Received: 26 March 2021 | Revised: 31 May 2021 | Accepted: 22 June 2021

DOI: 10.1111/ane.13496

ORIGINAL ARTICLE

Effects of insular involvement on functional outcome after

intracerebral hemorrhage

Matthias Wittstock1 | Kezia Meyer1 | Jan Klinke1 | Annette Grossmann2 |

Uwe Walter1 | Alexander Storch1

1
Department of Neurology, University of
Rostock, Rostock, Germany Objective: Ischemic stroke, as well as intracerebral hemorrhage (ICH), involving the
2
Institute of Diagnostic and Interventional insular cortex tends to be more severe. The impact of insular involvement on outcome
Radiology, Pediatric Radiology and
Neuroradiology, University of Rostock,
of ICH remains enigmatic.
Rostock, Germany Methods: We analyzed 159 patients with supratentorial ICH. Depending on insular

Correspondence
involvement the patients were classified into two groups (ICHnon-­insular vs. ICHinsular).
Matthias Wittstock, Department of Volume and symptom severity of ICH were assessed. Electrocardiography, chest X-­
Neurology, University Medical Centre
Rostock, University of Rostock,
ray, and laboratory examinations including myocardial enzymes and inflammatory
Gehlsheimer Str. 20, 18147 Rostock, markers were made. In-­hospital death and outcome at discharge from hospital were
Germany.
Email: matthias.wittstock@med.uni-
assessed on the modified Rankin scale (mRS).
rostock.de Results: The main finding was an association of insular involvement of ICH with worse

Funding information
This research did not receive any specific
grant from funding agencies in the public,
commercial, or not-­for-­profit sectors
short-­term outcome as measured by mRS (common odds ratio: 4.08 (95% CI: 2.09–­
7.92); p < .001). This association survived adjustment to relevant covariates such as
age, sex, ICH volume, intraventricular hemorrhage, pneumonia, and length of stay
(adjusted common odds ratio: 2.51 (95% CI: 1.21–­5.21); p = .014) but had no predic-
tive value for side of ICH or rate of atrial fibrillation. There was no association of ICH
localization with in-­hospital death rate.
Conclusion: Insular localization of ICH lesions predicts worse short-­term functional
outcome independent of side of bleeding or cardiac dysfunction such as new AF.
These findings need clarification in larger prospective cohorts assessed by detailed
autonomic/cardiac testing, as well as neuroimaging sub-­localization of ICH within the
insular region.

KEYWORDS
insular, intracerebral hemorrhage, modified ranking scale, outcome

1 | I NTRO D U C TI O N
Ischemic stroke, as well as intracerebral hemorrhage (ICH), involving
the insular cortex tends to be more severe.1–­4 Previous data sug-
gest that insular involvement is associated with poorer functional
outcome after ischemic and hemorrhagic stroke regardless of lesion
size and higher case fatality rates.5 The pathophysiological mech-
anisms explaining the apparent association of insular involvement
with poor ICH outcome remain unclear. However, changes of au-
tonomic nervous system characterized by impaired cardiovascular
regulation and shifted balance between sympathetic and parasym-
pathetic outflows have been found previously in patients with ICH

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© 2021 The Authors. Acta Neurologica Scandinavica published by John Wiley & Sons Ltd.

Acta Neurol Scand. 2021;144:559–565.  wileyonlinelibrary.com/journal/ane | 559

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560
and were attributed to functional outcome.5–­7 Differences in out-
comes between left and right insular cortex strokes arise because
of the laterality of autonomic representation in the brain, although
there is disagreement whether the right or left insula is the one most
associated with poor prognosis.8 We, therefore, examined the as-
sociation of insular involvement and its laterality with the outcome
after supratentorial ICH.
2 | M E TH O D S
We retrospectively screened the hospital charts of 164 consecu-
tive ICH patients admitted to the Department of Neurology of the
University Medicine Rostock between January 2016 and December
2017. The study was approved by the Institutional Review Board of
the Medical Faculty, University of Rostock (A-­2017-­0207).
2.1 | Patients and clinical data
The topology of ICH was assessed by a board-­certified neuroradi-
ologist (A.G.) with 25 years’ experience in brain imaging and blinded
to the hypothesis investigated here by using cerebral computed to-
mography (CT) or magnetic resonance imaging (MRI). Patients with
infratentorial ICH (N = 5) were excluded from further analysis (see
Figure 1). Hemorrhage was considered to involve the insular region
when at least a portion of the insula was compromised, regardless
of whether they also affected other brain regions. We determined
whether there was insular involvement based on the identifica-
9
tion of the appropriate ASPECTS region. Depending on insular in-
volvement, patients were divided into two groups: ICHnon-­insular and
ICHinsular. The occurrence of intraventricular hemorrhage (IVH) was
determined. Furthermore, the ICH score was calculated.10 Moreover
a subsequent analysis was performed regarding laterality (right vs.
left) of insular and non-­insular ICH.
All patients received standard-­of-­c are treatment according to
the European Stroke Organisation Guidelines for ICH.11 Clinical
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WITTSTOCK et al.
severity of ICH was assessed using the ICH score11 and the National
Institutes of Health Stroke Scale (NIHSS). For determination of ICH
volume the formula ABC/2 was used, where the imaging slice with
the largest area of hemorrhage was identified. The largest diame-
ter (A) of the hemorrhage on this slice was measured. The largest
diameter 90° to A on the same slice was measured next (B). Finally,
the approximate number of slices on which the ICH was seen was
calculated (C). C was calculated by a comparison of each slice with
hemorrhage to the slice with the largest hemorrhage on that scan.
If the hemorrhage area for a particular slice was greater than 75%
of the area seen on the slice where the hemorrhage was largest, the
slice was considered 1 hemorrhage slice for determining C. If the
area was approximately 25%–­75% of the area, the slice was consid-
ered half a hemorrhage slice; and if the area was less than 25% of
the largest hemorrhage, the slice was not considered a hemorrhage
slice. These hemorrhage slice values were then added to determine
the value for C. All measurements for A and B were made with the
use of the centimeter scale on the scan to the nearest 0.5 cm. A,
B, and C were then multiplied and the product divided by 2, which
yielded the volume of hemorrhage in cubic centimeters.12 The most
likely cause of bleeding was determined considering the clinical and
radiological characteristics and classified as follows: arterial hy-
pertension, cerebral amyloid angiopathy according to the modified
Boston criteria,13 hemorrhagic diathesis due to therapeutic antico-
agulation. An ECG examination at admission as well as continuous
ECG monitoring for at least 72 h was performed. From ECG record-
ings at admission, the heart rate frequency, QRS parameters, as
well as QTc time were obtained.14 ST elevations or depressions and
occurrence of bradycardia (<60 bpm) and tachycardia (>100 bpm)
were assessed in a dichotomized manner. Pre-­existing atrial fibrilla-
tion was obtained from medical history. During the continuous ECG
monitoring period alerts of atrial fibrillation (AF) were registered
and analyzed and new AF was documented.15 A chest X-­ray exam-
ination between 24 h and 14 days after admission was performed
in all patients. Functional outcome (modified Rankin scale [mRS)])
at discharge from hospital and the frequency of in-­hospital death
were assessed.
F I G U R E 1 Study Flowchart

WITTSTOCK et al.
2.2 | Statistical analysis
The Shapiro–­Wilk test was performed to test whether variables are
normally distributed. For non-­normally distributed variables the
median and interquartile range (IQR) was calculated. The Mann–­
Whitney U-­test or Kruskal–­Wallis test were used for comparison of
parametric data, and Pearson Chi²-­test or Fisher exact test for the
comparison of non-­parametric data as appropriate. For ordinal data,
we used the Jonckheere–­Terpstra test. Post hoc analyses results
were presented with Bonferroni adjustment. To test whether there
was an association between categorical clinical variables and the
outcome of interest, univariate and multivariate binary logistic (for
in-­hospital death as dependent outcome variable) or ordinal regres-
sion analyses (for mRS as dependent outcome measure) were per-
formed. To select relevant covariates, we performed Mann–­Whitney
U-­test and Chi2/Fisher Exact test in combination with univariate
regression models to determine the predictive values and Odds ra-
tios of the candidate covariates age, sex, NIHSS at admission, ICH
volume, intraventricular hemorrhage, ICH score, length of hospital
stay, advanced directive, surgical intervention, pneumonia, and atrial
fibrillation (see Table S1). We then checked for collinearity of candi-
date covariates using the Pearson correlation test. As expected, the
NIHSS showed a moderate correlation with ICH volume (r = .566, p
value < .001), and thus omitted in the multivariate regression analy-
ses. The compound ICH score was used to confirm the results from
regression using the single candidate covariates. In additional analy-
ses for determining the importance of the side of hemorrhage, the
odds ratios and 95% confidence intervals (95% CI) of each outcome
for insular strokes on right and left sides and non-­insular strokes
on the right side were compared with odds for non-­insular strokes
on the left side (reference level) using univariate and multivariate
logistic or ordinal regression analyses. Analyses were conducted
using SPSS, version 25.0 (SPSS, Chicago, IL), and all p-­values were
two-­sided and values of less than .05 were deemed statistically sig-
nificant (due to the limited sample size in our retrospective study, α
adjusting of p values was not carried out in order to preserve statisti-
cal power).
3 | R E S U LT S
Out of 159 ICH patients (median age 77 years, IQR 67.0–­83.0 years,
58.5% men), 43 patients (27%) displayed insular involvement. At
admission 107 patients received MRI (67.3%) and 42 (32.3%) CT
imaging. Concerning demographic and clinical characteristics,
ICHinsular patients were older and NIHSS at admission was higher
as compared to ICHnon-­insular patients (see Table 1 and Table S2 for
details). Hematoma volume was greater and consecutive modified
ICH score was higher in ICHinsular patients. 8.8% of the patients re-
ceived surgical intervention. There were no differences regarding
the etiology of ICH between ICHinsular versus ICHnon-­insular patients
(Table 1). There were no severe cardiac events in the entire study
cohort (Table S1). No significant differences of ECG parameters,
|
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561
including the frequency of atrial fibrillation (AF), were found be-
tween ICHnon-­insular and ICHinsular patients (Table S2). Of note, we
did not observe differences in the prevalence of pre-­diagnosed or
newly diagnosed AF between the groups. No differences in the rate
of pneumonia or inflammatory parameters were observed (Table 1).
When comparing ICHnon-­insular and ICHinsular patient with respect to
bleeding side, we observed similar results concerning demographic
and clinical parameters as well as ICH characteristics (Tables S3,S4).
The frequency of in-­hospital death as the first outcome measure
indicated worse outcome of the ICHinsular group as compared to the
ICHnon-­insular group (Table 2). However, after adjustment of the odds
ratio for relevant covariates (all candidate variables with significant
predictive value on death rate: age, ICH volume and length of hos-
pital stay, see Table S1) using multivariate binary logistic regression
analyses, insular location had no predictive value on death rate in
ICH patients (Table 2). Multivariate regression using the compound
ICH score as substitute covariate for age and ICH characteristics,
confirmed that ICHinsular had no predictive value on death rate in our
ICH cohort (Odds ratio: 1.65 [95% CI: 0.56–­4.82], p = .361).
The same approach was used predictive value of insular loca-
tion on mRS as the second outcome measure (Figure 2 and Table 2).
Univariate ordinal regression revealed significant predictive value of
insular location on mRS outcome with worse outcome in ICHinsular.
This result survived adjustment for relevant covariates (Table S1)
using multivariate ordinal regression analysis (Table 2). Using the ICH
score as a covariate for age and ICH characteristics in combination
with sex, length of hospital stay and pneumonia confirmed that in-
sular localization is predictive for worse outcome in ICH (Odds ratio:
2.30 [95% CI: 1.11–­4.76], p = .025). Addition of the ICH side or pres-
ence of AF as other covariates to both the univariate and the multi-
variate regression models did not demonstrate any predictive value
of these factors for both outcome measures (p-­Value ≥ .05; new AF
was not tested due to rare occurrence [<1%]).
When noting both location and laterality of ICH, left ICHnon-­insular
involvement was associated with decreased odds of functional
outcome (mRS) when compared with both left ICHinsular and right
ICHinsular, which however, did not survive adjustment to relevant co-
variates (Figure S1 and Table S5). The adjusted odds ratios compar-
ing mortality after insular versus non-­insular strokes for both sides
were again not significant.
4 | DISCUSSION
The main finding of the present study is the association of insular
involvement in ICH patients with a more than 2-­fold higher ad-
justed odds ratio for short-­
term functional outcome when com-
pared to non-­insular ICH independent from cardiac factors such as
AF. Functional outcome and mortality were independent from ICH
lateralization.
In our cohort there was no significant association of ICH local-
ization (including side of hemorrhage) and mortality when data were
adjusted to relevant covariates such as age, ICH volume, and length
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562 WITTSTOCK et al.

TA B L E 1 Demographic and basic clinical data

Total cohort Non-­insular Insular

(n = 159) (n = 116) (n = 43) p Value

Side (right/left/both sides), n (%) 55 (47%)/54 (47%)/7 (6%) 21 (49%)/22 (51%) 0.539a
Age (years) 77.0 (67.0–­83.0) 76.0 (65.0–­82.0) 79.5 (72.0–­83.7) 0.032a
Sex (m/f), n (%) 93 (58.5%)/66 (41.5%) 68 (58.6)5/48 (41.4%) 25 (58.1%)/18 (41.95) 1.000 b
NIHSS at admission 11.0 (5.0–­17.0) 8 (5–­16) 14.5 (8.2–­19.7) 0.003a
ICH volume (ml) 12.9 (4.3–­37.6) 8.9 (3.4–­25.1) 33.2 (23.7–­73.3) <0.001a
ICH score 2 (1–­2) 1 (0–­2) 2 (1–­3) <0.001c
0 (n, %) 39 (23.8%) 36 (29.8%) 3 (7.0%)
1 (n, %) 51 (31.1%) 43 (35.5%) 8 (18.6%)
2 (n, %) 45 (27.4%) 27 (22.3%) 18 (41.9%)
3 (n, %) 16 (9.8%) 9 (7.4%) 7 (16.3%)
4 (n, %) 13 (7.9%) 6 (5.0%) 7 (16.3%)
5 (n, %) 0 (0.0%) 0 (0.0%) 0 (0.0)
Intraventricular hemorrhage (IVH), 72 (45.3%) 53 (45.7%) 19 (44.2%) 0.866b
n (%)
Length of hospital stay (days) 15 (6–­20) 16 (8–­21) 13 (9–­18) 0.018a
Advanced directive, n (%)d 82 (57.3%) 53 (53.0)% 29 (67.4%) 0.109b
Bleeding etiology
Anticoagulation associated, n 90 (56.6%) 62 (53.4%) 28 (65.1%) 0.211b
(%)
Hypertensive, n (%) 89 (56.0%) 67 (57.8%) 22 (51.2%) 0.477b
Amyloid angiopathy, n (%) 13 (8.2%) 11 (9.5%) 2 (4.7%) 0.365b
Surgical therapy, n (%) 14 (8.8%) 9 (7.8%) 5 (11.6%) 0.529b
Pneumonia, n (%) 40 (25.2%) 26 (22.4%) 14 (32.6%) 0.219b

Note: Values are median and interquartile ranges (in brackets) or n (%).
a
Mann–­Whitney U-­test.
b
Pearson Chi² or Fisher exact test as appropriate.
c
Jonckheere–­Terpstra test.
d
Data available from 143 patients.

of hospital stay. The higher rates of mortality in insular versus non-­
insular ICH were indeed significantly confounded by age and ICH
volume. Sample size calculation for future prospective trials on influ-
ence of ICH localization on in-­hospital death according to standard
statistical procedures16 using the data from our study (p < .05, power
90%) indeed revealed that 51 subjects per group are sufficient when
not adjusting to relevant covariates, but 259 subjects per group are
needed when adjusting the sample size calculation to age, ICH volume
and length of hospital stay. Our data on fatal outcome may not sup-
port findings of post hoc analysis in ischemic stroke showing worse
outcome and higher rate of death of any cause in right insular stroke
8
in comparison with stroke in other regions of the brain. Moreover,
a recent study on ICH also reported that its insular localization is an
independent negative predictor for death, but the influence of later-
ality of ICH was not analyzed.5 Since the insular cortex is considered
an essential part of the cardiac central autonomous nervous sys-
6
tem, insular lesions might provoke autonomic imbalance and sub-
sequently cardiac arrhythmia including AF, other ECG abnormalities
and even Takotsubo-­like cardiomyopathy; a stroke-­heart-­syndrome
was postulated by Scheitz and colleagues4,6,13,17 Unfortunately, only
part of the large studies on outcome after insular versus non-­insular
stroke reported detailed cardiology data, 2,8 and the available data
on new AF in insular stroke are inconsistent with some studies re-
porting higher frequency of AF or new AF in insular stroke while
others did not report such association.3,4 In ICH new onset AF has
been found to be associated with early death with insular localiza-
tion of the bleeding.5 We did not observe any association of AF
or other autonomic abnormalities with insular localization of ICH
and—­consistently—­there was no significant predictive value of AF
or new AF for mortality. Since the cohorts of the earlier report on
insular ICH and the present study are rather similar (including basic
demographics, ICH characteristics, and AF detection method,5 the
reason for this discrepancy remains unclear. One reason might be
differences in the study design since Prats-­Sanchez and co-­workers
assessed the mortality after 3 months,5 while the present study
investigated in-­hospital deaths. Indeed, the AF detection method
was identical in both studies and thus would not explain the differ-
ences of new AF (6.0% new AF in Prats-­Sanchez and colleagues5
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WITTSTOCK et al. 563

TA B L E 2 Odds ratios for functional outcomes by non-­insular (reference) versus insular hemorrhage

Multivariate logistic/ordinal
Outcome Univariate logistic/ordinal regression regression

Non-­insular Insular Unadjusted Odds ratio Adjusted Odds ratio (95%

(n = 116) (n = 43) p Valuea (95% CI)b p Value CI)b , c p Valuec

In-­hospital 23 (19.8%) 21 (48.8%) <.001 3.86 (1.82–­8.19) <.001 1.93 (0.76–­4.92) .169
death, n (%)
mRS, median 4 (3–­5) 5 (4–­6) .002 4.08 (2.09–­7.92) <.001 2.51 (1.21–­5.21) .014
(IQR)d

Abbreviation: mRS, Modified ranking scale.

a
P values from Pearson Chi² test (in-­hospital death) or Jonckheere–­Terpstra test (mRS).
b
An Odds ratio > 1 indicates a lager risk for the respective outcome in the insular hemorrhage group.
c
Adjustments of Odds ratios for all covariates with predictive value in univariate analyses on the respective outcome (see Table S1) were performed
by multivariate logistic for in-­hospital death as dependent outcome variable (covariates: age, ICH volume and length of hospital stay) or ordinal
regressions for mRS as dependent outcome variable (covariates: age, sex, ICH volume, length of hospital stay, intraventricular hemorrhage,
pneumonia). All covariates except sex had still significant predictive values in the multivariate regression models.
d
For details of distribution of data, refer to Figure 1.

in parenchymal ICH and the exact insular localization of the lesion

F I G U R E 2 Modified Rankin Scale Scores at discharge from
hospital. Shown are the results of the ordinal analysis of the
modified Rankin scale scores at discharge from hospital. Scores
range from 0 to 6, with 0 indicating no neurologic deficit, 1 no
clinically significant disability, 2 slight disability (able to handle
own affairs without assistance but unable to carry out all previous
activities), 3 moderate disability requiring some help (e.g., with
shopping, cleaning, and finances but able to walk unassisted), 4
moderately severe disability (unable to attend to bodily needs
without assistance and unable to walk unassisted), 5 severe
disability (requiring constant nursing care and attention), and 6
death. Patients in the non-­insular group had a median score of 4, as
compared with a median score of 5 among patients in the insular
group (common odds ratio, 4.08 (95% CI: 2.09–­7.92); p < .001).
Percentages may not total 100 because of rounding
and 0.6% in the present study). However, new AF after ICH seems
to be often transient as after myocardial infarction or surgical pro-
5,17
cedures, and its valid detection might be challenging.
inconsistent data on cardiac involvement in insular lesion, indepen-
dent on whether it is ischemic or hemorrhagic, might be related to
the cortical involvement being more probable in ischemic stroke as
within autonomic areas. Future studies using prospective designs
and in-­depth diagnostic of cardiac/autonomic function and exact
localization of the lesion within the insular region are warranted to
finally clarify the frequency and importance of new AF for the out-
come of insular ICH.
It is still unclear why insular ICH influences functional outcome
when compared to non-­insular hemispheric bleeding. One apparent
reason might be that the insular region—­depending on the side—­is
involved in numerous functions with high impact on activities of
daily living such as spatial neglect and anosognosia, cognitive, and
emotional control, as well as language skills and verbal memory.18–­23
Moreover, the scales for assessment of functional outcome (mRS
and other scales) highly depend on spared motor function, which is
frequently involved in insular lesion. 21
Several limitations of our study need to be addressed: First, the
major limitation of our study is the very small sample size and the
retrospective single-­center design of the study. Therefore, this study
might be only hypothesis-­generating. To reduce bias we included all
consecutive patients within a certain time period with hemispheric
ICH admitted to our University-­based Neurology department into
the study. Secondly, we lacked electrocardiographic studies prior
to hospital admission (or ICH onset) and information on ECG, par-
ticularly the presence of preexisting AF, were mainly derived from
medical history and patient records putatively underestimating the
AF rate. ECG data were derived from ECG examinations at admission
and AF alerts from the 72 h ECG monitoring. All the more surprising,
we detected only one new and thus potentially ICH-­related AF in a
patient with ICHnon-­insular. Although we performed ECG monitoring
for at least 72 h after admission in all patients, intermittent new AF
might have been overlooked after the initial intensive/intermediate
Finally, the care treatment. Thirdly, we do not have enough data on long-­term
the specific cause of death is largely unknown since we neither ver-
ify cause of death independently nor perform pathological exam-
ination in our cohort. Together, our findings require confirmation in
 |
564
a larger cohort investigated in a prospective study design including
early and continuous monitoring of autonomic function and ECG, as
well as structured long-­term outcome determination.
In conclusion, our data support the hypothesis that insular local-
ization of ICH lesions predicts worse short-­term outcome indepen-
dent from laterality of bleeding or cardiac dysfunction such as new
AF. Together with the discussed findings of new AF and its associ-
ation with fatal outcome in both ischemic stroke and ICH in earlier
studies, it is likely that insular lesions lead to bad outcome by two
putatively independent mechanisms: firstly, autonomic dysfunction
due to damage of the autonomic insular cortex leading to AF, which
was demonstrated for example by Oppenheimer & Cechetto14 and
Prats-­Sánchez and colleagues,5 or due to autonomic dysbalance with
impaired heart rate variability.7 This could not be shown in our study
due to the retrospective design. Secondly, the injury of crucial struc-
tures involved in a myriad of functions with considerable may have
impact on activities of daily living. 22,23 Our results need further con-
firmation in prospective larger cohorts to clarify pathophysiological
mechanisms of a worse outcome in insular ICH. Indeed, we suggest
that future studies should include long-­term electrocardiographic or
autonomic monitoring and detailed neuroimaging in patients with
ICH to finally become a more clear view on these two outcome-­
related mechanisms.
AC K N OW L E D G M E N T S
The authors are thankful to the teams of the ICU and the Stroke
Unit of the Department of Neurology and the Neuroimaging facility
of the Department of Radiology at the University Medical Centre
Rostock for their continuous and passionate help in collecting the
data.
C O N FL I C T S O F I N T E R E S T
MW reports honoraria for presentations/lectures/consultancies or
advisory boards from Bristol-­Myers Squibb, Daiichi Sankyo, Bayer
Vital, Boehringer Ingelheim and Portola Germany. KM and AG de-
clare that they have no conflict of interests. JK reports honoraria
for presentations/lectures from Daiichi Sankyo. UW reports grants
and personal fees from Merz Pharma, personal fees from Bristol-­
Myers Squibb, personal fees from Daiichi Sankyo, personal fees
from Bayer Vital, personal fees from Pfizer, grants from European
Funds for Regional Development, outside the submitted work. He
serves as editor of the European Journal of Ultrasound. AS has re-
ceived funding from the Deutsche Forschungsgemeinschaft (DFG)
and the Helmholtz-­A ssociation. He received honoraria for presen-
tations/lectures/consultancies or advisory boards from AbbVie,
Bayer Healthcare, Bial, GKC, Grünenthal, UCB, Zambon, AbbVie,
TEVA, Lundbeck, and UCB Pharma, outside the submitted work.
He has served on the editorial boards of Stem Cells and Stem Cells
International.
E T H I C S S TAT E M E N T
The study was reviewed and approved by the Institutional Review
Board of the Medical Faculty, University of Rostock (A-­2017-­0207).
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WITTSTOCK et al.
DATA AVA I L A B I L I T Y S TAT E M E N T
Deidentified participant data will be shared, as well as the study pro-
tocol and statistical analyses, upon reasonable requests.
ORCID
Matthias Wittstock https://orcid.org/0000-0001-9904-6436
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