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Etiology, clinical characteristics and prognosis of spontaneous intracerebral hemorrhage in children: A prospective cohort study in China
Journal of the Neurological Sciences 358 (2015) 367–370
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Etiology, clinical characteristics and prognosis of spontaneous intracerebral hemorrhage in children: A prospective cohort study in China☆ Junfeng Liu 1, Deren Wang 1, Chunyan Lei, Yao Xiong, Ruozhen Yuan, Zilong Hao, Wendan Tao, Ming Liu ⁎ Stroke Clinical Research Unit, Department of Neurology, West China Hospital, Sichuan University, Chengdu, PR China
a r t i c l e
i n f o
Article history: Received 19 June 2015 Received in revised form 22 September 2015 Accepted 23 September 2015 Available online 28 September 2015 Keywords: Intracerebral hemorrhage Children Etiology Clinical characteristics Prognosis
a b s t r a c t Background and objective: Much is known about spontaneous intracerebral hemorrhage (SICH) in adults, but few studies have examined pediatric SICH, especially in China. The aim of the present study was to describe the etiology, clinical characteristics and prognosis of SICH in children from southwest China. Method: Consecutive patients aged 1–18 years with SICH at our medical center were prospectively enrolled from January 2012 to June 2014. SICH was defined by WHO criteria and confirmed by CT or MRI findings. Demographic and clinical information was collected at baseline, and follow-up assessments were conducted at 3 and 6 months after SICH, when patients were scored on the modified Rankin Scale (mRS) and events of deaths and recurrent hemorrhagic stroke were recorded. Results: Among the 70 children (43 males; median age, 12.0 years) in the final analysis, 44 patients (62.9%) had SICH due to arteriovenous malformation, and less frequent etiologies were cavernous malformation (n = 4), aneurysm (n = 2), tumors (n = 2), moyamoya (n = 2), hemophilia (n = 1), hypertension (n = 1), while 14 (20.0%) had SICH of unknown etiology. The mortality rate at 3 months and 6 months was equal, which was both 3%. The rate of disability was 12.1% at 3 months and 9.1% at 6 months. Conclusion: The most frequent etiology of pediatric SICH in this Chinese cohort was arteriovenous malformation. SICH of unknown etiology occurred much more often in our cohort than in previously published Caucasian patients in the US and Europe. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Stroke is a major cause of morbidity and mortality throughout the world, and spontaneous intracerebral hemorrhage (SICH) accounts for approximately 15% of all stroke cases [1]. Although the public often associates stroke with old age, stroke occurs in 2–13 children per 100 000 per year [2,3], and SICH accounts for as many as half of these cases [2,4]. Pediatric SICH leads to death in approximately one-third of cases, and in many more cases it leads to long-term disability, including seizures as well as cognitive and motor impairment [5–8]. This poses a substantial burden on the family and society, highlighting the need for a strong understanding of SICH in children. Despite the devastating effects of SICH in children, much less is known about it than about SICH in adults. The relatively few published studies on pediatric SICH are case series and retrospective chart reviews ☆ Disclosure of conflicts of interest: The authors declare no financial or other conflicts of interest. ⁎ Corresponding author at: Stroke Clinical Research Unit, Department of Neurology, West China Hospital, Sichuan University, No. 37, GuoXue Xiang, Chengdu, 610041 Sichuan Province, PR China. E-mail address: [email protected] (M. Liu). 1 The first two authors contributed equally to this work.
http://dx.doi.org/10.1016/j.jns.2015.09.366 0022-510X/© 2015 Elsevier B.V. All rights reserved.
[4–7,9]. Some prospective cohort studies have been reported, but they involve small samples of 11–22 children [3,10]. This lack of understanding of pediatric SICH poses a serious obstacle to predicting, diagnosing and managing the condition, since its etiology and outcomes appear to be different from those of adult SICH [2,11]. Even this is uncertain, however, since most studies of pediatric SICH have come from the US and Europe, leaving open the question of whether SICH etiology and outcomes are similar in children of other ethnic groups. In China, for example, very little has been published about pediatric SICH [12]. Therefore we prospectively enrolled patients aged 1–18 years with SICH at our medical center in southwest China and analyzed stroke etiology, clinical characteristics and outcomes during 6-month follow-up. We also tried to identify clinico-demographic predictors of poor outcomes.
2. Methods This research project was carried out under the auspices of the National Key Technology R&D Program of the 12th Five-Year Plan “Study on Etiology and Minimally Invasive Neurosurgery for Hemorrhagic Stroke”. The study protocol was approved by the Scientific
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Research Department of West China Hospital, Sichuan University. Written informed consent was obtained from participants or their guardians. Pediatric patients with spontaneous ICH were prospectively and consecutively enrolled upon being admitted to West China Hospital of Sichuan University in Chengdu, China. The enrollment period was from January 2012 to June 2014. To be enrolled, patients had to be 1–18 years old with a diagnosis of SICH based on World Health Organization stroke criteria [13] and confirmed by neuroimaging, which involved rapid computed tomography scanning or magnetic resonance imaging to distinguish SICH from ischemic stroke [1]. Children were excluded from the study if they had a history of head trauma; if their hemorrhage was restricted to epidural, subdural, intraventricular or subarachnoid compartments; or if patients had both CSVT and hemorrhagic transformation. A standardized form was used to collect data on patient demographic characteristics, level of consciousness on admission, stroke risk factors, diagnostic tests, treatment, stroke-related complications during hospitalization, and discharge medicine/interventions. Level of consciousness on admission was measured using the Glasgow Coma Score (GCS). Current medicine use and outcomes (death, disability, combined death or disability, and stroke recurrence) were assessed at 3 and 6 months after stroke onset by telephone interview or letter conducted by experienced stroke neurologists. A different group of stroke neurologists who were blinded to patient clinical data calculated modified Rankin score (mRS) scores. Disability was defined as a score of 3–5 on the modified Rankin Scale (mRS) [14–15]. Recurrence included intracerebral and subarachnoid hemorrhage. All statistical analyses were performed using SPSS 20.0 (IBM, Chicago, IL, USA). Two-sided P values b 0.05 were considered statistically significant. Results were expressed as odds ratios (ORs) and associated 95% confidence intervals (CIs). Results for categorical variables were compared between different groups using chi-squared or Fisher exact tests. Results for continuous variables were compared using ANOVA or Mann–Whitney U tests. Binary logistic regression was used to identify possible predictors of death or disability in pediatric SICH. 3. Results 3.1. Baseline patient characteristics A total of 70 patients with childhood SICH (43 males; median age, 12.0 ± 4.6 years) were included in the study. Most were diagnosed with pure ICH (50 patients), while 15 (21.4%) were diagnosed with a combination of intracerebral and intraventricular hemorrhage, and 5 (7.1%) had a combination of intracerebral and subarachnoid hemorrhage. Among the 70 patients, 56 children have undertaken enough imaging examination (eg. MRA, CTA or DSA). Etiology of SICH was undetermined in 14 patients due to lack enough imaging examination. SICH in most patients (n = 44) was caused by arteriovenous malformation; other, much less frequent etiologies were cavernous malformation (n = 4), aneurysm (n = 2), tumors (n = 2)and moyamoya (n = 2) (Table 1). One patient was diagnosed with hemophilia, consistent with the number of patients with hypertension. 46 (65.7%) patients received surgery after SICH (Table 1). Most patients (54, 77.1%) were transferred to our hospital after being admitted to local hospitals, while the remaining 16 (22.9%) were admitted directly to our tertiary care center. Median time from symptom onset to our hospital was 91 h, with 11 patients (15.7%) arriving at our hospital within 6 h and 49 (70.0%) arriving more than 24 h after symptom onset. SICH was accompanied by altered mental status in 26 patients (37.1%), by headache in 56 (80.0%), and by vomiting in 45 (64.3%). After admission to our medical center, focal deficits were detected upon initial examination in 38 patients (54.3%), seizures occurred in 9 (12.9%), and intracranial hypertension or herniation syndromes occurred in 13 (18.6%). In-hospital complications occurred
Table 1 Baseline characteristics of Chinese pediatric patients with SICH (n = 70). Characteristic
Value
Male sex, n (%) Age at index stroke in year, median (range) Stroke risk factors, n (%) Arteriovenous malformation Unknown Angiocavernoma Moyamoya Tumor Aneurysm Hemophilia Hypertension Localization, n (%) Lobe Multiple areas Deep brain Cerebellum Brainstem Laterality, n (%) Left Right Both Level of consciousness, n (%) Mild (13–15) Moderate (9–12) Severe (3–8) Treatment, n (%) Dehydration Surgery
43 (61.4) 12.0 (1–18) 44 (62.9) 14 (20.0) 4 (5.7) 2 (2.9) 2 (2.9) 2 (2.9) 1 (1.4) 1 (1.4) 40 (57.1) 22 (31.4) 13 (18.6) 5 (7.1) 4 (5.7) 41 (58.6) 22 (31.4) 7 (10.0) 53 (75.7) 6 (8.6) 11 (15.7) 59 (83.1) 46 (65.7)
in 10 patients (14.3%), including respiratory infection (n = 6), electrolyte disturbance (n = 2), urinary infection (n = 1), and acute renal failure (n = 1). 3.2. Outcomes at 3 and 6 months The patient diagnosed with hemophilia died of respiratory failure caused by herniation within 24 h after admission to our hospital; the remaining 69 patients were alive at discharge. Another child was dead within 3 months after ICH, while the cause of the death was unknown. Four patients were lost to follow-up. As a whole, the mortality rate at 3 months among the remaining 66 patients was 3% and the disability rate at 3 months was 12.1% (Table 2). The corresponding rates at 6 months were 3% and 9.1%. The combined rate of mortality or disability was 15.2% at 3 months and 12.1% at 6 months. Among the 66 patients who completed the 6-month follow-up, only 2 experienced recurrence of ICH. Recurrent hemorrhage occurred in one child with unknown etiology of hemorrhage who developed a second ICH 20 days after the initial event. Another child with AVM which was not resected during hospitalization had a secondary hemorrhage within 6 months after first hemorrhage. 3.3. Predictors of disability or death within 6 months of SICH Univariate analysis identified several variables that were significantly associated with disability or death at 6 months (Table 3): Age 1 (1–4 years old) (P = 0.04), focal deficits (P = 0.01), GCS on admission [3–8] (P = 0.03), deep brain (P = 0.04), use of dehydration therapy (P = 0.02), surgery (P = 0.03), and complications (P = 0.02).
Table 2 Rates of mortality and disability [n (%)] at 3 and 6 months after SICH (n = 66).
Mortality Disability Mortality or disability Recurrence of SICH
3 months
6 months
2 (3.0) 8 (12.1) 10 (15.2) 1 (1.5)
2 (3.0) 6 (9.1) 8 (12.1) 2 (3.0)
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Table 3 Univariate and multivariate analyses to identify predictors of death or disability at 6 months after SICH in children. Factor
Age, n (%) Age 1 (1–4 years old) Age 2 (5–9 years old) Age 3 (10–18 years old) Male, n (%) Headache, n (%) Emesis, n (%) Focal deficits, n (%) Seizure, n (%) GCS on admission, n (%) Mild (13–15) Moderate (9–12) Severe (3–8) Localization, n (%) Lobe Multiple areas Deep Brain Cerebellum Brainstem Treatment, n (%) Dehydration Surgery Complications, n (%)
Patients with good outcome, (n = 58)
Patients with poor outcome, (n = 8)
Univariate analysis
1 (1.7) 12 (20.7) 44 (75.9) 35 (60.3) 48 (82.8) 38 (65.5) 26 (44.8) 7 (12.1)
2 (25.0) 3 (37.5) 3 (37.5) 4 (50.0) 8 (100) 7 (87.5) 8 (100) 2 (25.0)
0.04* 0.39 0.04 0.71 0.34 0.42 0.005* 0.30
0.05 (0.004 to 0.67) 0.44 (0.09 to 2.08) 5.24 (1.11 to 24.74) 1.52 (0.35 to 6.70) 1.21 (1.07 to 1.36) 0.27 (0.03 to 2.36) 2.23 (1.68 to 2.97) 0.41 (0.07 to 2.45)
47 (81.0) 5 (8.6) 6 (10.3)
3 (37.5) 0 (0) 4 (50.0)
0.02* 1.00 0.02*
7.12 (1.48 to 34.39) 1.09 (1.01 to 1.18) 0.12 (0.02 to 0.59)
1.00 1.00 1.00
34 (58.6) 19 (32.8) 9 (15.5) 4 (6.9) 2 (3.4)
3 (37.5) 3 (37.5) 4 (50.0) 0 (0.0) 2 (25.0)
0.29 1.00 0.04* 1.00 0.07
2.36 (0.51 to 10.84) 0.81 (0.18 to 3.76) 0.18 (0.04 to 0.87) 1.07 (1.00 to 1.15) 0.11 (0.01 to 0.90)
0.51
55 (94.8) 41 (70.7) 6 (10.3)
5 (62.5) 2 (25.0) 4 (50.0)
0.02* 0.02* 0.02*
11.00 (1.74 to 69.52) 7.24 (1.33 to 39.50) 0.12 (0.02 to 0.59)
1.00 0.40 0.09
P
Multivariate analysis OR (95% CI)
P 1.00 0.54
1.00
1.00
Patients with poor outcome were defined as those who died or received an mRS score of 3–5 within the 6-month follow-up. All other patients were defined as patients with good outcome. ⁎ p b 0.05
These variables were then included in logistic regression to identify predictors of death or disability. Covariates in the regression were selected based on the univariate analysis and included age, focal deficits, GCS on admission, deep-brain and brainstem intracerebral hemorrhage, use of dehydration therapy, surgery and complications (all alpha ≤ 0.10). None of the variables tested in the model proved to be a significant independent predictor of disability or death at 6 months (Table 3).
4. Discussion This study provides some of the most detailed insights to date into the etiologies, clinical presentations, and outcomes of pediatric SICH in Chinese children. The median age of our patients was 12.0 years, which is older than in similar studies of non-Asian children [5,16,17]. This likely reflects the fact that our medical center is not a specialized pediatric hospital, where younger patients with SICH were most likely sent. The male:female ratio in our cohort was 1.59:1, similar to studies of SICH in children in the US [5] (1.7:1), Spain [16] (2.4:1), and Switzerland [17] (1.3:1). The most frequent location of intracerebral hemorrhage was the cerebral lobe (57.1%), which is consistent with studies in European children [3,17]. Arteriovenous malformation was the most frequent cause of SICH in our cohort, similar to observations in Spanish case series [16–18]. Indeed, intracerebral hemorrhage is a frequent clinical consequence in adults and children with arteriovenous malformation, which occurs more often in children than adults [19]. The second largest proportion of our patients had SICH of unknown etiology, due to insufficient examinations. We observed a similar result in a previous study of ICH in southwest China [20]. These findings highlight the need for clinicians to perform further tests on pediatric patients with suspected SICH. This will generate valuable epidemiological data for developing countries and other areas with high incidence of SICH. Hematological disorders are known to promote intracranial bleeding [5]. Only one child in our cohort was diagnosed with hemophilia, and she died during hospitalization. This incidence of hemophilia is much lower than that in a case series of 30 Spanish patients [18], of whom 7 had hematological disorders. This difference may reflect the
fact that the previous study included only patients younger than 15 years, and it recorded outcomes for a 16-year period. Aneurysms and brain tumors also can cause SICH in children. Only 2.9% of the SICH cases in our study were due to aneurysms, which is closer to the 0% reported in a study of 30 children from Spain [18] than to the 15% reported in a study of children from Switzerland [17]. Brain tumors occurred in only 2.9% of our cohort, which is lower than the 10% reported in a study of children from the US [21]. Our clinical experience, coupled with the present results, suggests that hemorrhaging in brain tumors rarely occurs. Combined rates of mortality and disability at 3 and 6 months were much lower in our study than in similar studies in US and Europe [5–8], while the mortality rate at 3 and 6 months in our study was similar to Beslow et al. study [10] (4.5% at 30-days). This difference may be attributable to the fact that SICH is an acute, sudden and often fatal disease [1,20]. As a result, many potential patients in our cohort may have died in local hospitals or en route to our hospital. Thus, our patient population may have been in more stable condition than the general pediatric SICH population, which also existed in Beslow et al. study [10]. Another possible factor behind our lower mortality and disability is age: a study of Swiss children with SICH reported higher mortality in those younger than 3 years than in those who were older [17]. Our cohort included children with a median age of 12.0 years, much older than other series [17,22]. In the univariate analysis, we identified that younger age, presence of focal deficits, lower GCS at admission, and presence of complications, which were associated with 6-month mortality and disability. Conversely, the same univariate analysis suggested that surgery and use of dehydration therapy may reduce risk of mortality and disability. However, none of these factors proved to be an independent predictor of death and disability in multivariate logistic regression. Future studies should clarify whether any of these factors can reliably predict mortality and disability. Our study provides several insights into the etiology and characteristics of pediatric SICH in China, but the findings should be interpreted with caution because of several limitations in the study. First, it was a single hospital-based study, so results may be different from cohorts treated at smaller or more specialized hospitals. Second, the study sample was relatively small and convenience-based, rather than
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population-based, increasing the risk of referral bias. Third, radiology images were unavailable, preventing us from calculating hemorrhage volume. Lastly, we evaluated disability using the mRS, even though this scale has yet to be validated for children. Despite its limitations, our study opens the door to more detailed analysis of pediatric SICH in Asian and non-Asian ethnicities, particularly in developing countries, which the literature has largely neglected. Our study also highlights the need for clinicians to perform auxiliary examinations on pediatric patients suspected of having SICH in order to elucidate the etiology, particularly in developing countries and countries with high incidence of SICH. 5. Conclusion Arteriovenous malformation was the most frequent cause of SICH in our Chinese pediatric cohort, similar to reports of mostly non-Asian children from developed countries. The incidence of pediatric SICH of unknown etiology was much higher in our cohort than in other published series. Many patients in our cohort presented with nonspecific symptoms of headache, vomiting, and focal deficits, suggesting that SICH may easily be misdiagnosed. Since none of the factors in our study proved to be an independent risk factor of death and disability, further studies are needed to help predict which pediatric patients are at higher risk of poor outcomes. Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper. Acknowledgments This research was supported by the National Key Technology R&D Program for the 12th Five-year Plan of the People's Republic of China (2011BAI08B05) and by the National Natural Science Foundation of China (81371282 and 81400964). References [1] L.B. Morgenstern, J.C. Hemphill III, C. Anderson, K. Becker, J.P. Broderick, E.S. Connolly Jr., S.M. Greenberg, J.N. Huang, M.D. RL, S.R. Messé, Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American heart association/American stroke association, Stroke 41 (2010) 2108–2129.
[2] H.J. Fullerton, Y.W. Wu, S. Zhao, S.C. Johnston, Risk of stroke in children: ethnic and gender disparities, Neurology 61 (2003) 189–194. [3] M. Giroud, M. Lemesle, J.B. Gouyon, J.L. Nivelon, C. Milan, R. Dumas, Cerebrovascular disease in children under 16 years of age in the city of Dijon, France: a study of incidence and clinical features from 1985 to 1993, J. Clin. Epidemiol. 48 (1995) 1343–1348. [4] J. Broderick, G.T. Talbot, E. Prenger, A. Leach, T. Brott, Stroke in children within a major metropolitan area: the surprising importance of intracerebral hemorrhage, J. Child Neurol. 8 (1993) 250–255. [5] A. Al-Jarallah, M.T. Al-Rifai, A.R. Riela, E.S. Roach, Nontraumatic brain hemorrhage in children: etiology and presentation, J. Child Neurol. 15 (2000) 284–289. [6] I. Blom, E.L. De Schryver, L.J. Kappelle, G.J. Rinkel, A. Jennekens-Schinkel, A.C. Peters, Prognosis of haemorrhagic stroke in childhood: a long-term follow-up study, Dev. Med. Child Neurol. 45 (2003) 233–239. [7] W.D. Lo, J. Lee, J. Rusin, E. Perkins, E.S. Roach, Intracranial hemorrhage in children: an evolving spectrum, Arch. Neurol. 65 (2008) 1629–1633. [8] V. Ganesan, A. Hogan, N. Shack, A. Gordon, E. Isaacs, F.J. Kirkham, Outcome after ischaemic stroke in childhood, Dev. Med. Child Neurol. 42 (2000) 455–461. [9] L.C. Jordan, A.E. Hillis, Hemorrhagic stroke in children, Pediatr. Neurol. 36 (2007) 73–80. [10] L.A. Beslow, D.J. Licht, S.E. Smith, P.B. Storm, G.G. Heuer, R.A. Zimmerman, A.M. Feiler, S.E. Kasner, R.N. Ichord, L.C. Jordan, Predictors of outcome in childhood intracerebral hemorrhage: a prospective consecutive cohort study, Stroke 41 (2) (Feb. 2010) 313–318. [11] V.L. Feigin, C.M. Lawes, D.A. Bennett, C.S. Anderson, Stroke epidemiology: a review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century, Lancet Neurol. 2 (2003) 43–53. [12] Y. Deng, Y. Wang, W. Yang, Y. Yu, J. Xu, Y. Wang, B. Gao, Risk factors and imaging characteristics of childhood stroke in China, J. Child Neurol. 30 (3) (2015) 339–343. [13] S. Hatano, Experience from a multicentre stroke register: a preliminary report, Bull. World Health Organ. 54 (1976) 541–553. [14] F.Y. Kong, W.D. Tao, Z.L. Hao, M. Liu, Predictors of one-year, disability and death in Chinese hospitalized women after ischemic stroke, Cerebrovasc. Dis. 29 (2010) 255–262. [15] R. De Haan, M. Limburg, P. Bossuyt, J. van der Meulen, N. Aaronson, The clinical meaning of rankin ‘handicap’ grades after stroke, Stroke J. Cereb. Circ. 26 (1995) 2027–2030. [16] M.E. May Llanas, E. Alcover Bloch, C.L. FJ, J. CampistolPlana, A. Palomeque Rico, Nontraumatic cerebral hemorrhage inchildhood: etiology, clinical manifestation and management, An. Esp. Pediatr. 51 (1999) 257–261. [17] A.D. Meyer-Heim, E. Boltshauser, Spontaneous intracranial haemorrhage inchildren: aetiology, presentation and outcome, Brain and Development 25 (6) (Sep. 2003) 416–421. [18] C. Veira, D. Castro-Vilanova, A. Ferreiro, C. Sanchez-Suarez, M.L. Cuadrado, R. Simon, et al., Spontaneous intracranial hemorrhages in childhood, Rev. Neurol. 25 (1997) 1381–1382. [19] C. Millar, B. Bissonette, R.P. Humphreys, Cerebral arteriovenous malformations in children, Can. J. Anaesth. 41 (1994) 321–331. [20] Q. Wang, S. Lin, W. Dong, M. Liu, Characteristics of etiological diagnostic workup across the past 10 years in patients with spontaneous intracerebral hemorrhage in a large general hospital, Dev. Neurorehabil. 31 (Jan. 2014). [21] J.P. Laurent, D.A. Bruce, L. Schut, Hemorrhagic brain tumors in pediatric patients, Childs Brain 8 (1981) 263–270. [22] L.C. Jordan, J.T. Kleinman, A.E. Hillis, Intracerebral hemorrhage volume predicts poor neurologic outcome in children, Stroke 40 (5) (2009 May) 1666–1671.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Etiology, clinical characteristics and prognosis of spontaneous intracerebral hemorrhage in children: A prospective cohort study in China☆ Junfeng Liu 1, Deren Wang 1, Chunyan Lei, Yao Xiong, Ruozhen Yuan, Zilong Hao, Wendan Tao, Ming Liu ⁎ Stroke Clinical Research Unit, Department of Neurology, West China Hospital, Sichuan University, Chengdu, PR China
a r t i c l e
i n f o
Article history: Received 19 June 2015 Received in revised form 22 September 2015 Accepted 23 September 2015 Available online 28 September 2015 Keywords: Intracerebral hemorrhage Children Etiology Clinical characteristics Prognosis
a b s t r a c t Background and objective: Much is known about spontaneous intracerebral hemorrhage (SICH) in adults, but few studies have examined pediatric SICH, especially in China. The aim of the present study was to describe the etiology, clinical characteristics and prognosis of SICH in children from southwest China. Method: Consecutive patients aged 1–18 years with SICH at our medical center were prospectively enrolled from January 2012 to June 2014. SICH was defined by WHO criteria and confirmed by CT or MRI findings. Demographic and clinical information was collected at baseline, and follow-up assessments were conducted at 3 and 6 months after SICH, when patients were scored on the modified Rankin Scale (mRS) and events of deaths and recurrent hemorrhagic stroke were recorded. Results: Among the 70 children (43 males; median age, 12.0 years) in the final analysis, 44 patients (62.9%) had SICH due to arteriovenous malformation, and less frequent etiologies were cavernous malformation (n = 4), aneurysm (n = 2), tumors (n = 2), moyamoya (n = 2), hemophilia (n = 1), hypertension (n = 1), while 14 (20.0%) had SICH of unknown etiology. The mortality rate at 3 months and 6 months was equal, which was both 3%. The rate of disability was 12.1% at 3 months and 9.1% at 6 months. Conclusion: The most frequent etiology of pediatric SICH in this Chinese cohort was arteriovenous malformation. SICH of unknown etiology occurred much more often in our cohort than in previously published Caucasian patients in the US and Europe. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Stroke is a major cause of morbidity and mortality throughout the world, and spontaneous intracerebral hemorrhage (SICH) accounts for approximately 15% of all stroke cases [1]. Although the public often associates stroke with old age, stroke occurs in 2–13 children per 100 000 per year [2,3], and SICH accounts for as many as half of these cases [2,4]. Pediatric SICH leads to death in approximately one-third of cases, and in many more cases it leads to long-term disability, including seizures as well as cognitive and motor impairment [5–8]. This poses a substantial burden on the family and society, highlighting the need for a strong understanding of SICH in children. Despite the devastating effects of SICH in children, much less is known about it than about SICH in adults. The relatively few published studies on pediatric SICH are case series and retrospective chart reviews ☆ Disclosure of conflicts of interest: The authors declare no financial or other conflicts of interest. ⁎ Corresponding author at: Stroke Clinical Research Unit, Department of Neurology, West China Hospital, Sichuan University, No. 37, GuoXue Xiang, Chengdu, 610041 Sichuan Province, PR China. E-mail address: [email protected] (M. Liu). 1 The first two authors contributed equally to this work.
http://dx.doi.org/10.1016/j.jns.2015.09.366 0022-510X/© 2015 Elsevier B.V. All rights reserved.
[4–7,9]. Some prospective cohort studies have been reported, but they involve small samples of 11–22 children [3,10]. This lack of understanding of pediatric SICH poses a serious obstacle to predicting, diagnosing and managing the condition, since its etiology and outcomes appear to be different from those of adult SICH [2,11]. Even this is uncertain, however, since most studies of pediatric SICH have come from the US and Europe, leaving open the question of whether SICH etiology and outcomes are similar in children of other ethnic groups. In China, for example, very little has been published about pediatric SICH [12]. Therefore we prospectively enrolled patients aged 1–18 years with SICH at our medical center in southwest China and analyzed stroke etiology, clinical characteristics and outcomes during 6-month follow-up. We also tried to identify clinico-demographic predictors of poor outcomes.
2. Methods This research project was carried out under the auspices of the National Key Technology R&D Program of the 12th Five-Year Plan “Study on Etiology and Minimally Invasive Neurosurgery for Hemorrhagic Stroke”. The study protocol was approved by the Scientific
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Research Department of West China Hospital, Sichuan University. Written informed consent was obtained from participants or their guardians. Pediatric patients with spontaneous ICH were prospectively and consecutively enrolled upon being admitted to West China Hospital of Sichuan University in Chengdu, China. The enrollment period was from January 2012 to June 2014. To be enrolled, patients had to be 1–18 years old with a diagnosis of SICH based on World Health Organization stroke criteria [13] and confirmed by neuroimaging, which involved rapid computed tomography scanning or magnetic resonance imaging to distinguish SICH from ischemic stroke [1]. Children were excluded from the study if they had a history of head trauma; if their hemorrhage was restricted to epidural, subdural, intraventricular or subarachnoid compartments; or if patients had both CSVT and hemorrhagic transformation. A standardized form was used to collect data on patient demographic characteristics, level of consciousness on admission, stroke risk factors, diagnostic tests, treatment, stroke-related complications during hospitalization, and discharge medicine/interventions. Level of consciousness on admission was measured using the Glasgow Coma Score (GCS). Current medicine use and outcomes (death, disability, combined death or disability, and stroke recurrence) were assessed at 3 and 6 months after stroke onset by telephone interview or letter conducted by experienced stroke neurologists. A different group of stroke neurologists who were blinded to patient clinical data calculated modified Rankin score (mRS) scores. Disability was defined as a score of 3–5 on the modified Rankin Scale (mRS) [14–15]. Recurrence included intracerebral and subarachnoid hemorrhage. All statistical analyses were performed using SPSS 20.0 (IBM, Chicago, IL, USA). Two-sided P values b 0.05 were considered statistically significant. Results were expressed as odds ratios (ORs) and associated 95% confidence intervals (CIs). Results for categorical variables were compared between different groups using chi-squared or Fisher exact tests. Results for continuous variables were compared using ANOVA or Mann–Whitney U tests. Binary logistic regression was used to identify possible predictors of death or disability in pediatric SICH. 3. Results 3.1. Baseline patient characteristics A total of 70 patients with childhood SICH (43 males; median age, 12.0 ± 4.6 years) were included in the study. Most were diagnosed with pure ICH (50 patients), while 15 (21.4%) were diagnosed with a combination of intracerebral and intraventricular hemorrhage, and 5 (7.1%) had a combination of intracerebral and subarachnoid hemorrhage. Among the 70 patients, 56 children have undertaken enough imaging examination (eg. MRA, CTA or DSA). Etiology of SICH was undetermined in 14 patients due to lack enough imaging examination. SICH in most patients (n = 44) was caused by arteriovenous malformation; other, much less frequent etiologies were cavernous malformation (n = 4), aneurysm (n = 2), tumors (n = 2)and moyamoya (n = 2) (Table 1). One patient was diagnosed with hemophilia, consistent with the number of patients with hypertension. 46 (65.7%) patients received surgery after SICH (Table 1). Most patients (54, 77.1%) were transferred to our hospital after being admitted to local hospitals, while the remaining 16 (22.9%) were admitted directly to our tertiary care center. Median time from symptom onset to our hospital was 91 h, with 11 patients (15.7%) arriving at our hospital within 6 h and 49 (70.0%) arriving more than 24 h after symptom onset. SICH was accompanied by altered mental status in 26 patients (37.1%), by headache in 56 (80.0%), and by vomiting in 45 (64.3%). After admission to our medical center, focal deficits were detected upon initial examination in 38 patients (54.3%), seizures occurred in 9 (12.9%), and intracranial hypertension or herniation syndromes occurred in 13 (18.6%). In-hospital complications occurred
Table 1 Baseline characteristics of Chinese pediatric patients with SICH (n = 70). Characteristic
Value
Male sex, n (%) Age at index stroke in year, median (range) Stroke risk factors, n (%) Arteriovenous malformation Unknown Angiocavernoma Moyamoya Tumor Aneurysm Hemophilia Hypertension Localization, n (%) Lobe Multiple areas Deep brain Cerebellum Brainstem Laterality, n (%) Left Right Both Level of consciousness, n (%) Mild (13–15) Moderate (9–12) Severe (3–8) Treatment, n (%) Dehydration Surgery
43 (61.4) 12.0 (1–18) 44 (62.9) 14 (20.0) 4 (5.7) 2 (2.9) 2 (2.9) 2 (2.9) 1 (1.4) 1 (1.4) 40 (57.1) 22 (31.4) 13 (18.6) 5 (7.1) 4 (5.7) 41 (58.6) 22 (31.4) 7 (10.0) 53 (75.7) 6 (8.6) 11 (15.7) 59 (83.1) 46 (65.7)
in 10 patients (14.3%), including respiratory infection (n = 6), electrolyte disturbance (n = 2), urinary infection (n = 1), and acute renal failure (n = 1). 3.2. Outcomes at 3 and 6 months The patient diagnosed with hemophilia died of respiratory failure caused by herniation within 24 h after admission to our hospital; the remaining 69 patients were alive at discharge. Another child was dead within 3 months after ICH, while the cause of the death was unknown. Four patients were lost to follow-up. As a whole, the mortality rate at 3 months among the remaining 66 patients was 3% and the disability rate at 3 months was 12.1% (Table 2). The corresponding rates at 6 months were 3% and 9.1%. The combined rate of mortality or disability was 15.2% at 3 months and 12.1% at 6 months. Among the 66 patients who completed the 6-month follow-up, only 2 experienced recurrence of ICH. Recurrent hemorrhage occurred in one child with unknown etiology of hemorrhage who developed a second ICH 20 days after the initial event. Another child with AVM which was not resected during hospitalization had a secondary hemorrhage within 6 months after first hemorrhage. 3.3. Predictors of disability or death within 6 months of SICH Univariate analysis identified several variables that were significantly associated with disability or death at 6 months (Table 3): Age 1 (1–4 years old) (P = 0.04), focal deficits (P = 0.01), GCS on admission [3–8] (P = 0.03), deep brain (P = 0.04), use of dehydration therapy (P = 0.02), surgery (P = 0.03), and complications (P = 0.02).
Table 2 Rates of mortality and disability [n (%)] at 3 and 6 months after SICH (n = 66).
Mortality Disability Mortality or disability Recurrence of SICH
3 months
6 months
2 (3.0) 8 (12.1) 10 (15.2) 1 (1.5)
2 (3.0) 6 (9.1) 8 (12.1) 2 (3.0)
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Table 3 Univariate and multivariate analyses to identify predictors of death or disability at 6 months after SICH in children. Factor
Age, n (%) Age 1 (1–4 years old) Age 2 (5–9 years old) Age 3 (10–18 years old) Male, n (%) Headache, n (%) Emesis, n (%) Focal deficits, n (%) Seizure, n (%) GCS on admission, n (%) Mild (13–15) Moderate (9–12) Severe (3–8) Localization, n (%) Lobe Multiple areas Deep Brain Cerebellum Brainstem Treatment, n (%) Dehydration Surgery Complications, n (%)
Patients with good outcome, (n = 58)
Patients with poor outcome, (n = 8)
Univariate analysis
1 (1.7) 12 (20.7) 44 (75.9) 35 (60.3) 48 (82.8) 38 (65.5) 26 (44.8) 7 (12.1)
2 (25.0) 3 (37.5) 3 (37.5) 4 (50.0) 8 (100) 7 (87.5) 8 (100) 2 (25.0)
0.04* 0.39 0.04 0.71 0.34 0.42 0.005* 0.30
0.05 (0.004 to 0.67) 0.44 (0.09 to 2.08) 5.24 (1.11 to 24.74) 1.52 (0.35 to 6.70) 1.21 (1.07 to 1.36) 0.27 (0.03 to 2.36) 2.23 (1.68 to 2.97) 0.41 (0.07 to 2.45)
47 (81.0) 5 (8.6) 6 (10.3)
3 (37.5) 0 (0) 4 (50.0)
0.02* 1.00 0.02*
7.12 (1.48 to 34.39) 1.09 (1.01 to 1.18) 0.12 (0.02 to 0.59)
1.00 1.00 1.00
34 (58.6) 19 (32.8) 9 (15.5) 4 (6.9) 2 (3.4)
3 (37.5) 3 (37.5) 4 (50.0) 0 (0.0) 2 (25.0)
0.29 1.00 0.04* 1.00 0.07
2.36 (0.51 to 10.84) 0.81 (0.18 to 3.76) 0.18 (0.04 to 0.87) 1.07 (1.00 to 1.15) 0.11 (0.01 to 0.90)
0.51
55 (94.8) 41 (70.7) 6 (10.3)
5 (62.5) 2 (25.0) 4 (50.0)
0.02* 0.02* 0.02*
11.00 (1.74 to 69.52) 7.24 (1.33 to 39.50) 0.12 (0.02 to 0.59)
1.00 0.40 0.09
P
Multivariate analysis OR (95% CI)
P 1.00 0.54
1.00
1.00
Patients with poor outcome were defined as those who died or received an mRS score of 3–5 within the 6-month follow-up. All other patients were defined as patients with good outcome. ⁎ p b 0.05
These variables were then included in logistic regression to identify predictors of death or disability. Covariates in the regression were selected based on the univariate analysis and included age, focal deficits, GCS on admission, deep-brain and brainstem intracerebral hemorrhage, use of dehydration therapy, surgery and complications (all alpha ≤ 0.10). None of the variables tested in the model proved to be a significant independent predictor of disability or death at 6 months (Table 3).
4. Discussion This study provides some of the most detailed insights to date into the etiologies, clinical presentations, and outcomes of pediatric SICH in Chinese children. The median age of our patients was 12.0 years, which is older than in similar studies of non-Asian children [5,16,17]. This likely reflects the fact that our medical center is not a specialized pediatric hospital, where younger patients with SICH were most likely sent. The male:female ratio in our cohort was 1.59:1, similar to studies of SICH in children in the US [5] (1.7:1), Spain [16] (2.4:1), and Switzerland [17] (1.3:1). The most frequent location of intracerebral hemorrhage was the cerebral lobe (57.1%), which is consistent with studies in European children [3,17]. Arteriovenous malformation was the most frequent cause of SICH in our cohort, similar to observations in Spanish case series [16–18]. Indeed, intracerebral hemorrhage is a frequent clinical consequence in adults and children with arteriovenous malformation, which occurs more often in children than adults [19]. The second largest proportion of our patients had SICH of unknown etiology, due to insufficient examinations. We observed a similar result in a previous study of ICH in southwest China [20]. These findings highlight the need for clinicians to perform further tests on pediatric patients with suspected SICH. This will generate valuable epidemiological data for developing countries and other areas with high incidence of SICH. Hematological disorders are known to promote intracranial bleeding [5]. Only one child in our cohort was diagnosed with hemophilia, and she died during hospitalization. This incidence of hemophilia is much lower than that in a case series of 30 Spanish patients [18], of whom 7 had hematological disorders. This difference may reflect the
fact that the previous study included only patients younger than 15 years, and it recorded outcomes for a 16-year period. Aneurysms and brain tumors also can cause SICH in children. Only 2.9% of the SICH cases in our study were due to aneurysms, which is closer to the 0% reported in a study of 30 children from Spain [18] than to the 15% reported in a study of children from Switzerland [17]. Brain tumors occurred in only 2.9% of our cohort, which is lower than the 10% reported in a study of children from the US [21]. Our clinical experience, coupled with the present results, suggests that hemorrhaging in brain tumors rarely occurs. Combined rates of mortality and disability at 3 and 6 months were much lower in our study than in similar studies in US and Europe [5–8], while the mortality rate at 3 and 6 months in our study was similar to Beslow et al. study [10] (4.5% at 30-days). This difference may be attributable to the fact that SICH is an acute, sudden and often fatal disease [1,20]. As a result, many potential patients in our cohort may have died in local hospitals or en route to our hospital. Thus, our patient population may have been in more stable condition than the general pediatric SICH population, which also existed in Beslow et al. study [10]. Another possible factor behind our lower mortality and disability is age: a study of Swiss children with SICH reported higher mortality in those younger than 3 years than in those who were older [17]. Our cohort included children with a median age of 12.0 years, much older than other series [17,22]. In the univariate analysis, we identified that younger age, presence of focal deficits, lower GCS at admission, and presence of complications, which were associated with 6-month mortality and disability. Conversely, the same univariate analysis suggested that surgery and use of dehydration therapy may reduce risk of mortality and disability. However, none of these factors proved to be an independent predictor of death and disability in multivariate logistic regression. Future studies should clarify whether any of these factors can reliably predict mortality and disability. Our study provides several insights into the etiology and characteristics of pediatric SICH in China, but the findings should be interpreted with caution because of several limitations in the study. First, it was a single hospital-based study, so results may be different from cohorts treated at smaller or more specialized hospitals. Second, the study sample was relatively small and convenience-based, rather than
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population-based, increasing the risk of referral bias. Third, radiology images were unavailable, preventing us from calculating hemorrhage volume. Lastly, we evaluated disability using the mRS, even though this scale has yet to be validated for children. Despite its limitations, our study opens the door to more detailed analysis of pediatric SICH in Asian and non-Asian ethnicities, particularly in developing countries, which the literature has largely neglected. Our study also highlights the need for clinicians to perform auxiliary examinations on pediatric patients suspected of having SICH in order to elucidate the etiology, particularly in developing countries and countries with high incidence of SICH. 5. Conclusion Arteriovenous malformation was the most frequent cause of SICH in our Chinese pediatric cohort, similar to reports of mostly non-Asian children from developed countries. The incidence of pediatric SICH of unknown etiology was much higher in our cohort than in other published series. Many patients in our cohort presented with nonspecific symptoms of headache, vomiting, and focal deficits, suggesting that SICH may easily be misdiagnosed. Since none of the factors in our study proved to be an independent risk factor of death and disability, further studies are needed to help predict which pediatric patients are at higher risk of poor outcomes. Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper. Acknowledgments This research was supported by the National Key Technology R&D Program for the 12th Five-year Plan of the People's Republic of China (2011BAI08B05) and by the National Natural Science Foundation of China (81371282 and 81400964). References [1] L.B. Morgenstern, J.C. Hemphill III, C. Anderson, K. Becker, J.P. Broderick, E.S. Connolly Jr., S.M. Greenberg, J.N. Huang, M.D. RL, S.R. Messé, Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American heart association/American stroke association, Stroke 41 (2010) 2108–2129.
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