging to
confirm the stroke diagnosis. Therefore, the absolute
majority of the registry entries coded as ‘‘ischemic
stroke’’ were radiologically confirmed. In the rare
cases when CT and/or MRI was negative or MRI
was not performed, the diagnosis was based on
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clinical judgment of the stroke physician. Patients
coded as ‘‘TIA’’ and ‘‘stroke mimics’’ were excluded.
The following variables entered the analysis: age, sex,
IV tPA treatment, National Institute of Health
Stroke Scale (NIHSS) score at admission and dis-
charge, modified Rankin Scale (mRS)—pre-stroke,
and at three months, hypertension, diabetes, hyper-
cholesterolemia, smoking, previous stroke, atrial fib-
rillation, coronary heart disease, peripheral artery
disease, etiology according to TOAST criteria, and
symptomatic intracerebral hemorrhage (sICH)
according to ECASS3 criteria.12
For the purpose of this study, patients were
grouped according to admission NIHSS score (0–1
versus 2–5 points) and according to IVT or non-IVT
treatment. Efficacy outcome measures were defined as
achieving NIHSS 0 at discharge from the stroke unit,
achieving mRS 0 points at three months or mRS 0–1
points at three months. Safety outcomes included
symptomatic intracranial hemorrhage (sICH), early
neurological deterioration (END) defined as clinical
deterioration by equal or more than four NIHSS
points in the first 24–48 h after admission, any increase
(shift) between pre-stroke mRS score and follow-up
mRS score at three months and mortality at three
months.
Data availability statement
Data that support the findings of this study are avail-
able from the corresponding author upon reasonable
request.
Statistics
Continuous variables are summarized by their median
and interquartile range (IQR), while categorical vari-
ables are represented by absolute and relative frequen-
cies. Patients were categorized into groups based on
admission NIHSS (0–1 versus 2–5) and IVT adminis-
tration. Mann–Whitney U-test was used to compare
the locations of continuous and ordinal variables with-
out a normal distribution. Pearson’s �2 test and
Fisher’s exact test were comparing frequency and dis-
tribution of categorical variables. Multivariable logistic
regression models were applied to adjust for covariates
including age, sex, anterior/posterior syndrome, stroke
etiology, pre-stroke mRS, hypertension, diabetes melli-
tus, previous stroke, myocardial infarction, hyperlipid-
emia, atrial fibrillation, and peripheral arterial disease.
Due to the exploratory and hypothesis-generating char-
acter of the study, the effects of multiple testing have
not been adjusted by applying the Bonferroni correc-
tion. All statistics were performed using statistical soft-
ware R, version 3.0.1.
Sykora et al. 111
Results
Study population
At the time of the recent download, the Austrian Stroke
Unit Registry included data of 136,895 ischemic stroke
patients admitted to Austrian stroke units between
2003 and 2019. We extracted 134,882 completed indi-
vidual data sets with confirmed ischemic stroke, aged
� 18 years. Of those, 87,169 patients (64.6%) presented
with mild stroke symptoms with admission NIHSS
score 0–5. After excluding those undergoing thrombec-
tomy and those with missing information on i.v.
thrombolysis, 80,634 subjects entered the final analysis.
Functional outcome at three months was available for
29,723 patients. The comparison of those with and
without available follow-up information at three
months is given in (Supplemental Table 1).
Baseline characteristics and risk factors
Baseline characteristics and risk factors differed signifi-
cantly between NIHSS 0–1 (n ¼ 35,113) and NIHSS 2–5
(n ¼ 45,521) stroke patients, see Table 2. Summarized,
NIHSS 0–1 stroke patients were slightly younger, had
lower frequencies of stroke risk factors, less pre-stroke
disability, and less cardioembolic and more unknown
etiologies, see Table 1.
NIHSS 0–1 stroke patients undergoing IVT
Seven hundred and three (2%) of stroke patients pre-
senting with NIHSS 0–1 underwent IVT. As compared
to those with no IVT (n ¼ 34,402), IVT patients were
younger, had more anterior circulation strokes and less
lacunar syndromes, more cardioembolism and large
vessel disease as etiology, less premorbid disability
and fewer risk factors, and a slightly higher admission
NIHSS score, see Table 2.
NIHSS 2–5 stroke patients undergoing IVT
A total of 6316 (13.9%) of NIHSS 2–5 stroke patients
underwent IVT. As compared to the non-IVT group
(n ¼ 39,176), those with IVT were younger, had more
anterior circulation and less lacunar stroke syndrome,
less microangiopathy etiology, more unknown etiology,
less premorbid disability, fewer risk factors, and slightly
higher admission NIHSS score, see Table 3.
Safety outcomes of IVT in NIHSS 0–1
stroke patients
sICH occurred in 10 (1.4%) patients receiving IVT
as compared to 61 (0.2%) patients without IVT
(p < 0.001). Deterioration of NIHSS � 4 points between
admission and discharge was present in 64 (9.9%) in the
IVT group and in 422 (1.3%) in the non-IVT group
(p < 0.001). Any deterioration in mRS between admis-
sion and follow-up at three months was present in 107
(42.3%) in IVT group as compared to 229 (32.9%) in
the conservative group (p ¼ 0.003) Mortality at three
months was 12 (4.7%) in the IVT group and 339
(2.6%) in the non-IVT group (p < 0.001). After adjust-
ment, IVT in NIHSS 0–1 stroke patients was associated
with sICH (adjusted OR 9.32, 95% CI 4.53–19.15),
deterioration of NIHSS � 4 points (adjusted OR 8.84,
CI 6.61–11.83), any negative shift in the mRS score at
three months (adjusted OR 1.55, CI 1.17–2.05), and
mortality at three months (adjusted OR 10.55, CI
3.95–28.21), see Table 4.
Efficacy outcomes of IVT in NIHSS 0–1
stroke patients
Seven hundred and three (2%) of NIHSS 0–1 stroke
patients received IVT and 34,402 (98%) received con-
servative (non-IVT) therapy, see Table 2 for compari-
son. NIHSS 0 points at discharge was present in 373
(57.6%) in the IVT group and 25,089 (75.8%) in the
non-IVT group (p < 0.001). Follow-up at three months
was available for 253 patients in the IVT group and
12,857 in the non-IVT group. In the IVT group 191
(75.5%) and in the non-IVT group 10,386 (80.8%)
achieved mRS 0–1 at three months (p ¼ 0.09), see
Figure 1. After adjustment, IVT in NIHSS 0–1 stroke
patients was negatively associated with NIHSS 0 points
at discharge (adjusted OR 0.43, CI 0.36–0.5) and with
mRS 0–1 at three months (adjusted OR 0.57, CI 0.4–
0.81), see Table 4.
Safety outcomes of IVT in NIHSS 2–5
stroke patients
sICH occurred in 126 (2%) patients receiving IVT as
compared to 149 (0.4%) patients without IVT
(p < 0.001). Deterioration of NIHSS � 4 points between
admission and discharge was present in 262 (4.5%) and
1046 (2.8%) in the IVT group and in the non-IVT group,
respectively (p < 0.001). Any deterioration between pre-
stroke mRS and follow-up at three months was present in
1265 (54.9%) in the IVT group as compared to 8299
(58.1%) in the conservative group (p ¼ 0.017). Mortality
at three months was 133 (5.8%) in the IVT group and 878
(6.1%) in the non-IVT group (p ¼ 0.5). After adjustment,
IVT in NIHSS 2–5 patients was positively associated with
sICH (adjusted OR 5.75, 95% CI 4.45–7.45), with deteri-
oration of NIHSS � 4 points (adjusted OR 1.70, CI 1.47–
1.98), negatively associated with any increase in the mRS
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Table 1. Characteristics of stroke patients presenting with NIHSS 0–1 and NIHSS 2–5

NIHSS 0–1 NIHSS 2–5

N N ¼ 35,113 N ¼ 45,521 P-value

Sex male, N (%) 19,396 (55.2) 25,902 (56.9) <0.001

Sex female, N (%) 15,717 (44.8) 19,619 (43.1)

Age in years, median (Q0.25, Q0.75) 71 (59, 79) 73 (63, 81) <0.001

PACS, N (%) 10,073 (28.7) 16,864 (37.1) <0.001

LACS, N (%) 14,319 (40.8) 17,303 (38)

TACS, N (%) 638 (1.8) 1381 (3)

POCS, N (%) 6627 (18.9) 8515 (18.7)

Other clinical syndrome, N (%) 3413 (9.7) 1425 (3.1)

Hypertension, N (%) 23,226 (78.2) 39,676 (78.3)

Diabetes mellitus, N (%) 7007 (23.6) 12,255 (24.2)

Previous stroke, N (%) 6227 (21) 10,836 (21.4)

Myocardial infarction, N (%) 2434 (8.2) 4033 (8)

Hypercholesterolemia, N (%) 17,306 (58.3) 29,181 (57.6)

Atrial fibrillation, N (%) 5369 (18.1) 9081 (17.9)

Coronary artery disease, N (%) 5235 (18.6) 8887 (19.4)

Peripheral artery disease, N (%) 1682 (6) 2626 (5.7)

Smoking, N (%) 5693 (19.2) 9420 (18.6)

Thrombolysis 703 (2) 6316 (13.9)

Cardioembolism 5903 (16.8) 9807 (21.5) <0.001

Microangiopathy 10,042 (28.6) 13,371 (29.4)

Macroangiopathy 3750 (10.7) 5285 (11.6)

Other 847 (2.4) 884 (1.9)

Unknown 14,571 (41.5) 16,174 (35.5)

Premorbid mRS 0, N (%) 29,124 (82.9) 31,524 (69.3) <0.001

Premorbid mRS 1, N (%) 2966 (8.4) 5792 (12.7)

Premorbid mRS 2, N (%) 1354 (3.9) 3338 (7.3)

Premorbid mRS 3, N (%) 1068 (3) 3094 (6.8)

Premorbid mRS 4, N (%) 562 (1.6) 1661 (3.6)

Premorbid mRS 5, N (%) 39 (0.1) 112 (0.2)

NIHSS: National Institute of Health Stroke Scale; mRS: modified Rankin Score; PACS: partial anterior circulation syndrome; LACS: Lacunar syndrome;
TACS: total anterior circulation syndrome; POCS: posterior circulation syndrome.

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Table 2. Characteristics of stroke patients with NIHSS 0-1 receiving IVT and conservative therapy

No IVT IVT
N ¼ 34,402 N ¼ 703 P-value

Sex male, N (%) 18,975 (55.2) 416 (59.2) 0.097

Sex female, N (%) 15,427 (44.8) 287 (40.8)

Age in years, median (Q0.25, Q0.75) 71 (59, 79) 69 (57, 78) <0.001

PACS, N (%) 9796 (28.5) 276 (39.3) <0.001

LACS, N (%) 14,092 (41) 222 (31.6)

TACS, N (%) 602 (1.8) 36 (5.1)

POCS, N (%) 6491 (18.9) 134 (19.1)

Other clinical syndrome, N (%) 3379 (9.8) 34 (4.8)

Thrombolysis 0 (0) 703 (100)

Cardioembolism 5748 (16.7) 152 (21.6) <0.001

Microangiopathy 9888 (28.7) 153 (21.8)

Macroangiopathy 3659 (10.6) 89 (12.7)

Other 827 (2.4) 19 (2.7)

Unknown 14,280 (41.5) 290 (41.3)

Premorbid mRS 0, N (%) 28,507 (82.9) 611 (86.9) 0.153

Premorbid mRS 1, N (%) 2910 (8.5) 54 (7.7)

Premorbid mRS 2, N (%) 1335 (3.9) 19 (2.7)

Premorbid mRS 3, N (%) 1056 (3.1) 12 (1.7)

Premorbid mRS 4, N (%) 556 (1.6) 6 (0.9)

Premorbid mRS 5, N (%) 38 (0.1) 1 (0.1)

Admission NIHSS, median (Q0.25, Q0.75) 0 (0, 1) 1 (0, 1) <0.001

Hypertension, N (%) 25,701 (74.8) 491 (71) 0.018

Diabetes mellitus, N (%) 7100 (20.7) 135 (19.5) 0.377

Previous stroke, N (%) 6355 (18.5) 98 (14.2) 0.006

Myocardial infarction, N (%) 2573 (7.5) 38 (5.5) 0.101

Hypercholesterolemia, N (%) 19,569 (57) 384 (55.5) 0.431

Atrial fibrillation, N (%) 5207 (15.2) 93 (13.4) 0.223

Coronary artery disease, N (%) 5539 (17.7) 102 (16.9) 0.735

Peripheral artery disease, N (%) 1594 (5.1) 26 (4.3) 0.374

Smoking, N (%) 6141 (17.9) 145 (21) 0.305

NIHSS: National Institute of Health Stroke Scale; mRS: modified Rankin Score; PACS: partial anterior circulation syndrome; LACS: lacunar syndrome;
TACS: total anterior circulation syndrome; POCS: posterior circulation syndrome.

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Table 3. Characteristics of stroke patients with NIHSS 2-5 receiving IVT and conservative therapy

No IVT IVT P-value

N ¼ 39,176 N ¼ 6316

Sex male, N (%) 22,204 (56.7) 3681 (58.3) 0.057

Sex female, N (%) 16,972 (43.3) 2635 (41.7)

Age in years, median (Q0.25, Q0.75) 73 (63, 81) 72 (61, 80) <0.001

PACS, N (%) 13,702 (35) 3146 (49.8) <0.001

LACS, N (%) 15,441 (39.4) 1855 (29.4)

TACS, N (%) 1111 (2.8) 268 (4.2)

POCS, N (%) 7577 (19.4) 935 (14.8)

Other clinical syndrome, N (%) 1317 (3.4) 107 (1.7)

Thrombolysis 0 (0) 6316 (100)

Cardioembolism 8374 (21.4) 1427 (22.6) <0.001

Microangiopathy 11,716 (29.9) 1649 (26.1)

Macroangiopathy 4541 (11.6) 736 (11.7)

Other 793 (2) 90 (1.4)

Unknown 13,752 (35.1) 2414 (38.2)

Premorbid mRS 0, N (%) 26,467 (67.6) 5034 (79.7) <0.001

Premorbid mRS 1, N (%) 5167 (13.2) 624 (9.9)

Premorbid mRS 2, N (%) 3042 (7.8) 295 (4.7)

Premorbid mRS 3, N (%) 2846 (7.3) 246 (3.9)

Premorbid mRS 4, N (%) 1549 (4) 110 (1.7)

Premorbid mRS 5, N (%) 105 (0.3) 7 (0.1)

Admission NIHSS, median (Q0.25, Q0.75) 3 (2, 4) 4 (3, 5) <0.001

Hypertension, N (%) 31,875 (81.5) 4814 (77.4) <0.001

Diabetes mellitus, N (%) 10,735 (27.5) 1287 (20.7) <0.001

Previous stroke, N (%) 9528 (24.4) 1079 (17.3) <0.001

Myocardial infarction, N (%) 3360 (8.6) 493 (7.9) 0.202

Hypercholesterolemia, N (%) 22,864 (58.5) 3646 (58.6) 0.907

Atrial fibrillation, N (%) 8170 (20.9) 980 (15.8) <0.001

Coronary artery disease, N (%) 7473 (20.5) 1008 (18.4) <0.001

Peripheral artery disease, N (%) 2428 (6.7) 260 (4.7) <0.001

Smoking, N (%) 7652 (19.6) 1167 (18.8) 0.465

NIHSS: National Institute of Health Stroke Scale; mRS: modified Rankin Score; PACS: partial anterior circulation syndrome; LACS: lacunar syndrome;
TACS: total anterior circulation syndrome; POCS: posterior circulation syndrome.

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Table 4. Safety and efficacy outcomes in NIHSS 0–1 and NIHSS 2–5 stroke patients receiving IVT

Adjusted
NIHSS 0–1 IV (N ¼ 703) No IVT (N ¼ 34,402) P ORa CI

Early neurological deterioration, N (%) 64 (9.9) 422 (1.3) <0.001 8.84 6.61–11.83

sICH ECASS3, N (%) 10 (1.4) 61 (0.2) <0.001 9.32 4.53–19.15

Any mRS shift >0, N (%) 107 (42.3) (N ¼ 253) 229 (32.9) (N ¼ 12,857) 0.003 1.55 1.17–2.05

Mortality three months, N (%) 12 (4.7) (N ¼ 253) 339 (2.6) (N ¼ 12,857) <0.001 10.55 3.95–28.21

NIHSS 0 at discharge, N (%) 373 (57.6) 25089 (75.8) <0.001 0.43 0.36–0.5

mRS 0 at three months, N (%) 137 (54.2) (N ¼ 253) 7824 (60.9) (N ¼ 12,857) 0.01 0.67 0.5–0.9

mRS 0–1 at three months, N (%) 191 (75.5) (N ¼ 253) 10,386 (80.8) (N ¼ 12,857) 0.090 0.57 0.4–0.81

NIHSS 2–5 N ¼ 6316 N ¼ 39,176

Early neurological deterioration, N (%) 262 (4.5) 1046 (2.8) <0.001 1.70 1.47–1.98

sICH ECASS 3, N (%) 126 (2) 149 (0.4) <0.001 5.75 4.45–7.45

Any mRS shift > 0, N (%) 1265 (54.9) (N ¼ 2304) 8299 (58.1) (N ¼ 14,292) 0.017 0.83 0.76–0.92

Mortality three months, N (%) 133 (5.8) (N ¼ 2304) 878 (6.1) (N ¼ 14,292) 0.500 1.72 1.15–2.57

NIHSS 0 at discharge, N (%) 1953 (33.3) 9178 (24.4) <0.001 1.42 1.33–1.51

mRS 0 at three months, N (%) 914 (39.7) (N ¼ 2304) 4457 (31.2) (N ¼ 14,292) <0.001 1.23 1.11–1.36

mRS 0–1 at three months, N (%) 1542 (66.9) (N ¼ 2304) 8227 (57.6) (N ¼ 14,292) <0.001 1.21 1.08–1.34
sICH ECASS3: symptomatic intracranial haemorrhage according to ECASS3 criteria; NIHSS: National Institute of Health Stroke Scale; mRS: modified
Rankin Score.
a
Adjusted for: age, sex, anterior/posterior localization, etiology, pre-stroke mRS, hypertension, diabetes mellitus, previous stroke, myocardial infarction,
hyperlipidemia, atrial fibrillation and peripheric arterial disease.

score (adjusted OR 0.83, CI 0.76–0.92), and positively

associated with mortality at three months (adjusted OR
1.72, CI 1.15–2.57), see Table 5.
Efficacy outcomes of IVT in NIHSS 2–5
stroke patients
A total of 6316 (13.9%) of NIHSS 2–5 stroke patients
received IVT treatment and 39,176 (86.1%) received con-
servative non-IVT treatment, see Table 3. NIHSS 0 points
at discharge was present in 1953 (33.3%) and 9178
(24.4%) patients in the IVT and the non-IVT group,
respectively (p < 0.001). In the IVT group 1542 (66.9%)
and in the non-IVT group 8227 (57.6%) achieved
mRS 0–1 at three months (p < 0.001) (Figure 1). After
adjustment, IVT in NIHSS 2–5 stroke patients was posi-
tively associated with NIHSS 0 points at discharge
(adjusted OR 1.42, CI 1.33–1.51) and with mRS 0–1 at
three months (adjusted OR 1.21, CI 1.108–1.34), see
Table 4.
Sensitivity analysis including NIHSS 0–1
stroke patients undergoing computer
tomography angiography
A total of 6008 of 35,113 (17.1%) NIHSS 0–1 stroke
patients underwent computer tomography angiography
(CTA). Of those, 227 patients received IVT. NIHSS 0–1
stroke patients with CTA undergoing IVT had more
partial anterior clinical syndromes (39.2% versus
31.3%, p < 0.001), more large vessel occlusions
(26.3% versus 10.4%, p < 0.001), and higher median
admission NIHSS (1 versus 0, p < 0.001) as compared
to those not undergoing IVT (n ¼ 5781). Other baseline
characteristics were distributed equally. After adjust-
ment, IVT in NIHSS 0–1 stroke patients with CTA
was associated with SICH (adjusted OR 13.67, 95%
CI 3.81–49.11), deterioration of NIHSS � 4 points
(adjusted OR 7.38, CI 4.54–11.99), any negative shift
in the mRS score at three months (adjusted OR 1.69, CI

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Figure 1. Comparison of funtional outcomes of NIHSS 0–1 and NIHSS 2–5 stroke patiens receiving and not receiving intra-
venous thrombolysis.

0.95–3.03), and negatively associated with NIHSS 0
points at discharge (adjusted OR 0.42, CI 0.3–0.57)
and with mRS 0–1 at three months (adjusted OR
0.35, CI 0.18–0.70).
Discussion
The main finding of our study is the increased likeli-
hood of unfavorable outcome associated with IVT use
in patients with admission NIHSS score of 0 or 1. In
analogy, the recently published PRISMS study rando-
mizing non-disabling stroke patients NIHSS  5 to IVT
versus aspirin indicated possible harm for IVT, mainly
due to increased frequency of sICH.7 In our study,
sICH occurred in 1.4–2% which is lower than in
PRISMS (3.2%), however, in line with previous esti-
mates found in larger cohorts.5,13 Nevertheless, it
seems not to be proportional to the observed frequency
of neurological deterioration and poor outcome.
Indeed, sensitivity analysis after excluding patients
experiencing sICH produced nearly identical results
regarding the distribution of neurological deterioration
and poor outcome (data not shown). Thus, it seems
that non-sICH-related END rather than sICH might
be responsible for the observed unfavorable outcome.
Mechanism of END is poorly understood. According
to a recent meta-analysis, END occurs in approxi-
mately 14% of patients after IVT.14 Apart from

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Sykora et al. 117
mechanisms of neurological deterioration as sICH and
malignant edema, more than 50% END remain unex-
plained.15,16 Proposed mechanisms in patients treated
with rtPA may include reperfusion injury, effects of
hyperglycemia, or thrombus migration or re-emboliza-
tion.15 In line with the later, some studies showed asso-
ciations of post-IVT END with proximal arterial
occlusions,16,17 large vessel disease,17,18 cardiac embol-
ism,19 or fluctuating symptoms.20 Accordingly, large
vessel disease and cardioembolism were more prevalent
in the thrombolysed subgroup of NIHSS 0–1 stroke
patients as compared to those not receiving IVT.
Unfortunately, the Austrian Stroke Registry does not
contain sufficient data on vessel imaging for this sub-
group, mainly due to the fact that patients with non-
disabling/mild stroke only inconstantly underwent
acute vessel imaging. Nonetheless, sensitivity analysis
including a small subgroup of patients undergoing
vessel imaging seems to confirm the main results.
The effects of END and sICH in the general stroke
population undergoing IVT are commonly outweighed
by the benefits of rtPA-treatment. According to our
data, this seems to hold true for mild strokes presenting
with NIHSS 2–5 and undergoing IVT. Despite END
and sICH frequency of 4.5% and 2%, respectively,
stroke patients with NIHSS 2–5 achieved better func-
tional outcome with IVT. In line, previous studies
focusing on the effects of the IVT therapy uniformly
suggested benefit of IVT therapy in mild stroke patients
with NIHSS  5.5,21 On the contrary, the hypothetical
positive effects of IVT in strokes with NIHSS 0–1 seem
to be overruled by the effects of END and sICH driving
the worse outcome after IVT in this subgroup. Moreover,
one could speculate that a specific bias by indication may
account for the different behavior of NIHSS 2–5 and
NIHSS 0–1 stroke patients treated with IVT. Whereas,
in the NIHSS 2–5 subgroup, probably, a huge proportion
of patients presented with a clear disabling and stable
deficit justifying IVT, NIHSS 0–1 stroke patients most
likely harbored undescribed ‘‘factors’’ which lead the
treating physicians to administer IVT despite very low
NIHSS score or even non-disabling symptoms. These fac-
tors may have included brain stem or cerebellar symp-
toms not well captures by the NIHSS scale, results from
vessel imaging including findings of a vessel occlusion or
clinically fluctuating symptoms. Posterior circulation
strokes, LVO, and fluctuating symptoms have been sug-
gested previously to be predictive of neurological deteri-
oration and worse outcome.20,22–26 Hypothetically, the
uneven distribution of these factors might have been
responsible for the largely contra-intuitive outcomes in
IVT-treated NIHSS 0–1 stroke patients. If so, it may indi-
cate that all acute patients irrespectively of stroke severity
could benefit from vessel and perfusion imaging to guide
the treatment decision. In some patients with NIHSS 0–1,
IVT therapy alone may eventually be insufficient to
prevent deterioration by the natural course; in others,
deterioration may relate to IVT complications such as
sICH or thrombus fragmentation. Thus, our data indi-
cate that unselected IVT in NIHSS 0–1 stroke patients
may not be justified and is eventually associated with
harm.
Limitations of our study need to be addressed. We
consider the above-mentioned bias by indication to be
the main limitation hindering the clear interpretation of
our findings. Further limitations include the retrospect-
ive and non-randomized design allowing hypothetically
for more sources of bias. Moreover, as the follow-up at
three months was not mandatory by legislation in this
nationwide registry at the time of the study, the huge
number of patients lost to follow-up may limit the stat-
istical power. However, no differences have been found
in the comparison of patients with follow-up and those
without. Finally, the Austrian Stroke Unit Registry
only contains NIHSS scores and not the information
to what degree the stroke symptoms were functionally
disabling. Indeed, some patients with a very low NIHSS
score might still have an important deficit that might be
functionally disabling. This may limit the extrapola-
tions of our data to real life, where, mostly, the func-
tional disability and not the NIHSS score establishes
the IVT indication. Thus, our results have to be inter-
preted with caution and with regard to the mentioned
limitations. On the other hand, the strength of our
study is the rigorously collected large prospective multi-
center dataset reflecting closely the real-world setting in
acute stroke therapy.
Conclusion
Our data may indicate that IVT is not associated with
better functional outcomes when administered non-
selectively and may eventually be associated with
harm in NIHSS 0–1 strokes. Further research aiming
at better characterization of patients presenting with
very low NIHSS and/or non-disabling symptoms
seems to be highly warranted.
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 iDs
Marek Sykora https://orcid.org/0000-0003-3508-2176
Thomas Gattringer https://orcid.org/0000-0002-6065-6576
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118 International Journal of Stroke 17(1)
Supplemental material
Supplemental material for this article is available online.
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Appendix 1
Austrian Stroke Unit Registry Collaborators (Co-
Investigators): Johannes Sebastian Mutzenbach, MD
(Christian-Doppler-Clinic, Salzburg); Nele Bubel, MD
(Christian-Doppler-Clinic, Salzburg); Katharina
Sykora et al. 119
Millesi, MD (Christian-Doppler-Clinic, Salzburg);
Regina Katzenschlager, MD (Donauspital, Vienna);
Sabine Torma, MD (Donauspital, Vienna); Miroslav
Krstic, MD (Donauspital, Vienna); Franz Gruber,
MD (General Hospital, Linz); Milan R.Vosko, MD
(General Hospital, Linz); Cornelia Brunner,
MD (General Hospital, Linz), Michael Brainin, MD
(Hospital Donauregion, Tulln); Karl Matz,
MD (Hospital Donauregion, Tulln); Yvonne Teuschl,
MD (Hospital Donauregion); Omid Hosseiny, MD
(Hospital Göttlicher Heiland, Vienna); Wolf
Muellbacher, MD (Hospital Göttlicher Heiland,
Vienna); Dietlind Resch, MD (Hospital Hietzing,
Vienna); Martina Mayr, MD (Hospital Hietzing,
Vienna) Robert Paur, MD (Hospital Hietzing,
Vienna); Otto Berger, MD (Hospital Kaiser Franz-
Josef, Vienna); Vera Nussgruber, MD (Hospital
Kaiser Franz-Josef, Vienna);Wolfgang Grisold, MD
(Hospital Kaiser Franz-Josef, Vienna); Joerg Weber,
MD (Hospital Klagenfurt); Heinz Kohlfuerst, MD
(Hospital Klagenfurt); Klaus Berek, MD (Hospital
Kufstein); Maertin Sawires, MD (Hospital
Kufstein);Stefan Haaser, MD (Hospital Kufstein);
Susanne Asenbaum-Nan, MD (Hospital Mostviertel,
Amstetten); Awini Barwari, MD (Hospital
Mostviertel, Amstetten); Sarah Doerfler, MD
(Hospital Mostviertel, Amstetten); Stefan Oberndorfer
(Hospital St Poelten); Andreas Gatterer (Hospital St
Poelten); Alexander Tinchon (Hospital St Poelten);
Alexandra Herbst, MD (Hospital Oberwart);Barbara
Muellauer, MD (Hospital Oberwart); Eva Schubert-
Vadon, MD (Hospital Oberwart); Christian Eggers,
MD (Hospital of the Mercy Friars Linz); Christof
Bocksrucker, MD (Hospital of the Mercy Friars
Linz); Andrea Hackenbuchner, MD (Hospital Otto
Wagner, Vienna); Martin Krichmayr, MD (Hospital
Rudolfstiftung, Vienna); Peter Sommer, MD
(Hospital Rudolfstiftung, Vienna); Elisabeth Fertl,
MD (Hospital Rudolfstiftung, Vienna); Herbert
Koller, MD (Hospital LSF Graz); Franz-Stefan
Höger, MD (Hospital LSF, Graz); Nenad Mitrovic,
MD (Hospital Vöcklabruck); Thomas Salletmayr,
MD (Hospital Vöcklabruck); Monika Grunenberg,
MD (Hospital Vöcklabruck); Hanspeter Haring, MD
(Hospital Wagner-Jauregg, Linz); Nakajima Takeshi,
MD (Hospital Waldviertel Horn); Alexandra
Rieseneder, MD (Hospital Waldviertel Horn); Martin
Gabler (Hospital Waldviertel Horn); Andreas
Doppelbauer, MD (Hospital Weinviertel Mistelbach);
Stefan Pingitzer, MD (Hospital Weinviertel
Mistelbach); Manfred Eder; MD (Hospital
Weinviertel Mistelbach); Peter Schnider, MD
(Hospital Wiener Neustadt); Isabelle Csmarich, MD
(Hospital Wiener Neustadt); Andrea Hager-Seifert,
MD (Hospital Wiener Neustadt); Franz Fazekas, MD
(Medical University of Graz); Kurt Niederkorn, MD
(Medical University of Graz), Thomas Gattringer,
MD (Medical University of Graz); Johann Willeit,
MD (Medical University of Innsbruck); Michael
Knoflach, MD (Medical University of Innsbruck);
Stefan Kiechl, MD (Medical University of
Innsbruck); Claude Alf, MD (Neurological Center
Rosenhügel, Hospital Hietzing Vienna—1st
Department of Neurology); Georg Dimitriadis, MD
(Neurological Center Rosenhügel, Hospital Hietzing
Vienna—1st Department of Neurology); Manfred
Schmidbauer, MD (Neurological Center Rosenhügel,
Hospital Hietzing Vienna—1st Department of
Neurology); Elsa Fröschl, MD (Neurological Center
Rosenhügel, Hospital Hietzing Vienna—2nd
Department of Neurology); Christoph Baumgartner,
MD (Neurological Center Rosenhügel, Hospital
Hietzing Vienna—2nd Department of Neurology);
Judith Stanek, MD (Wilhelminen Hospital, Vienna);
Gerhard Daniel, MD (Wilhelminen Hospital, Vienna);
Silvia Parigger, MD (Wilhelminen Hospital, Vienna);
Josef Grossmann, MD (Hospital Lienz); Martin
Kosco, MD (Hospital Lienz); Robert Perfler, MD
(Hospital Lienz); Sylvia Promisch, MD (Hospital
LKH Villach); Peter Kapeller, MD (Hospital LKH
Villach); Magret Niederkorn-Duft, MD (Hospital
LKH Knittelfeld); Philipp Werner, MD (LKH
Feldkirch); Wolfgang Serles (Medical University of
Vienna); Eduard Auff (Medical UniversityofVienna);
Martin Heine, MD (Hospital Feldbach); Harald
Wurzinger, MD (Hospital Feldbach); Gesundheit
Österreich GmbH/BIQG (M. Moritz, A. Gollmer, R.
Kern,), Steering Group at the GÖG/BIQG.
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