|Ahead of print
Long-term outcome in children with arterial ischemic stroke: A North Indian center-based study
Aparna Mishra1, Arushi Gahlot Saini2, Jitendra Kumar Sahu2, Prahbhjot Malhi3, Naveen Sankhyan2, Niranjan Khandelwal4, Pratibha Singhi2
1 Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Pediatric Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Child Psychology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
4 Department of Radiodiagnosis, Postgraduate Institute of Medical Education and Research, Chandigarh, India
|Date of Submission||26-Jul-2020|
|Date of Decision||03-Oct-2020|
|Date of Acceptance||22-Nov-2020|
|Date of Web Publication||12-Jul-2021|
Jitendra Kumar Sahu,
Room 5108, 5A, Advanced Pediatric Center, Postgraduate Institute of Medical Education and Research, Chandigarh.
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Objective: To describe the long-term outcome in children with acute ischemic stroke (AIS) from a tertiary-care center. Materials and Methods: Prospective, observational study of children diagnosed with AIS between the ages of six months and 12 years and who completed two to five years of follow-up. Results: Forty-nine children (35 boys, 14 girls) were included. The mean age at onset of stroke was 35.6 ± 31.5 months (6–108 months). A majority of children had presented with hemiparesis (93.8%). Risk factors were identified in 65.4% of cases. Moyamoya vasculopathy (28%), iron-deficiency anemia (24.4%), and trauma (12.2%) were the most common risk factors. The majority of infarcts were cortical (32.6%), followed by combined cortical and subcortical (30.6%), and isolated subcortical (26.5%). At follow-up, recurrent stroke (24.4%), residual epilepsy (24.4%), and motor disability requiring support for ambulation (6%) were noted. The mean general developmental score (GDS) was 71.2 ± 18.7. Global developmental delay in 46.9% and delayed social intelligence in 22.4% was noted. On subset analysis, children had physical (42.9%), cognitive (34.7%), communication (30.6%), adaptive-behavior (26.5%), and social–emotional (22.4%) delay. Predictors of good cognitive outcome were younger age at onset (OR 0.964, P = 0.006), isolated subcortical infarcts (OR 26.386, P = 0.028), and absence of seizures at presentation (OR 0.197, P = 0.044). Predictors of poor social quotient were seizures at onset (OR 0.049, P = 0.012) and recurrent stroke (OR 0.055, P = 0.012). Conclusion: Neurodevelopmental problems and epilepsy occur in a significant proportion of children with AIS in the long term. Good outcomes are predicted by the younger age of onset, subcortical infarcts, absence of seizures, and absence of recurrence of stroke.
Keywords: Arterial ischemic stroke, children, epilepsy, moyamoya, neurodevelopmental outcome
| Introduction|| |
Childhood AIS is defined as an acute-onset neurological deficit with a radiographic image showing cerebral parenchymal infarct conforming to known arterial territory and corresponding to clinical manifestations and occurring in children starting from one month to 18 years of age. The incidence of childhood stroke varies from two to 13:100,000 children per year in developed countries., Strokes in children differ from adults in the subtype, risk factors, clinical presentation, and outcomes. Causes of pediatric stroke are heterogeneous, and no specific cause may be ascertained in one-third to one-half of the patients. These factors make the diagnosis challenging and result in delayed and even missed diagnoses.
The majority of clinical and prognostic information on childhood AIS has been reported from developed countries. Only a handful of studies have described the etiological spectrum and clinical characteristics in Asian children.,,, Although determinants of poor outcome in childhood AIS such as age at a stroke, lesion characteristics, presence of seizures, degree of residual neurological impairment, and neuro-rehabilitative efforts have been identified, there is an overall paucity of long-term neurodevelopmental, cognitive, and epilepsy outcome data in Indian children with AIS. Therefore, the current study was planned to assess the long-term outcomes in children with AIS as well as to determine the predictors of outcome in pediatric AIS survivors.
| Materials and Methods|| |
We retrospectively reviewed all children from our neurodevelopmental clinic who had been diagnosed with AIS between six months and 12 years of age and prospectively assessed their long-term neurodevelopmental and epilepsy outcomes at two to five years of follow-up. Patients with hemorrhagic stroke, cerebral sino-venous thrombosis, perinatal/neonatal stroke, central nervous system (CNS) infections, or follow-up of <2 years and >5 years from the onset of AIS were excluded. Informed consent from the parents/guardians and assent of child, wherever applicable, was obtained. Clinical data were recorded on prestructured proforma. Stroke recurrences, motor impairment, epilepsy, and neurodevelopmental outcomes were assessed after a minimum of two years and not more than five years after the diagnosis of AIS. The study was approved by the Institute Ethics Committee.
The AIS was defined as an acute neurological deficit or seizures with neuroimaging evidence of a focal infarct conforming to an established cerebral arterial territory consistent with the patient’s clinical presentation. Based on TOAST (Trial of ORG 10172 in Acute Stroke Treatment) classification, etiology of stroke was categorized as large artery atherosclerosis, small vessel occlusion, cardioembolism, a stroke of other determined etiology, and stroke of undetermined etiology. Motor disability was assessed by using the Gross Motor Function Classification System–Expanded and Revised (GMFCS-ER). Neurodevelopment outcome was evaluated by Development Profile-3 (DP-3), which assesses children’s functioning in five critical areas such as physical, adaptive behavior, social–emotional, cognition, and communication. Each of the five individual sectors was scored, and a GDS was estimated. The GDS value <70 was used as a cutoff for “delayed development.” Vineland Social Maturity Scale (VSMS) was used to assess the social intelligence as social quotient (SQ) comparable to the intelligent quotient (IQ, <25 profound, 25–40 severe, 40–55 moderate, 55–70 mild, 70–79 borderline, 80–89 low average, 90–109 average, 110–119 high average, 120–129 superior, and >130 very superior). Seizures were considered acute symptomatic if they occurred within the first seven days of cerebrovascular disease. Epilepsy was defined by any one of the following conditions: (a) ≥2 unprovoked (or reflex) seizures occurring >24 hours apart; (b) one unprovoked (or reflex) seizure with a probability of further seizures at least 60%; (c) two unprovoked seizures occurring over the next 10 years; or (4) diagnosis of an electroclinical syndrome. The socioeconomic status of the family was assessed by using the Kuppuswamy Scale. Anemia was defined as a condition in which the number of red blood cells (and consequently their oxygen-carrying capacity) is insufficient to meet the body’s physiologic needs.
Statistical analysis was performed by using Statistical Package for Social Sciences (SPSS Inc., version 22). Continuous variables were estimated by using mean, median, and standard deviation. The group means were compared by using the Student’s t-test or Mann-Whitney U test wherever applicable. Categorical variables were presented as proportions. The group proportions were compared by using χ2 or Fisher’s exact test wherever applicable. The relationship between the two continuous variables was calculated by using the Spearman correlation coefficient. P value of <0.05 was categorized as statistically significant. Multivariate logistic regression was used to determine the predictor variables, and the odds ratio was calculated.
| Results|| |
A total of 102 cases of AIS were screened over a period of one year at our neurodevelopmental clinic. Of these, 53 cases were excluded for the following reasons: 28 children had a stroke within the past two years (insufficient follow-up), nine children had venous infarcts, seven children had hemorrhagic strokes, four children had associated CNS infection, and five children had stroke in the first six months of life (perinatal stroke). Hence, a total of 49 children (35 boys and 14 girls) with AIS were evaluated. The demographic, clinical, and radiological characteristics of the study cohort are provided in [Table 1].
|Table 1: Demographic, clinical, and radiological characteristics of children with AIS (N = 49)|
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The mean GDS of children with AIS in follow-up was in the borderline range (71.2 ± 18.7). Delayed neurodevelopment (GDS below 70) was seen in 46.9% (n = 23/49) of the children. On subset analysis, 42.9% (n = 21/49) of the children had a physical delay, 34.7% (n = 17/49) cognitive delay, 30.6% (n = 15/49) communication delay, 26.5% (n = 13/49) adaptive-behavior delay, and 22.4% (n = 11/49) social–emotional delay. On VSMS, the social quotient below <70 was seen in 22.4% (n = 11/49) of the children.
Epilepsy and Recurrence of stroke
Epilepsy characteristics and outcomes in children with AIS are presented in [Table 2]. Recurrent strokes were noticed in 24.4% (n = 12/49) of children with AIS.
Marked parent-reported improvement in the functional status was noted in the follow-up. Using GMFCS-ER, 93.9% (n = 46/49) of children achieved a level I and 6.1% (n = 3/49) achieved a level III motor activity. Overall, 30% of the children who had a severe disability at the onset also showed marked improvement and were ambulant at assessment.
Predictors of outcome
The association of various predictors of stroke with neurodevelopmental and epilepsy outcome parameters is shown in [Table 3]. On multivariable logistic regression analysis using a forward stepwise regression model, it was observed that the odds of having a normal cognition were higher for younger age at onset of stroke (odds ratio 0.964, P = 0.006). The odds of having a normal cognitive outcome was lower for children who had seizures than the ones who did not have seizures (odds ratio 0.197, P = 0.04). Subcortical infarcts predicted a better cognitive outcome (odds ratio 26.386, P = 0.02). Predictors of poor social intelligence and adaptability were seizures at onset (odds ratio 0.049, P = 0.012) and recurrent stroke (odds ratio 0.055, P = 0.01). Similarly, the location of infarct as a predictor of epilepsy did not reach statistical significance, although cortical infarcts appear to be associated with a higher risk of epilepsy (odds ratio 4.0, P = 0.065).
|Table 3: Association of predictors of outcome with DP-3 GDS and subscales, VSMS-based social quotient, and development of epilepsy|
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| Discussion|| |
Our study provides relevant clinical data on the long-term neurodevelopmental and epilepsy outcomes in children with AIS from resource-limited settings. As there is a dearth of clinical studies on children with AIS from developing countries, the current research is both relevant and essential in identifying the predictors of long-term stroke outcomes in these children.
In our study, the mean GDS of children with AIS was borderline low, which is lower than seen in studies from developed countries. Overall, delayed neurodevelopment was noted in nearly half of the children with AIS, and 22–43% of children were delayed in physical-skill, cognitive, communicative, adaptive-behavior, and social–emotional domains. In addition, impaired SQ was noted in nearly one-fifth of the patients. Studies from developed countries also show that after AIS, children perform in the lower normative range in cognitive measures. Almost 50–85% of pediatric stroke survivors suffer from long-term problems such as epilepsy, motor disability, language, or learning difficulties. Specifically, poor performance has been noted in cognitive ability, intellectual functioning and memory, executive function, and inhibitory control. This may be explained by maladaptive plasticity at a young age, resulting in chronic motor and neurodevelopmental disabilities. As the working memory is vulnerable to insults in children and is linked to a range of cognitive functions, this affects the ability to acquire new knowledge and skills in children. No comparable data on neurodevelopmental outcomes in children with AIS are available from Indian studies., Hence, our study brings to attention the neurodevelopmental problems in children with AIS for early intervention.
Interestingly, our study showed that younger children (below two years of age) had significantly better cognitive outcomes than children above two years of age at the onset of stroke. This finding is in contrast to other studies where younger age has been a predictor of poor cognitive outcome.,, One of the possible reasons for this finding could be that we excluded children below six months of age whereas the majority of studies have included children above one month of age, thus including the neonatal and perinatal strokes, which have a comparatively poorer cognitive outcome. In addition, children with subcortical infarcts are known to have a better cognitive outcome, and 62% (n = 8/13) children with subcortical infarcts were below two years of age in our study. Although the immature brain has the potential to reorganize and support early developing functions, it may not support the multifaceted tasks that are acquired during later childhood with increasing academic needs and result in poorer outcomes in later onset of stroke.
In our study, children who did not have seizures at presentation scored better on the cognitive as well as social intelligence scales as compared with children who had seizures in concordance with the reported literature., The neurobiology of the developing brain may remain disrupted for long and may be months to years and predispose to the development of future cognitive impairment and sensitization to further injury. Children with subcortical infarcts had better cognitive scores as compared with cortical and combined cortical and subcortical infarcts in our study commensurate with the reported literature., Possibly, sparing of cortical gray matter and smaller size of subcortical infarcts disrupt fewer neural networks and, therefore, result in lesser impairments as compared with the larger cortical and combined infarcts. No significant association could be ascertained between other lesion characteristics, such as laterality or arterial territory and cognitive outcomes. Poor social intelligence and adaptability were also predicted by recurrent strokes in our study. Understandably, repeated insults in a growing brain result in broader damage and more significant impairments.
The most common clinical manifestation in our study at the time of presentation was hemiparesis. This hemiparesis resulted in motor disability requiring assistance in ambulation and maintaining postures (corresponding to GMFCS-Level III) in nearly two-thirds of the patients. Overall, one-third of children had a severe disability and were non-ambulatory, and almost half (53.8%) of the younger children (<2 years) were non-ambulatory at presentation. Motor outcome at follow-up revealed marked improvement in the functional status; 93% of the children were independently ambulant, and only 6% required minimal assistance. Almost one-third (30%) of children with severe disability at onset also showed marked improvement and were ambulant at assessment. Residual motor weakness has been reported in 58% of the children with arterial ischemic stroke, but functional deficits may be higher., As we did not use any standardized scale to assess the functional outcome, the motor deficits in our study may have underrepresented the functional deficits in children with AIS.
In our study, nearly half (47%) of the children presented with seizures, and almost one-fourth (24%) had residual epilepsy at two to five years of follow-up. Acute seizures have been seen in 8–27% of children and adolescents with AIS, with residual epilepsy in one-third to one-fourth requiring ongoing antiepileptic treatment.,,, Comparative studies from India are not available. Hence, our study highlights epilepsy as a significant neurodisability in pediatric survivors of AIS, especially in resource-limited settings. Although subcortical infarcts predicted a lesser chance of developing epilepsy than cortical or combined infarcts, yet no significant association could be drawn on multivariate regression analysis.
The usual investigations for stroke in our clinic include tests for prothrombotic disorders (factor V Leiden mutation, proteins S and C, antithrombin III, anti-phospholipid, and anticardiolipin antibodies), cardiac evaluation, iron studies, complete blood count with red cell indices and peripheral blood film, hemoglobin electrophoresis, lipid profile, homocysteine profile, neurometabolic screen, and specific genetic analyses if indicated. Based on these, the most common risk factor identified in our study was arteriopathy in nearly one-third of the cases. Moyamoya vasculopathy is common in the Asian population and has been seen in 12–31% of children,,, Iron-deficiency anemia and trauma are two important risk factors in the developing countries that also emerged from our study., Indian studies on the etiology of pediatric AIS are limited. A hospital-based recent survey has shown CNS infection-related AIS as the most common risk factor (40%) followed by cryogenics (21%), cardioembolism (9%), prothrombosis (8%), and arteriopathy (6%). We excluded CNS infections from our study, as these may confound the accurate clinical picture as well as the outcome of pediatric AIS. Also, as we included patients from the neurodevelopmental clinic, children with cardioembolic stroke are probably underrepresented. Further, our cohort underrepresented the diagnoses of mineralizing angiopathy and focal vasculopathy. History of trauma was present as a risk factor in six children, and mineralizing angiopathy may be an underlying etiology in a few children of this subgroup. However, because of the retrospective identification of the cases, we could not precisely characterize the diagnoses of mineralizing and focal vasculopathy further. There was another limitation regarding outcome assessment. The Pediatric Stroke Outcome Measure scale, which is a disease-specific and objective tool for measurement of stroke outcomes, was not used in the study.
| Conclusion|| |
Neurodevelopmental problems and epilepsy occur in a significant proportion of children with AIS in the long term. Younger age at the time of stroke, subcortical infarcts, absence of seizures, and absence of stroke recurrence predict good outcomes.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]