Keywords:
stroke - disability - cerebrovascular disorders - cerebral infarction
Palabras clave:
accidente cerebrovascular - trastornos cerebrovasculares - infarto cerebral
Arterial ischemic stroke (AIS) is the most prevalent cerebrovascular disease encountered
in children beyond the newborn period, with an estimated annual incidence of 2.4/100,000
persons[1]. Even though the developing brain possesses remarkable structural and functional
plasticity in response to injury, at least half of the children who have suffered
an AIS have persistent neurological impairment[2],[3],[4],[5]. Additionally, the mortality rate has remained unchanged for at least the past 15
years (7-28%) and is associated with significant age and ethnic variations[2],[5],[6].
Research concerning prognosis after childhood AIS is mainly focused on short-term
outcome, and only a few studies have examined the impact of clinical features on the
development of long-term neurologic impairment. The initial stroke severity and one-year
functional status were the strongest predictors of long-term outcome in two larger
series[5],[7], but the possibility that radiological features in MRIs may be risk factors for
functional and survival outcomes has not been evaluated sufficiently in children[8].
While studies of newborns with ischemic stroke have revealed the extraordinary value
of the site and size of the lesion for motor and cognitive outcome[9],[10], research in older children exploring the influence of infarct characteristics on
the long-term functional outcome is lacking and, except for the size of the lesion,
these associations have not been fully established[11],[12],[13].
Our purpose in the present study was to explore the influence of the infarct location,
particularly subcortical involvement, on functional outcome in a cohort of children
who were followed for at least four years after the occurrence of a first, isolated,
supratentorial AIS. We hypothesized that the influence of stroke location on the outcome
mentioned above is significant.
METHODS
Study design and participants
We undertook a prospective study of a cohort involving 39 consecutive patients who
suffered a first, isolated, supratentorial AIS during childhood. The participants
were enrolled in the study while hospitalized at the Pontificia Universidad Católica
of Chiles Clinical Hospital between January 2003 and July 2012. We included all patients
with a neurologic deficit of acute onset, and MRI showing an isolated parenchymal
infarct conforming to known arterial territory and corresponding to clinical manifestations,
experienced between the ages of 29 days and 18 years[14]. To avoid factors possibly confounding the prognosis, we excluded patients with
bilateral, multiple, infratentorial or watershed infarcts, previous cerebrovascular
disease (including, presumed perinatal stroke and cerebral sinovenous thrombosis[15]), concomitant hypoxic-ischemic encephalopathy, associated disorder with neurologic
impairment at the time of the stroke, and functional impairment before the acute event.
This study was approved by the institutional ethics committee and written informed
parental consent was obtained.
Data collection
A pediatric neurologist filled out a standardized data collection form during the
hospital stay. This document enabled us to collect information about each patient's
clinical picture at the onset of symptoms, underlying conditions, and neurologic features
from neuroimages. Outcome data was collected with a form evaluating functional impairment
(according to the modified Rankin scale (mRS) for children[5],[16]) and abnormalities on the neurologic examination. These measures were applied by
a pediatric neurologist during an outpatient appointment or home visit four to eight
years after the index stroke. Marked functional impairment, as in a previous study[5], was defined as neurologic deficits interfering with daily life activities (mRS
score 3 to 5). All information was entered into a database, corrected according to
a review of medical and neuroimaging records, and enrolled according to the institutional
protocols.
Imaging analysis
The MRI studies were performed in all patients within 36 hours after symptom onset
and were repeated if new neurologic signs or symptoms appeared. Vascular imaging was
available in 21 children and was performed within three weeks. All MRI sequences (diffusion
weighted image, fluid- attenuated inversion recovery, double inversion recovery and
T1 with gadolinium, using 1.5 T with 5 mm thick slices, and 2.5 mm separation between
cuts) were evaluated by a radiologist and subsequently reviewed by two physicians
(a radiologist, and a pediatric neurologist) together.
Lesion and whole brain (cerebral hemispheres, brainstem, cerebellum, and ventricles)
volumes were measured by manual segmentation using “NIH Image J” public domain software
available on the National Institute of Health homepage. This method was applied to
diffusion-weighted images obtained at the onset of the illness. The lesion size was
expressed as a percentage of total brain volume, to adjust for changes in the brain
volume with age, and was classified into large infarct: ≥ 4% of total brain volume,
and small infarct: < 4% of total brain volume, in order to compare with previous studies[13].
The infarct location was classified into two categories based on the absence or presence
of a subcortical involvement infarct (basal ganglia, thalamus, internal capsule and
centrum semiovale) with or without cortical ischemia. The involvement of the anterior
cerebral artery, middle cerebral artery, and posterior cerebral artery territories
were assessed.
Data analysis
The IBM SPSS Statistics version 22 software (IBM Corp., Somers, NY, USA) was used
to identify differences in study variables between children admitted with AIS with
and without subcortical infarcts, applying Fisher's exact test and the t-test for categorical and continuous variables, respectively. Three logistic binary
regression models were created to identify the association between (1) subcortical
involvement, (2) large infarcts, and (3) middle cerebral artery infarcts, and the
odds of long-term functional impairment. These models were adjusted for age, stroke
location, infarct size and middle cerebral artery territory involvement. A P-value
of < 0.05 was considered statistically significant.
RESULTS
Sample characteristics
Of 42 children who met the study's inclusion criteria, three could not be contacted
(7.14%). Among the 39 patients included in the study, 14 were girls (35.9%) while
25 were boys (64.1%). The median age at the time of stroke was 5.38 years (interquartile
range, 0.49-9.91). Seven children died before outcome assessment (17.9%); their mean
survival time was 8.3 months (range, four days to 2.3 years), the causes of death
were stroke (two patients), cardiac disease (two patients), leukemia, primary intracranial
tumor (discovered five months after the stroke) and a systemic infection (one of each).
Thirty-two children with a follow-up duration ranging between 4.2 and 8.72 years (mean
5.87 years) were considered for an outcome assessment. Baseline demographics, clinical
features and radiological variables of the children are summarized in [Table 1]. There were no detected cases of either hemorrhagic transformation of infarction
or intracranial hemorrhage in the cohort.
Table 1
Demographics, identified etiologies, and radiological features of children with arterial
ischemic stroke with and without an isolated subcortical infarct (Pontificia Universidad
Católica of Chile's Clinical Hospital: 2003 – 2012).
|
Variables
|
With subcortical infarct
|
Without subcortical infarct
|
p-value
|
|
Overall, n (%)
|
26 (67)
|
13 (33)
|
|
|
Demographics and treatment
|
|
|
|
|
Female, n (%)
|
11 (42.3)
|
3 (23.1)
|
0.304
|
|
Male, n (%)
|
15 (577)
|
10 (76.9
|
0.304
|
|
Age in years, mean (SD)
|
6.16 (5.37)
|
3.83 (4.20)
|
0.148
|
|
Time of follow-up, mean (SD)
|
4.95 (2.69)
|
4.93 (1.98)
|
0.982
|
|
Anticoagulant treatment, n (%)
|
19 (73.1)
|
10 (76.9)
|
0.999
|
|
Clinical presentation
|
|
|
|
|
GCS < 12, n (%)
|
12 (46.2)
|
8 (61.5)
|
0.501
|
|
Headache, n (%)
|
5 (19.2)
|
2 (15.4)
|
1.000
|
|
Acute seizures, n (%)
|
9 (34.6)
|
5 (38.5)
|
1.000
|
|
Focal neurologic deficits, n (%)
|
20 (76.9)
|
9 (69.2)
|
0.704
|
|
Stroke etiology
|
|
|
|
|
Cardioembolic, n (%)
|
11 (42.3)
|
6 (46.2)
|
1.000
|
|
Arteriopathy, n (%)
|
5 (19.2)
|
2 (15.4)
|
1.000
|
|
Thrombophilia*, n (%)
|
2 (77)
|
1 (7.7)
|
1.000
|
|
Other etiology**, n (%)
|
3 (11.5)
|
3 (23.1)
|
0.380
|
|
Multifactorial, n (%)
|
3 (11.5)
|
0 (0)
|
0.538
|
|
Undetermined, n (%)
|
5 (19.2)
|
2 (15.4)
|
1.000
|
|
Stroke-related radiological variables
|
|
|
|
|
Right sided, n (%)
|
15 (57.7)
|
7 (53.8)
|
1.000
|
|
ACA territory, n (%)
|
11 (42.3)
|
3 (23.1)
|
0.304
|
|
MCA territory, n (%)
|
11 (42.3)
|
7 (53.8)
|
0.520
|
|
PCA territory, n (%)
|
4 (15.4)
|
3 (23.1)
|
0.666
|
|
Large lesion (≥ 4% TBV), n (%)
|
17 (65.4)
|
6 (46.2)
|
0.312
|
|
Stroke recurrence, n (%)
|
3 (13)
|
1 (8.3)
|
1.000
|
*Including acquired and genetic thrombophilias;
**Head/neck trauma (3), Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like
episodes (2), intracranial tumor (1). GCS: Glasgow coma scale; ACA: anterior cerebral
artery; MCA: middle cerebral artery; PCA: posterior cerebral artery; TBV: total brain
volume.
Functional outcome
For the neurological evaluation, marked functional impairment (mRS score 3-5) was
found in 10 children (25.7%), severe spastic hemiplegia in seven and profound cognitive
impairment and mild spastic hemiplegia in three. Seventeen patients had mild spastic
hemiplegia (43.6%), which was not functionally limiting (mRS score 1), and five children
had normal functionality (12.8%).
After adjusting for age, arterial distribution and lesion size, a significantly larger
proportion of children with marked functional impairment displayed subcortical infarcts
(OR 8.36; CI 1.76-53.6; p 0.025) on MRI, compared to the group of survivors without
marked impairment. We also found a positive correlation between the lesion size and
adverse outcome (OR 9.92; CI 1.76-55.9; p 0.009). [Table 2] summarizes the associations between radiological variables and the outcomes.
Table 2
Effect of stroke-related radiological features on long-term functional outcome.
|
Variable
|
Univariate
|
Multivariate*
|
Multivariate**
|
|
OR (95% CI)
|
p-value
|
OR (95% CI)
|
p-value
|
OR (95% CI)
|
p-value
|
|
Subcortical involvement
|
|
|
|
|
|
|
|
Minimal or absent impairment
|
Reference
|
|
Reference
|
|
Reference
|
|
|
Marked impairment
|
6.5 (1.2-36.6)
|
0.03
|
778 (1.3-479)
|
0.02
|
9.33 (1.2-72.3)
|
0.03
|
|
Large lesion (≥ 4% TVB)
|
|
|
|
|
|
|
|
Minimal or absent impairment
|
Reference
|
|
Reference
|
|
Reference
|
|
|
Marked impairment
|
743 (1.6-35.5)
|
0.01
|
7.54 (1.6-36.3)
|
0.01
|
764 (1.3- 43.4)
|
0.02
|
|
MCA infarct
|
|
|
|
|
|
|
|
Minimal or absent impairment
|
Reference
|
|
Reference
|
|
Reference
|
|
|
Marked impairment
|
1.71 (0.4-6.6)
|
0.44
|
1.77 (0.4-72)
|
0.42
|
2.75 (0.5-16.4)
|
0.27
|
TBV: Total Brain Volume; MCA: middle cerebral artery; OR: odd ratio; SD: standard
deviation; CI: confidence interval;
*Adjusted for age;
**Adjusted for age, stroke location, size and MCA infarct.
DISCUSSION
The primary goal of this study was to explore whether the lesion location could predict
the occurrence of an adverse functional outcome in pediatric patients beyond the newborn
period following a first AIS; in this regard, the main finding of our study was that
in this cohort of Chilean children with an isolated supratentorial infarct, there
was an association between the subcortical location of the stroke and the presence
and severity of long-term functional impairment.
Research in children with perinatal AIS has documented the relationship between basal
ganglia and thalamic injury and altered cognitive outcome[17], but ours is the first study that strongly associates subcortical lesions with functional
impairment in older children. This finding is in contrast to previous studies, which
showed that combined cortical and subcortical lesions are significantly more likely
to result in cognitive impairment in the long term compared to isolated cortical or
subcortical infarctions[18],[19]. One study even associated the presence of isolated subcortical lesions with a favorable
outcome[20]. Although the study criteria could explain these differences, the leading cause
of these results may lie in the size of the stroke, since combined lesions are likely
to be the largest, as well. Consistent with research in pediatric populations, our
results showed that patients who had large infarcts were much more likely to develop
a long-term disability. Thus, we performed a logistic regression analysis to adjust
for confounding variables, including stroke size, allowing us to identify independent
predictors of the outcome. In the results section, we showed that there were no significant
differences between children with or without subcortical involvement with respect
to age, sex, underlying conditions, initial clinical manifestations or other radiological
features.
The role of the subcortical nuclei in motor regulation and cognitive functions has
been well established[21]. Subcortical pathways reciprocally interconnect neuronal activity of an important
and diverse set of cerebral cortical areas with the basal ganglia and thalamus. It
is noteworthy that the functional organization of these circuits changes across development,
allowing the improvement of motor and cognitive behaviors[22]. However, the molecular mechanism implicated in these changes is particularly vulnerable
to injury in energy failure[23]. Thus, impaired neural plasticity due to ischemia in the developing brain, particularly
during critical periods, may be the pathophysiology basis of functional deterioration
in these patients.
It is a unique characteristic of our study that we evaluated stroke features in a
South American pediatric population and their impact on long-term functional outcomes.
The results are characterized by a high prevalence of poor outcomes following pediatric
AIS; these data are consistent with those of previous studies that included other
geographic groups[2],[18],[24],[25].
The limitations of this study must be considered when reviewing these results. Firstly,
this is a single center study with a relatively small sample size. The prevalence
of adverse outcomes found in our cohort may not accurately reflect our country's statistics;
thus, future research should include tertiary centers across several regions to obtain
results that may be generalized. Furthermore, our study population included many children
with heart diseases and relatively few with CNS arteriopathies; this was probably
because the study was conducted in a referral center for the surgical resolution of
complex congenital heart diseases, as well as because there was a relative lack of
vascular imaging studies undertaken at the time of diagnosis.
The strengths of the study lie in its clear selection criteria, controlled for confounding
variables, prospective recruitment, and uniform evaluation. This study has also contributed
to an increase in the understanding of the long-term outcomes of stroke in children.
Finally, the scale used to assess functional outcome does not include any direct measure
of cognitive function or self-perceived quality of life; thus, we believe that future
research focused on these outcomes may result in the development of a risk scoring
system for the development of neurologic disability following an AIS.
In conclusion, early identification of children at increased risk for impairment would
allow for early interventions and could be useful in reducing permanent disability.
In this regard, the size and subcortical involvement of the infarcts are potential
predictors of adverse outcome following an isolated supratentorial stroke.
