Thalamic Volume Loss Is Greater in Children Than in Adults Following Middle Cerebral Artery Territory Arterial Ischemic Stroke

Abstract

Background: Younger stroke patients may suffer worse outcomes than older patients; however, the extent to which age at stroke impacts remote areas of the brain remains unclear. The objective of this study was to determine thalamic volume changes ipsilateral to middle cerebral artery territory strokes based on age at acute ischemic stroke onset. Methods: Acute ischemic stroke patients <9 years, 9-18 years, and >18 years old were retrospectively recruited from a large quaternary care system. Each subject underwent an acute (<72 hours from AIS) and chronic (>90 days) magnetic resonance imaging (MRI) scan. Manual thalamic segmentation was performed. Results: Younger and older children had significantly greater stroke-side thalamic volume loss compared to adults (48.2%, P = .022; 40.7%, P = .044, respectively). Conclusions: Stroke-side thalamic volumes decreased across the age spectrum but to a greater degree in pediatric patients. This observation can affect functional and cognitive outcomes post stroke and warrants further research.

Keywords

arterial ischemic stroke magnetic resonance imaging (MRI)thalamus pediatric stroke

Introduction

Stroke is the fifth-leading cause of death and a leading cause of disability in the United States, with about 795 000 new acute ischemic events and 137 000 deaths every year.¹ Even though the greatest stroke burden affects the older adult population, acute ischemic stroke (AIS) can occur at any stage of life. Approximately 10% to 15% of all acute ischemic stroke occurs in patients younger than 50 years old and about 1% occurs in the pediatric population.^2,3 AIS patients suffer from an increase in mortality and morbidity, including long-term neurologic injuries such as cognitive and motor disability.^4,5 Stroke risk factors, symptoms, and recovery present differently in children and adults.⁴ Although stroke recovery in adults is largely influenced by stroke size and location, recovery in children is more complex.⁶ Some controversy has existed over whether stroke recovery in children is influenced more by enhanced plasticity (ie, improved recovery due to the pediatric brain's ability to rewire or regenerate following injury) or selective vulnerability (ie, worsened recovery due to impaired maturation of distant brain structures requiring the damaged areas for normal neurodevelopment). More recent studies have shown that younger children often experience relatively worse cognitive outcomes after AIS, with additional influence based on location of stroke.^7,8 Conversely, hippocampal volume on the stroke side in children <9 years of age is relatively preserved compared with older children, implying a mechanism of enhanced plasticity.⁹

The thalamus has been observed to be affected by strokes remote from it in both adults and children.^10–12 However, the extent to which age affects poststroke degeneration of brain structures remote from the injury remains unclear.

The purpose of this study was to determine the effect of remote ischemia on thalamic volumes over time in pediatric and adult patients with unilateral middle cerebral artery territory AIS as a surrogate indicator of differential brain plasticity and selective vulnerability. Specifically, we aimed to determine differences in thalamic volume changes in both the stroke and contralateral cerebral hemispheres by age (ie, children younger than 9 years, older children, and adults).

Material and Methods

Study Population

Patients were retrospectively recruited from University of Colorado Hospital and Children's Hospital Colorado, a large quaternary health system. Subjects were eligible if they were diagnosed with an AIS involving a unilateral middle cerebral artery cortical distribution between 2011 and 2017 and had undergone a magnetic resonance imaging (MRI) of the brain within 72 hours of the AIS admission and at >90 days of initial AIS admission. To ensure thalamic volume was not influenced by other pathology, exclusion criteria included any history of brain tumors, intracranial hemorrhage with secondary AIS, history of epilepsy, new strokes (ischemic or hemorrhagic) prior to the repeat MRI scan at >90 days, AIS involving bilateral middle cerebral arteries, poor image quality, or any evidence of chronic hippocampal sclerosis on the initial AIS MRI. Additionally, neonates were not included in this study. Demographic and clinical information, including age at stroke, sex, race, ethnicity, presenting signs and symptoms, and treatment, were recorded via chart review. This study protocol was approved by the institutional review board at the University of Colorado Anschutz Medical Center (Aurora, CO).

Imaging and Segmentation Protocol

Each subject underwent an acute (<72 hours from AIS admission) and chronic (>90 days from AIS admission) MRI scan. Scans were performed on multiple different MRI platforms with different protocols, but all included diffusion-weighted and T1-weighted sequences. All acute images were reviewed by a neurologist and neuroradiologist to confirm isolated middle cerebral artery AIS sparing subcortical structures. Commercially available segmentation software (Aquarius iNtuition, TeraRecon, Forest City, CA) was used to manually segment thalamic volumes¹³ on T1-weighted imaging according to published protocols, as well as volumes of the individual cerebral hemispheres and acute stroke volumes on diffusion-weighted imaging. An example of segmentation can be found in Supplemental Figure S1. Stroke-side and contralateral-side thalamic and cerebral hemisphere volumes were measured on both the acute and chronic scans.

Volumetric Variables and Definitions

Change in volume over time was calculated for stroke side and contralateral side and is defined as

\begin{aligned} Change in Volume \\ = \frac{Volume at Chronic Scan - Volume at Acute Scan}{Volume at Acute Scan} * 100 % \end{aligned}

In addition, because many of the subjects were children, we used the contralateral side, which was unaffected by AIS, to account for differences in brain size and growth over time. Stroke-side volumes were normalized to stroke/contralateral (S/C) ratios and are defined as:

\frac{S}{C} Ratio = \frac{Stroke Side Volume}{Contralateral Side Volume}

Controlled volume change represents the change in the stroke-side structures from acute to chronic while using the contralateral structures as a control. This variable encompasses the acute and chronic measurements for the stroke-side and contralateral structures. It allows for the comparison of volume changes between age groups. Controlled volume change (CVC) is defined as

CVC = Chronic \frac{S}{C} Ratio - Acute \frac{S}{C} Ratio

Statistical Analysis

Patients were categorized into 3 groups based on age at the time of AIS: young children (<9 years), older children (9-18 years), and adults (>18 years). Supported by a previous study, age 9 was used as a cutoff to evenly divide the pediatric age spectrum.⁹ Volumetric measurements were compared using 3-way or pairwise comparisons. The acute and chronic measurements for each structure were compared using paired t test. Variables were checked for the distributional assumption of normality using Shapiro-Wilks test. Radiomic features were compared using 1-way analysis of variance when data were normally distributed; otherwise, Kruskal-Wallis was used. Lastly, pairwise comparisons within the groups were calculated using the Tukey honestly significant differences test for normally distributed data and the Dunn test otherwise. Pairwise comparison results were adjusted for the false discovery rate using the Benjamini Hochberg procedure. Effect size, d, was defined as the difference in population means divided by pooled population standard deviation. Analyses were performed with the statistical software package R v4.1.0. P values <.05 were deemed as statistically significant.

Results

Study Population

Eight younger children (<9 years old), 9 older children (9-18 years old), and 13 adults (>18 years old) were included in the study (Table 1). One subject <9 years of age and 1 subject >9 years of age were excluded because of poor imaging quality. Stroke etiology in pediatric patients per the CASCADE classification¹⁴ included cardioembolic (4), other (5), bilateral cerebral arteriopathy (1), focal cerebral arteriopathy (5), small vessel arteriopathy (1), and aortic/cervical arteriopathy (1). Stroke etiology in adult patients per the TOAST criteria¹⁵ included cardioembolic (3), small-vessel occlusion (3), large-artery atherosclerosis (3), other (1), and undetermined etiology (3).

Table 1.

Cohort Demographics.^a

	All	Younger children	Older children	Adults	P value
Total, n	30	8	9	13
Age at AIS, y	14.93 (2.56-87.79)	6.77 (2.56-8.51)	12.08 (9.14-16.71)	70.59 (50.75-87.79)	<.001
Gender, n					.073
Female	16	7	2	7
Male	14	1	7	6
Stroke side, n					.96
Right	9	2	3	4
Left	21	6	6	9
Race/ethnicity, n					.45
Hispanic white	5	1	3	1
Non-Hispanic black	4	1	0	3
Non-Hispanic white	20	6	6	8
Non-Hispanic Asian	1	0	0	1
More than 1 race	0	0	0	0
NIHSS	5.5 (0-21)	12 (2-17)	9 (0-21)	3(0-19)
Presenting signs and symptoms, n					.36
Headache	6	1	4	1
Hemiparesis	26	8	7	11
Reduced consciousness	7	3	3	1
Seizure	5	2	2	1
Speech deficit	21	5	5	11
Vomiting	5	2	3	0
Seizure activity >1 month post-AIS, n	5	2	0	3	.26
Time between scans, y	1.30 (0.26-6.46)	2.02 (1.52-2.97)	0.44 (0.27-2.04)	1.22 (0.26-6.46)	.11
Treatment at diagnosis, n					.15
ASA	19	5	6	8
UFH	4	3	1	0
TPA	5	0	1	4
Thrombectomy	1	0	0	1
None	1	0	1	0
Uncertain	0	0	0	0
Treatment at discharge, n					.16
ASA	24	6	6	12
LMWH	4	2	2	0
Clopidogrel	2	0	0	2
Coumadin	3	0	0	3
None	1	0	1	0

Abbreviations: AIS, acute ischemic stroke; ASA, aspirin; LMWH, low-molecular-weight heparin; NIHSS, the National Institutes of Health Stroke Scale; TPA, tissue plasminogen activator; UFH, unfractionated heparin.

Age, NIHSS score, and time between scan measurements are reports as median and range.

Thalamic Volume

There was no difference in acute stroke volumes proportional to total brain volume between the 3 groups (Table 2). All groups experienced significant volume loss in the stroke-side thalamus between the acute and chronic MRI scans ranging from 9% to 48% volume decrease (young children P = .002; older children P = .002; adults P = .03, Figure 1).

Table 2.

Comparison of Volumetric Variables.^a

	Young children	Older children	Adults	P value
Acute stroke volume (cm³)	68.64 (11.7, 125)	119.9 (2.27, 239)	39.29 (1.27, 23.95)	.26
Acute stroke volume (% of total brain volume)	1.95 (1.56, 9.42)	3.38 (0.23, 10.66)	0.85 (0.12, 2.23)	.28
Controlled volume change	−0.48 (−0.58, 0.27)	−0.42 (−0.59, −0.18)	−0.05 (−0.08, −0.008)	.031
Change stroke, side (%)	−48.2 (−57.8, −28.7)	−40.7 (−61.1, −30.3)	−8.9 (−14.65, −4.4)	.014
Change contralateral side (%)	−0.078 (−3.1, −4.1)	0.27 (−9.12, 2.9)	−6.1 (−9.23, 2.7)	.59

Measurements reported as median and interquartile range. Pairwise P values are in Supplement.

Young and older children experienced significant declines in S/C ratios, indicating volume loss on stroke side when controlled for contralateral volume (young children: d = 1.56, P = .002; older children: d = 1.43, P = .003, Figure 2). Adults, however, did not experience a significant decline in S/C ratio, indicating no significant stroke-side thalamic volume loss when controlled for contralateral thalamic volume (d = 0.71, P = .067).

There was a significant difference in the controlled volume change between younger children and adults (−0.43, P = .023) and older children and adult (−0.37, P = .044). There was no significant difference in thalamus controlled volume change between the younger and older children. In other words, although all 3 age groups showed significant volume loss within the stroke-side thalamus over time, older and younger children experienced significantly greater thalamic loss compared with adults when controlling for contralateral thalamic volume. Figure 3 displays a visual comparison of acute infraction and chronic thalamic volume loss between pediatric and adult patients. Volumetric measures obtained from manual segmentation can be found in the supplemental material (Table I). Pairwise comparisons between the three groups can be found in the supplemental material (Table II). Supplemental Figures 2 and 3 display change in thalamic volume and change in S/C ratios, respectively.

Discussion

We found that stroke-side thalamic volumes significantly decreased after 90 days of stroke onset, and the decline was more pronounced in children than in adults. Previous studies have found thalamic atrophy in adult patients in the contralateral and ipsilateral side 3 months after stroke.¹⁶

For decades, scientists believed that children's brains were highly adaptable and could recover from injury through plasticity^17–19 because of the younger brain's ability to quickly respond to injury and restore physical phenotypes.²⁰ In this theory, the earlier a brain injury occurs, the better the brain recovers. However, many competing factors contribute to the recovery process.^17,21,22 More recent studies have suggested that pediatric stroke recovery may be affected more by the concept of selective vulnerability, where brain development is adversely affected long-term by early injuries.^17,18,23 Westmacott reported that lesion location modulated the effect of age at stroke on cognitive performance, and perinatal stroke patients performed worse on cognitive outcome measures.⁷ More recently, younger age at stroke has been associated with poorer outcomes.^8,24 Our results indicate subcortical structures remote from middle cerebral artery territory stroke are injured to a greater degree in younger patients, supporting these recent studies that report differential developmental outcomes.

The thalamus was chosen for this study because it is supplied by the posterior cerebral circulation and should not suffer direct ischemia in middle cerebral artery territory AIS.²⁵ However, the thalamus may be susceptible to secondary injury following an infarction in remote areas of the brain to which it is anatomically connected. Prior work in neonatal AIS patients has described acute diffusion restriction in the ipsilateral thalamus after middle cerebral artery territory infarction, which the authors hypothesized represented acute secondary network injury due to excitotoxicity or deafferentation.¹⁰ Therefore, the relatively greater ipsilateral thalamic volume loss experienced by the younger population of our middle cerebral artery infarction patients may indicate a greater vulnerability to a similar type of network injury. Another study in neonatal AIS patients also demonstrated decreases in neonatal stroke patients’ thalamic volumes ipsilateral to the infarction. The same study also demonstrated that these patients’ motor outcomes correlated inversely with contralateral thalamic volume, indicating a role for developmental plasticity in the contralesional hemisphere.¹¹

Our findings highlight the need for further exploration into the effect of age at time of injury on long-term recovery and outcomes. A better understanding of the differences in response of various subcortical gray matter nuclei after stroke and the related effect on long-term neurodevelopmental outcomes could lead to improved rehabilitative strategies.

Study limitations include small sample size, a typical problem in the study of a rare pediatric process. Although there were statistically significant results, the study population size is not large enough to formally declare differences within these subcortical gray matter volumes. Although all chronic scans were obtained by our definition more than 90 days after the acute stroke, differences in timing of the chronic scans could result in occasional underestimation of chronic volume loss. Additionally, we assumed that the contralateral side was unaffected. Further work with more subject numbers and longer follow-up is needed to investigate poststroke thalamic volume differences across age groups and their impacts on functional and cognitive outcomes.

Conclusion

In patients with middle cerebral artery territory acute ischemic stroke, stroke-side thalamic volumes decreased across the age spectrum, but the volume loss was greater in children compared to adults. This finding supports the notion that younger patients are at risk of worse neurodevelopmental outcomes following acute ischemic stroke.

Supplemental Material

sj-docx-1-jcn-10.1177_08830738221118807 - Supplemental material for Thalamic Volume Loss Is Greater in Children Than in Adults Following Middle Cerebral Artery Territory Arterial Ischemic Stroke

Supplemental material, sj-docx-1-jcn-10.1177_08830738221118807 for Thalamic Volume Loss Is Greater in Children Than in Adults Following Middle Cerebral Artery Territory Arterial Ischemic Stroke by Emily J. Mastej, Michelle H. Leppert, Sharon Poisson, Zak Ritchey, Megan Barry, Tatjana Rundek, David S. Liebeskind, David Mirsky, Timothy J. Bernard and Nicholas V. Stence in Journal of Child Neurology

Footnotes

Author Contributions

EM performed the data analysis, interpreted data, drafted the manuscript, and approved the final version for publication. ML, SP, MB, TR, DL, and TB contributed to the conception and design, critically reviewed the manuscript, and approved the final version for publication. ZR, DM, and ML assisted with data acquisition, critically reviewed manuscript, and approved the final version of the manuscript. NS assisted with data acquisition, interpreted data analysis, drafting the manuscript, critically reviewing the manuscript, and approved the final version for publication.

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.

Ethical Approval

This study was reviewed by the Colorado Multiple Institutional Reviewed Board (COMIRB) and deemed exempted (protocol #17-1027).

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Colorado Biomedical Informatics Training Program, American Stroke Association (grant number T15LM009451, Bugher Foundation Grant 14BFSC17680001).

ORCID iD

Emily J. Mastej

Supplemental Material

Supplemental material for this article is available online.

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