- Email: [email protected]
Prognostic predictors for outcome after childhood stroke – Authors' reply
Correspondence
Prognostic predictors for outcome after childhood stroke On the basis of data collected from the International Pediatric Stroke Study, Goldenberg and colleagues1 reported the frequencies of acute treatments and outcomes, the relation between acute treatments and prognostic factors, and prognostic predictors for early adverse outcomes in patients with acute childhood-onset arterial ischaemic stroke (AIS). Although multinational studies of AIS in children are challenging, the study by Goldenberg and colleagues1 is a model example and its findings should be useful for researchers who design future clinical trials in children with AIS. Goldenberg and colleagues1 indicated that there is substantial variation in use of acute antithrombotic treatments on different continents, that antithrombotic drug use varies with AIS subtype, and that prognostic predictors of AIS—including bilateral ischaemia, decreased consciousness, and arteriopathy—are associated with adverse outcomes. However, the significance of prognostic predictors derived in the present study is limited and the selection of prognostic factors is controversial. In addition to the prognostic factors listed in this study, we think delay of diagnosis and blood pressure are two important factors influencing early and long-term outcomes in children with AIS. Early diagnosis and management of diseases are important in reducing mortality and disability and might improve prognosis in the long term. However, substantial delays to diagnosis exist in paediatric AIS, including prehospital delays (symptom onset to hospital arrival) and in-hospital delays (presentation to diagnosis).2 AIS might not be recognised at the time of onset in children because parents are unaware www.thelancet.com/neurology Vol 9 February 2010
of its symptoms and signs, which might cause a delay in taking children to hospital. Also, substantial delays can occur after arrival at hospital and are most likely to be associated with the lack of awareness of stroke symptoms among medical staff members. The average interval from symptom onset to diagnosis was 22·7–24·8 h, substantially longer than the time limit (6 h) for stroke-specific thrombolytic and neuroprotective strategies.2,3 Therefore, delayed diagnosis of paediatric AIS can directly result in treatment delays, which might increase the risk of adverse outcomes. Blood pressure is associated with occurrence of first stroke, and higher blood pressure increases the risk of recurrent stroke. In a systematic review,4 high blood pressure was reported to occur commonly after acute stroke, including AIS, and is associated with poor outcomes such as disability, neurological deterioration, and death. Additionally, early antihypertensive treatments can reduce mortality and disability in acute stroke without increasing serious adverse events.4,5 Thus, although few studies focus on the relation between blood pressure and acute AIS in children, blood pressure could be a significant predictor of outcome after acute childhood-onset AIS. In conclusion, because of the variation of acute treatments used in different continents and for different AIS subtypes, prospective clinical trials of antithrombotic treatments in children with AIS are essential for standardisation of future treatments. The design of the study by Goldenberg and colleagues1 is a foundation for future clinical trials and the data from the International Pediatric Stroke Study are important. However, in future studies, factors that predict outcome after paediatric AIS should be derived from more important prognostic factors. We have no conflicts of interest
Zhou Fei, Peng Luo, Lei Zhang [email protected] Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China 1
2
3
4
5
Goldenberg NA, Bernard TJ, Fullerton HJ, et al. Antithrombotic treatments, outcomes, and prognostic factors in acute childhood-onset arterial ischaemic stroke: a multicentre, observational, cohort study. Lancet Neurol 2009; 8: 1120–27. Rafay MF, Pontigon AM, Chiang J, et al. Delay to diagnosis in acute pediatric arterial ischemic stroke. Stroke 2009; 40: 58–64. Srinivasan J, Miller SP, Phan TG, et al. Delayed recognition of initial stroke in children: need for increased awareness. Pediatrics 2009; 124: e227–34. Tikhonoff V, Zhang H, Richart T, Staessen JA. Blood pressure as a prognostic factor after acute stroke. Lancet Neurol 2009; 8: 938–48. Potter JF, Robinson TG, Ford GA, et al. Controlling hypertension and hypotension immediately post-stroke (CHHIPS): a randomised, placebo-controlled, double-blind pilot trial. Lancet Neurol 2009; 8: 48–56.
Authors’ reply We appreciate Fei and colleagues’ letter suggesting the need for more extensive analysis of prognostic factors associated with adverse outcomes after childhood-onset arterial ischaemic stroke (AIS). Fei and colleagues suggest that our candidate predictors of death or neurological deficit—age, low level of consciousness, bilateral ischaemia, arterial distribution, arteriopathy, cardiac disease, sickle cell disease, isolated patent foramen ovale, intracranial haemorrhage, and geographical region—are incomplete and controversial. We agree that the factors assessed in our analysis are not all inclusive. In adult AIS, National Institutes of Health stroke scale (NIHSS) score, acute hypertension (as pointed out by Fei and colleagues), subtypes of stroke based upon the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification, and numerous biomarkers have been identified as predictive of outcome.1–3 Prognostic indicators of neurological impairment investigated so far in single-centre studies of paediatric AIS have included age, sex, underlying neurological disorders, stroke size, and need for inpatient rehabilitation.4–6 Although
If you would like to respond to an article published in The Lancet Neurology, please submit your correspondence online at: http://ees.elsevier. com/thelancetneurology
141
Correspondence
acute hypertension and lag time from presentation to diagnosis, as suggested by Fei and colleagues, are also worthy of investigation, these data were not collected in the early years of our study, and therefore could not be analysed. With regard to our choice of predictors, some variables were chosen on the basis of published work: stroke size and age have previously been associated with adverse neurological outcome in childhoodonset stroke.4–6 However, there is a relative paucity of studies of outcome after childhood stroke to guide the selection of predictors. Hence, our analysis was exploratory and intended to generate new predictors in view of the limited research in this area. Stroke subtypes were particularly of interest given the predictive value of the TOAST classification in adults. Indeed, we found that arteriopathy was associated with an increased risk of early adverse outcome. Further studies of childhood-onset AIS are needed to substantiate our observations of novel prognostic factors such as arteriopathy. The success of future efforts towards developing risk-stratified therapeutic approaches for childhood-onset AIS depends in
part upon a broader knowledge of prognostic factors of this disease. As part of this effort, research is underway by the International Pediatric Stroke Study investigators to evaluate the prognostic usefulness of a paediatric adaptation of the NIHSS, to evaluate the relations between inflammation, arteriopathy, and outcome, and to develop a consensus-based classification system for childhood-onset AIS.
3
4
5
6
We have no conflicts of interest.
Timothy J Bernard, Neil A Goldenberg, Heather J Fullerton, Anne Gordon, Gabrielle deVeber
Surveillance of H1N1related neurological complications
[email protected] Department of Pediatrics, University of Colorado Denver, Children’s Hospital, and Mountain States Regional Hemophilia and Thrombosis Center, Aurora, CO, USA (TJB, NAG); Section of Hematology, Oncology, and Bone Marrow Transplantation (NAG), Section of Child Neurology (TJB), and Departments of Neurology and Pediatrics (HJF), University of California San Francisco, San Francisco, CA, USA; Children’s Neuroscience Centre, Royal Children’s Hospital and Murdoch Children’s Research Institute, Melbourne, Australia (AG); and Division of Neurology, Hospital for Sick Children, Toronto, Ontario, Canada (GdV) 1
We read with interest the recent editorial urging the neurological community to make plans for coordinated surveillance programmes to estimate the overall burden of pandemic H1N1 influenza-related and vaccine-related neurological complications.1 The report by the US Centers for Disease Control and Prevention (CDC) described the first patients who developed neurological complications associated with the 2009 influenza A H1N1 virus, the first influenza pandemic of the
Winbeck K, Poppert H, Etgen T, Conrad B, Sander D. Prognostic relevance of early serial C-reactive protein measurements after first ischemic stroke. Stroke 2002; 33: 2459–64. Potter J, Robinson T, Ford G, et al. CHHIPS (controlling hypertension and hypotension immediately post-stroke) pilot trial: rationale and design. J Hypertens 2005; 23: 649–55.
2
Adams HP Jr, Davis PH, Leira EC, et al. Baseline NIH stroke scale score strongly predicts outcome after stroke: a report of the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Neurology 1999; 53: 126–31. Ganesan V, Hogan A, Shack N, Gordon A, Isaacs E, Kirkham FJ. Outcome after ischaemic stroke in childhood. Dev Med Child Neurol 2000; 42: 455–61. deVeber GA, MacGregor D, Curtis R, Mayank S. Neurologic outcome in survivors of childhood arterial ischemic stroke and sinovenous thrombosis. J Child Neurol 2000; 15: 316–24. Gordon AL, Ganesan V, Towell A, Kirkham FJ. Functional outcome following stroke in children. J Child Neurol 2002; 17: 429–34.
Sex; age (years)
Comorbidities
Onset (day of Neurological influenza-like diagnosis illness)
CT scan of brain
MRI scan of brain
EEG
CSF analysis
Treatment
Outcome
1
Female; 43
Myasthenia gravis
4
Exacerbation of myasthenia gravis
··
··
··
··
Intravenous immunoglobulin, oseltamivir
RWS
2
Male; 28
Chronic progressive 2 external ophthalmoplegia
First seizure
Brain atrophy
··
··
Increased protein concentrations
Oseltamivir, carbamazepine
RWS
3
Female; 16
None
2
First seizure
Normal
Normal
··
··
None
RWS
4
Male; 30
Migraine, asthma, gout
7
Migraine exacerbation
Normal
··
··
··
Oseltamivir, cafergot
RWS
5
Female; 16
Febrile seizures
4
First seizure
Brain atrophy
Brain atrophy
Normal
··
None
RWS
6
Male; 19
Previous seizure, asthma
7
Recurrent seizure
··
Normal
··
··
Oseltamivir, sodium valproate
RWS
7
Male; 18
None
2
First seizure
Normal
Normal
··
Normal
Oseltamivir
RWS
8
Male; 15
None
3
First seizure
··
··
··
··
Oseltamivir
RWS
9
Male; 57
Diabetes mellitus, hypertension, ischaemic heart disease
4
Acute ischaemic stroke
··
Right corona radiata infarct
··
··
Aspirin
Stroke rehabilitation
EEG=electroencephalogram. RWS=recovered without sequelae. ··=not done.
Table: Patients with influenza A H1N1 virus with neurological complications and their clinical features, investigations, treatment, and outcomes
142
www.thelancet.com/neurology Vol 9 February 2010
Prognostic predictors for outcome after childhood stroke On the basis of data collected from the International Pediatric Stroke Study, Goldenberg and colleagues1 reported the frequencies of acute treatments and outcomes, the relation between acute treatments and prognostic factors, and prognostic predictors for early adverse outcomes in patients with acute childhood-onset arterial ischaemic stroke (AIS). Although multinational studies of AIS in children are challenging, the study by Goldenberg and colleagues1 is a model example and its findings should be useful for researchers who design future clinical trials in children with AIS. Goldenberg and colleagues1 indicated that there is substantial variation in use of acute antithrombotic treatments on different continents, that antithrombotic drug use varies with AIS subtype, and that prognostic predictors of AIS—including bilateral ischaemia, decreased consciousness, and arteriopathy—are associated with adverse outcomes. However, the significance of prognostic predictors derived in the present study is limited and the selection of prognostic factors is controversial. In addition to the prognostic factors listed in this study, we think delay of diagnosis and blood pressure are two important factors influencing early and long-term outcomes in children with AIS. Early diagnosis and management of diseases are important in reducing mortality and disability and might improve prognosis in the long term. However, substantial delays to diagnosis exist in paediatric AIS, including prehospital delays (symptom onset to hospital arrival) and in-hospital delays (presentation to diagnosis).2 AIS might not be recognised at the time of onset in children because parents are unaware www.thelancet.com/neurology Vol 9 February 2010
of its symptoms and signs, which might cause a delay in taking children to hospital. Also, substantial delays can occur after arrival at hospital and are most likely to be associated with the lack of awareness of stroke symptoms among medical staff members. The average interval from symptom onset to diagnosis was 22·7–24·8 h, substantially longer than the time limit (6 h) for stroke-specific thrombolytic and neuroprotective strategies.2,3 Therefore, delayed diagnosis of paediatric AIS can directly result in treatment delays, which might increase the risk of adverse outcomes. Blood pressure is associated with occurrence of first stroke, and higher blood pressure increases the risk of recurrent stroke. In a systematic review,4 high blood pressure was reported to occur commonly after acute stroke, including AIS, and is associated with poor outcomes such as disability, neurological deterioration, and death. Additionally, early antihypertensive treatments can reduce mortality and disability in acute stroke without increasing serious adverse events.4,5 Thus, although few studies focus on the relation between blood pressure and acute AIS in children, blood pressure could be a significant predictor of outcome after acute childhood-onset AIS. In conclusion, because of the variation of acute treatments used in different continents and for different AIS subtypes, prospective clinical trials of antithrombotic treatments in children with AIS are essential for standardisation of future treatments. The design of the study by Goldenberg and colleagues1 is a foundation for future clinical trials and the data from the International Pediatric Stroke Study are important. However, in future studies, factors that predict outcome after paediatric AIS should be derived from more important prognostic factors. We have no conflicts of interest
Zhou Fei, Peng Luo, Lei Zhang [email protected] Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China 1
2
3
4
5
Goldenberg NA, Bernard TJ, Fullerton HJ, et al. Antithrombotic treatments, outcomes, and prognostic factors in acute childhood-onset arterial ischaemic stroke: a multicentre, observational, cohort study. Lancet Neurol 2009; 8: 1120–27. Rafay MF, Pontigon AM, Chiang J, et al. Delay to diagnosis in acute pediatric arterial ischemic stroke. Stroke 2009; 40: 58–64. Srinivasan J, Miller SP, Phan TG, et al. Delayed recognition of initial stroke in children: need for increased awareness. Pediatrics 2009; 124: e227–34. Tikhonoff V, Zhang H, Richart T, Staessen JA. Blood pressure as a prognostic factor after acute stroke. Lancet Neurol 2009; 8: 938–48. Potter JF, Robinson TG, Ford GA, et al. Controlling hypertension and hypotension immediately post-stroke (CHHIPS): a randomised, placebo-controlled, double-blind pilot trial. Lancet Neurol 2009; 8: 48–56.
Authors’ reply We appreciate Fei and colleagues’ letter suggesting the need for more extensive analysis of prognostic factors associated with adverse outcomes after childhood-onset arterial ischaemic stroke (AIS). Fei and colleagues suggest that our candidate predictors of death or neurological deficit—age, low level of consciousness, bilateral ischaemia, arterial distribution, arteriopathy, cardiac disease, sickle cell disease, isolated patent foramen ovale, intracranial haemorrhage, and geographical region—are incomplete and controversial. We agree that the factors assessed in our analysis are not all inclusive. In adult AIS, National Institutes of Health stroke scale (NIHSS) score, acute hypertension (as pointed out by Fei and colleagues), subtypes of stroke based upon the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification, and numerous biomarkers have been identified as predictive of outcome.1–3 Prognostic indicators of neurological impairment investigated so far in single-centre studies of paediatric AIS have included age, sex, underlying neurological disorders, stroke size, and need for inpatient rehabilitation.4–6 Although
If you would like to respond to an article published in The Lancet Neurology, please submit your correspondence online at: http://ees.elsevier. com/thelancetneurology
141
Correspondence
acute hypertension and lag time from presentation to diagnosis, as suggested by Fei and colleagues, are also worthy of investigation, these data were not collected in the early years of our study, and therefore could not be analysed. With regard to our choice of predictors, some variables were chosen on the basis of published work: stroke size and age have previously been associated with adverse neurological outcome in childhoodonset stroke.4–6 However, there is a relative paucity of studies of outcome after childhood stroke to guide the selection of predictors. Hence, our analysis was exploratory and intended to generate new predictors in view of the limited research in this area. Stroke subtypes were particularly of interest given the predictive value of the TOAST classification in adults. Indeed, we found that arteriopathy was associated with an increased risk of early adverse outcome. Further studies of childhood-onset AIS are needed to substantiate our observations of novel prognostic factors such as arteriopathy. The success of future efforts towards developing risk-stratified therapeutic approaches for childhood-onset AIS depends in
part upon a broader knowledge of prognostic factors of this disease. As part of this effort, research is underway by the International Pediatric Stroke Study investigators to evaluate the prognostic usefulness of a paediatric adaptation of the NIHSS, to evaluate the relations between inflammation, arteriopathy, and outcome, and to develop a consensus-based classification system for childhood-onset AIS.
3
4
5
6
We have no conflicts of interest.
Timothy J Bernard, Neil A Goldenberg, Heather J Fullerton, Anne Gordon, Gabrielle deVeber
Surveillance of H1N1related neurological complications
[email protected] Department of Pediatrics, University of Colorado Denver, Children’s Hospital, and Mountain States Regional Hemophilia and Thrombosis Center, Aurora, CO, USA (TJB, NAG); Section of Hematology, Oncology, and Bone Marrow Transplantation (NAG), Section of Child Neurology (TJB), and Departments of Neurology and Pediatrics (HJF), University of California San Francisco, San Francisco, CA, USA; Children’s Neuroscience Centre, Royal Children’s Hospital and Murdoch Children’s Research Institute, Melbourne, Australia (AG); and Division of Neurology, Hospital for Sick Children, Toronto, Ontario, Canada (GdV) 1
We read with interest the recent editorial urging the neurological community to make plans for coordinated surveillance programmes to estimate the overall burden of pandemic H1N1 influenza-related and vaccine-related neurological complications.1 The report by the US Centers for Disease Control and Prevention (CDC) described the first patients who developed neurological complications associated with the 2009 influenza A H1N1 virus, the first influenza pandemic of the
Winbeck K, Poppert H, Etgen T, Conrad B, Sander D. Prognostic relevance of early serial C-reactive protein measurements after first ischemic stroke. Stroke 2002; 33: 2459–64. Potter J, Robinson T, Ford G, et al. CHHIPS (controlling hypertension and hypotension immediately post-stroke) pilot trial: rationale and design. J Hypertens 2005; 23: 649–55.
2
Adams HP Jr, Davis PH, Leira EC, et al. Baseline NIH stroke scale score strongly predicts outcome after stroke: a report of the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Neurology 1999; 53: 126–31. Ganesan V, Hogan A, Shack N, Gordon A, Isaacs E, Kirkham FJ. Outcome after ischaemic stroke in childhood. Dev Med Child Neurol 2000; 42: 455–61. deVeber GA, MacGregor D, Curtis R, Mayank S. Neurologic outcome in survivors of childhood arterial ischemic stroke and sinovenous thrombosis. J Child Neurol 2000; 15: 316–24. Gordon AL, Ganesan V, Towell A, Kirkham FJ. Functional outcome following stroke in children. J Child Neurol 2002; 17: 429–34.
Sex; age (years)
Comorbidities
Onset (day of Neurological influenza-like diagnosis illness)
CT scan of brain
MRI scan of brain
EEG
CSF analysis
Treatment
Outcome
1
Female; 43
Myasthenia gravis
4
Exacerbation of myasthenia gravis
··
··
··
··
Intravenous immunoglobulin, oseltamivir
RWS
2
Male; 28
Chronic progressive 2 external ophthalmoplegia
First seizure
Brain atrophy
··
··
Increased protein concentrations
Oseltamivir, carbamazepine
RWS
3
Female; 16
None
2
First seizure
Normal
Normal
··
··
None
RWS
4
Male; 30
Migraine, asthma, gout
7
Migraine exacerbation
Normal
··
··
··
Oseltamivir, cafergot
RWS
5
Female; 16
Febrile seizures
4
First seizure
Brain atrophy
Brain atrophy
Normal
··
None
RWS
6
Male; 19
Previous seizure, asthma
7
Recurrent seizure
··
Normal
··
··
Oseltamivir, sodium valproate
RWS
7
Male; 18
None
2
First seizure
Normal
Normal
··
Normal
Oseltamivir
RWS
8
Male; 15
None
3
First seizure
··
··
··
··
Oseltamivir
RWS
9
Male; 57
Diabetes mellitus, hypertension, ischaemic heart disease
4
Acute ischaemic stroke
··
Right corona radiata infarct
··
··
Aspirin
Stroke rehabilitation
EEG=electroencephalogram. RWS=recovered without sequelae. ··=not done.
Table: Patients with influenza A H1N1 virus with neurological complications and their clinical features, investigations, treatment, and outcomes
142
www.thelancet.com/neurology Vol 9 February 2010