Neurologic Outcome Predictors in Pediatric Intracerebral Hemorrhage
A Prospective Study
Background and Purpose—Intracerebral hemorrhage is a considerable source of morbidity and mortality. This 3-center study describes outcomes of pediatric intracerebral hemorrhage and identifies 2-year neurological outcome predictors.
Methods—Children 29 days to 18 years of age presenting with intracerebral hemorrhage from March 2007 to May 2015 were enrolled prospectively. Exclusion criteria included trauma; intracranial tumor; hemorrhagic transformation of arterial ischemic stroke or cerebral sinovenous thrombosis; isolated subdural, epidural, or subarachnoid hemorrhage; and abnormal baseline neurological function. Intracerebral hemorrhage and total brain volumes were measured on neuroimaging. The Pediatric Stroke Outcome Measure assessed outcomes.
Results—Sixty-nine children were included (median age: 9.7 years; interquartile range: 2.2–14). Six children (9%) died during hospitalization. Outcomes in survivors were assessed at early follow-up in 98% (median 3.1 months; interquartile range: 3.1–3.8) and at later follow-up in 94% (median: 2.1 years; interquartile range: 1.3–2.8). Over a third had a significant disability at 2 years (Pediatric Stroke Outcome Measure >2). Total Pediatric Stroke Outcome Measure score improved over time (P=0.0003), paralleling improvements in the sensorimotor subscore (P=0.0004). Altered mental status (odds ratio, 13; 95% confidence interval, 3.9–46; P<0.001), hemorrhage volume ≥4% of total brain volume (odds ratio, 17; 95% confidence interval, 1.9–156; P=0.01), and intensive care unit length of stay (odds ratio, 1.1; 95% confidence interval, 1.0–1.2; P=0.002) were significantly associated with poor 2-year outcome.
Conclusions—Over one third of children experienced significant disability at 2 years. Improvements in outcomes were driven by recovery of sensorimotor function. Altered mental status, hemorrhage volume ≥4% of total brain volume, and intensive care unit length of stay were independent predictors of significant disability at 2 years.
Although approximately half of pediatric strokes are hemorrhagic, studies of pediatric intracerebral hemorrhage (ICH) have rarely examined outcome predictors, and retrospective studies are limited by the inadequacy of International Classification of Diseases, Ninth Revision, code-based case identification.1 Prospective studies have been small or have focused on short-term outcomes (<1 year).2,3 Study aims were to describe the spectrum of outcomes of pediatric spontaneous ICH prospectively at 3 pediatric centers and to identify predictors of poor 2-year neurological outcome.
Case Identification and Clinical Data
All children presenting with ICH from March 2007 to May 2015 were included. The Institutional Review Board approved the study at each site; informed consent was obtained. Inclusion criteria were age 29 days to 18 years, spontaneous ICH confirmed by computed tomograpy or magnetic resonance imaging. Exclusion criteria included trauma, intracranial tumor, hemorrhagic transformation of arterial ischemic stroke or cerebral sinovenous thrombosis, isolated epidural/subdural/subarachnoid hemorrhage, and abnormal baseline neurological function. Data supporting the study findings are available from the corresponding author upon request.
Pediatric stroke neurologists collected data via parental interview, medical record abstraction, and at follow-up stroke clinic visits. Glasgow Coma Score ≤9 was not obtained consistently. Thus, we defined altered mental status (AMS) as obtunded, comatose, or unresponsive on initial physician examination, or if Glasgow Coma Score ≤9, when recorded.
Cause was determined by medical history, imaging review, intraoperative observation, and surgical pathology. Parenchymal hemorrhage volume was measured as previously described and expressed as a percentage of total brain volume (TBV).4 Cutoffs of 2% of TBV and 4% of TBV defined large and very large hemorrhage. Children with isolated intraventricular hemorrhage were excluded from volumetric analyses.
Outcomes were assessed at 3-month and 2-year clinic visits using the Pediatric Stroke Outcome Measure (PSOM), a standardized score of neurological function commonly used in pediatric ischemic and hemorrhagic stroke.2,4,5 Scores are assigned from 0 to 2 for 5 domains (right and left sensorimotor, expressive and receptive language, cognitive/behavioral) and are summed for a total PSOM score. A total score of >2 or death represented “poor” outcome. A score >2 reflects a deficit in >1 domain and was chosen to distinguish between children with residual disability but a good degree of function and children at risk of long-term dependence. A short parent survey regarding the child’s level of functioning, which is included in the most recent International Pediatric Stroke Study PSOM Short Neuro Exam form, was also administered at these visits.6
Wilcoxon signed-rank tests and Stuart–Maxwell tests compared equality of distributions and differences in proportions over time. Univariable logistic regressions evaluated associations between possible predictors and poor outcome at 2-year follow-up. The multivariable logistic regression model included the 3 most significant predictors on univariable analysis, adjusting for age. Analyses were conducted in STATA 15.0.
Sixty-nine children met inclusion criteria, median age 9.7 years (interquartile range [IQR]: 2.2–14; range: 30 days–18 years). Table I in the online-only Data Supplement summarizes patient characteristics. Known medical risk factors were present in 20%, including cardiac, hematologic, immunologic, or genetic diagnoses. A precipitating factor for ICH was present in 19%, including hypertension (3%), infection (13%), surgery within 1 month (3%), coagulopathy (13%), and multiple factors (69%).
Hemorrhage was isolated parenchymal in 45%, isolated intraventricular in 9%, and involved >1 compartment in 46%. ICH volume could be calculated in 61 children (88%) and was <2% TBV in 54%, 2% to <4% TBV in 25%, and ≥4% TBV in 10%. Vascular malformations accounted for 63% of hemorrhages and coagulopathy for 17%. Cause could not be determined in 19%, although vascular malformations were suspected in one third of these cases. Children were carefully evaluated for ICH cause (online-only Data Supplement). Median hospital length of stay was 15 days (IQR: 9–22); median intensive care unit stay was 11 days (IQR: 5–18). Six children died during hospitalization (9%). Most children were discharged to inpatient rehabilitation (52%) or home with outpatient rehabilitation (27%).
Outcomes were assessed at a median of 3.1 months (IQR: 2.8–3.8) in 98% and again at 2.1 years (IQR: 1.3–2.8 years) in 94%. Median total 3-month PSOM was 1.5 (IQR: 0.5–3) and 2-year PSOM was 1 (IQR: 0–2.5). Overall, 38% and 34% of children had poor outcomes, respectively (Figure 1). Although total PSOM scores improved over time (median: 1.5 at 3 months–1.0 at 2 years; P=0.0003), this was largely because of improvements in sensorimotor subscores (median: 1.0 at 3 months–0.5 at 2 years; P=0.0004), whereas language and cognitive/behavioral subscores did not change significantly. Figure 2 shows direction of change for these subscores. From a functional standpoint, at 2 years 76% of parents reported that their children had not made a complete recovery, with 20% also noting the need for extra help with day-to-day activities compared with peers and 19% an impact on emotional state, behavior, and self-esteem.
In univariable analyses, AMS and hemorrhage ≥4% of TBV were strongly associated with poor 2-year outcome (odds ratio, 13; 95% confidence interval, 3.9–46; P<0.001 and odds ratio, 17; 95% confidence interval, 1.9–156; P=0.01; Table I in the online-only Data Supplement). Longer hospital and intensive care unit (ICU) stay were significantly associated with poor outcomes (odds ratio, 1.1; 95% confidence interval, 1.0–1.1; P=0.005 and odds ratio, 1.1; 95% confidence interval, 1.0–1.2; P=0.002). Other associations with poor 2-year outcome included male sex, hemiparesis, hydrocephalus, and herniation. The 3 strongest outcome predictors (AMS, ICH volume ≥4% of TBV, and ICU length of stay) remained significantly associated with poor outcome in multivariable regression adjusted for age (Table I in the online-only Data Supplement). In univariable logistic regression, death was significantly associated with AMS, hemorrhage volume ≥4% of TBV, and coagulopathy (Table II in the online-only Data Supplement); hemorrhage volume ≥2% of TBV, edema, hydrocephalus, and herniation syndrome were not.
In this multicenter prospective study, we describe outcomes of pediatric spontaneous ICH over time and identify 2-year outcome predictors. Over one third of children had a poor 2-year outcome measured by dichotomized PSOM scores. Four prior studies have examined outcomes of pediatric ICH after 1 year.3,7–9 Comparing studies is challenging because of the use of different outcome assessments, study designs, and inclusion criteria. Studies show widely divergent outcomes, with 10% to 75% of children experiencing clinically significant deficits, variably defined (Table III in the online-only Data Supplement). Mortality ranged from 4.5% to 39%.2–4,7–9 Lower mortality (9%) in our study may reflect exclusion of children with intracranial tumors, management by dedicated stroke teams, and improvements in neurocritical care, including aggressive neurosurgical management.
AMS, hemorrhage volume, and ICU length of stay were strongly associated with poor 2-year outcome on age-adjusted multivariable analysis. Prolonged ICU stay may reflect underlying medical complexity, hemorrhage severity, treatment complications, or a combination. The association of poor 2-year outcome with AMS at presentation and hemorrhage volume ≥4% of TBV is consistent with previous studies assessing short-term outcomes and confirms its importance as a predictor in a larger prospective study.2–4 AMS has not been a predictor in other pediatric studies, possibly because of differences in mental status assessment. Consistent with others’ findings, we did not observe an association between poor functional outcome and infratentorial location, intraventricular extension, or coagulopathy.2 Coagulopathy was associated with mortality along with AMS and hemorrhage volume ≥4% of TBV. Consistent with other reports, volume ≥2% of TBV was not associated with death, which suggests a threshold effect.3
The improvements in sensorimotor subscores, without change in language and cognitive/behavioral subscores, are consistent with evidence in both pediatric hemorrhagic and ischemic stroke that cognitive and language deficits are increasingly observed over time, perhaps because of poor sensitivity of assessment measures at young ages or emerging deficits as cognitive demands children face increase.3,10
Study limitations include lack of a specific outcome measure validated for pediatric ICH. We chose the PSOM over other metrics because it was developed and validated for pediatric ischemic stroke, relies on a detailed physical examination, and correlates with results from standardized neuropsychological measures.5,11,12 The PSOM, however, is limited in its ability to capture functional impairments. Sample size is a weakness of pediatric ICH studies because of low incidence. Our study is one of the largest prospective studies of pediatric ICH to have followed children beyond 1 year. Its prospective and multicenter nature are important strengths given difficulties with ascertainment and bias in single-center or retrospective studies, providing wider generalizability of results.
Over one third of children had significant functional disability at 2 years, with a 9% mortality rate. Better outcomes over time were driven by improvements in the sensorimotor domain, compared with the language and cognitive/behavioral domains where deficits may emerge/become more evident with age. AMS, large hemorrhage volume, and ICU length of stay were associated with significant functional disability at 2 years. Improved understanding of outcomes after pediatric ICH and factors that affect long-term outcomes will allow physicians to counsel families on prognosis.
Sources of Funding
This study was supported by grants from the National Institutes of Health (number: NIH-K23-NS062110 and UL1 TR002243).
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.118.021845/-/DC1.
- Received February 12, 2018.
- Revision received May 10, 2018.
- Accepted May 15, 2018.
- © 2018 American Heart Association, Inc.
- Beslow LA,
- Licht DJ,
- Smith SE,
- Storm PB,
- Heuer GG,
- Zimmerman RA,
- et al
- Lo WD,
- Hajek C,
- Pappa C,
- Wang W,
- Zumberge N
- Jordan LC,
- Kleinman JT,
- Hillis AE
- Kitchen L,
- Westmacott R,
- Friefeld S,
- MacGregor D,
- Curtis R,
- Allen A,
- et al
- Lo WD,
- Ichord RN,
- Dowling MM,
- Rafay M,
- Templeton J,
- Halperin A,
- et al
- Westmacott R,
- MacGregor D,
- Askalan R,
- deVeber G
- Murphy LK,
- Compas BE,
- Gindville MC,
- Reeslund KL,
- Jordan LC