Australian Clinical Consensus Guideline: The diagnosis and acute management of childhood stroke

Australian Clinical Consensus Guideline: The diagnosis and acute management of childhood stroke

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  Guidelines Australian Clinical ConsensusGuideline: The diagnosis and acute management of childhood stroke Tanya L Medley1,2 , Christina Miteff3 , Ian Andrews4 , Tyson Ware5 , Michael Cheung1,2,6 , Paul Monagle1,2,7 , Simone Mandelstam1,2,7 , Alison Wray2,7 , Clair Pridmore8 , Christopher Troedson9 , Russell C Dale10 , Michael Fahey11 , Adriane Sinclair12 , Peter Walsh13 , Belinda Stojanovski1,7 and Mark T Mackay1,2,14 Abstract Stroke is among the top 10 causes of death in children and survivors carry resulting disabilities for decades, at substantial cost to themselves and their families. Children are not currently able to access reperfusion therapies, due to limited evidence supporting safety and efficacy and long diagnostic delays. The Australian Clinical Consensus Guideline for the Diagnosis and Acute Management of Childhood Stroke was developed to minimize unwarranted variations in care and document best evidence on the risk factors, etiologies, and conditions mimicking stroke that differ from adults. Clinical questions were formulated to inform systematic database searches from 2007 to 2017, limited to English and pediatric studies. SIGN methodology and the National Health and Medical Research Council system were used to screen and classify the evidence. The Grades of Recommendation, Assessment, Development, and Evaluation system (GRADE) was used to grade evidence as strong or weak. The Guideline provides more than 60 evidence-based recommendations to assist prehospital and acute care clinicians in the rapid identification of childhood stroke, choice of initial investigation, to confirm diagnosis, determine etiology, selection of the most appropriate interventions to salvage brain at risk, and prevent recurrence. Recommendations include advice regarding the management of intracranial pressure and congenital heart disease. Implementation of the Guideline will require reorganization of prehospital and emergency care systems, including the development of regional stroke networks, pediatric Code Stroke, rapid magnetic resonance imaging and accreditation of primary pediatric stroke centers with the capacity to offer reperfusion therapies. The Guideline will allow auditing to benchmark timelines of care, access to acute interventions, and outcomes. It will also facilitate the development of an Australian childhood stroke registry, with data linkage to international registries, to allow for accurate data collection on stroke incidence, treatment, and outcomes. Keywords Acute, childhood stroke, clinical guidelines, management, pediatrics, protocols Received: 5 April 2018; accepted: 13 June 2018 1 Murdoch Children’s Research Institute, University of Melbourne, Melbourne, Australia 2 Department of Paediatrics University of Melbourne, Melbourne, Australia 3 John Hunter Children’s Hospital, Sydney, Australia 4 Sydney Children’s Hospital, School of Women’s and Children’s Health, University of New South Wales, Sydney, Australia 5 Royal Hobart Hospital, Hobart, Australia 6 Department of Cardiology Royal Children’s Hospital, Melbourne, Australia 7 Royal Children’s Hospital, Melbourne, Australia 8 Women’s and Children’s Hospital. Adelaide, Australia 9 Children’s Hospital at Westmead, Discipline of Child and Adolescent Health, University of Sydney, Sydney, Australia 10 Children’s Hospital at Westmead and University of Sydney, Sydney Australia 11 Department of Paediatrics Monash University, Department of Medicine Melbourne University, and Monash Children’s Hospital, Melbourne, Australia 12 Lady Cilento Children’s Hospital, University of Queensland, Brisbane, Australia 13 Perth Children’s Hospital, Perth, Australia 14 Department of Neurology Royal Children’s Hospital, Melbourne Australia Corresponding author: Mark MacKay, Royal Children’s Hospital Melbourne, Victoria, Australia. Email: [email protected] International Journal of Stroke, 14(1) International Journal of Stroke 2019, Vol. 14(1) 94–106 ! 2018 World Stroke Organization Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/1747493018799958 journals.sagepub.com/home/wso
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  Introduction Stroke is amajor cause of morbidity and mortality in children across the world. The Global Burden of Disease study has reported a 35% increase in the num- bers of childhood strokes from 1990 to 2013. Childhood arterial ischemic stroke (AIS) has incidence of 1.2–2.1 per 100,000 children per year1–3 and hemor- rhagic stroke (HS) an incidence of 0.7–5.1/100,000 chil- dren per year.3–5 Mortality ranges from 3.6–14% for AIS6–9 and 6–54% for HS3–5 with death due to the stroke or the underlying disease. In Australia, the inci- dence of childhood stroke remains unknown. More than half of survivors have long-term neuro- logical impairment and 10–20% suffer recurrent strokes. Stroke places significant demands on families, the community, and health system. Studies from the US have estimated average costs of US$20,972 per child for acute hospital care10 and a five-year direct cost of US$130,000 per patient.11 These costs are diffi- cult to translate to the Australian healthcare system and a comprehensive economic analysis should be a research priority for Australia. Childhood stroke differs from adult stroke in terms of risk factors, etiologies, and pathophysiology.1,12 Data, predominantly from uncontrolled case series, suggest that nonatherosclero- tic arteriopathies and cardiac disorders are the most commonly identified causes of childhood AIS,1,2,12 and arteriovenous malformations are the most common cause of HS.13,14 One-third of children with AIS are less than 1-year old and one-half less than 5 years.15 The catch-cry ‘‘Time is Brain’’ is, therefore, very applicable to children, because failure to salvage brain with reperfusion thera- pies means worse functional outcomes, and survivors face living with disability for decades. Outcomes follow- ing stroke in the immature brain are likely to be different to those in adults, with failure of achieving normal devel- opmental milestones being as important as loss of func- tion. The higher frequency of stroke mimics, age-related variability in clinical presentation, diversity of causes and comorbidities are important challenges to early diagnosis and, collectively, necessitate child-specific approaches. It is unknown whether children have differ- ent pharmacologic responses to reperfusion and second- ary preventative therapies, due to developmental differences in hemostatic systems. Thus, while some care principles are relevant, direct application of adult guidelines to the investigation and management of childhood stroke is not appropriate. This Guideline addresses the diagnosis and acute management of childhood ischemic stroke and non- traumatic intracranial hemorrhagic stroke in (i) chil- dren beyond the neonatal period (ages 29 days to 18 years) and (ii) neonates and children with congenital heart disease who are at increased risk of stroke. It is not inclusive of cerebral sinovenous thrombosis, Moyamoya or sickle cell disease, noncardiac perinatal, or spinal cord stroke. Guideline development methodology The Australian Childhood Stroke Advisory Committee, representing a panel of Australia’s’ leading clinical experts and guideline developers from all ter- tiary pediatric centers, agreed on questions of clinical importance, to inform the scope and priority areas for the Guideline. Literature was systematically identified from Pubmed and EMBASE databases, limited to English, the last 10 years and pediatric studies key rele- vant studies older than 10 years were however included. Final search strings for each question can be found in The Diagnosis and Acute Management of Childhood Stroke—Technical Document.16 The literature was inde- pendently screened for inclusion and assessed for quality using SIGN methodology17 by two committee members, and conflicting assessments resolved by a third reviewer. Existing guidelines, where available, were independently assessed using AGREE II methodology.18 Evidence sum- mary tables for each question were created to provide an overview of relevant literature, which was then graded by the quantity, quality, consistency, clinical impact, gener- alizability, and applicability (using the National Health and Medical Research Council) system. Drafted recom- mendations were graded strong or weak, based on their benefit over harm to the patient, in alignment with the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) system.19 All evidence sum- maries and resulting recommendations were approved by the full committee. The drafted guideline underwent a period of targeted external consultation, suggestions reviewed in a blinded fashion, and a consensus process used to modify recommendations. Australian Childhood Stroke Clinical Guideline recommendations The following sections provide an overview of recom- mendations for the diagnosis and acute management of childhood stroke. The PICO (Population, Intervention or exposure, Comparison and Outcome) framework was used formulate questions deemed to be clinical importance. These questions informed areas of focus which included (i) clinical identification of stroke in the emergency department, (ii) neuroimaging to con- firm diagnosis, (iii) investigations to determine under- lying etiology, (iv) stabilization of modifiable factors (such as seizures) to minimize further injury, (iv) treat- ments including intravenous and endovascular reperfu- sion therapies, secondary preventative antiplatelet and International Journal of Stroke, 14(1) Medley et al. 95
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  anticoagulant therapies, corticosteroidsagents, and management interventions for suspected raised intra- cranial pressure, and (vi) specific recommendations for children with congenital heart disease (not pre- sented here, but found online at www.mcri.edu.au). Section 1: Clinical identification of stroke in the emergency department Significant delays in the diagnosis of childhood stroke limit access to reperfusion therapies. Factors contribut- ing to the delays include the low incidence, varying clin- ical presentations, limited access to urgent diagnostic neuroimaging, and poor awareness of childhood stroke among physicians and carers.20–27 Implementation of immediate response protocols in pediatric emergency departments have been shown to reduce delays in diag- nosis.25–28 Developed here is a Quick Reference Guide to the diagnosis and acute management of childhood stroke (Figure 1). Diagnosis of childhood stroke begins with know- ledge of the signs and symptoms and of presenting fea- tures that differentiate stroke from mimics29 (Figure 1). Clinical presentation varies depending on stroke type, vessels involved, and the child’s age. Focal neurological deficits and seizures are more common presenting features of AIS, whereas headache, vomit- ing, and altered mental status are more common and focal neurological deficits less common in HS.29–31 Conditions mimicking childhood stroke differ from adult stroke32,33 where migraine is a common non- stroke diagnosis.32 Stroke recognition tools, which are widely used by emergency responders to differentiate stroke from its mimics in adults, have been shown to improve diagnos- tic accuracy, decrease time to diagnosis, and increase access to reperfusion therapies. In children, currently available tools do not accurately distinguish strokes from mimics.34,35 Further work is, therefore, required to develop, validate, and implement pediatric specific recognition tools to reduce the diagnostic delay in child- hood stroke. In contrast, the pediatric modification of the National Institutes of Health Stroke Scale (PedNIHSS) has good to excellent interrater reliability to determine severity of stroke symptoms.36 Section 2: Neuroimaging Neuroimaging is essential to confirm a stroke diagnosis. Here we present recommendations (Section 2) and a rapid and full diagnostic protocol (Figure 2) for neu- roimaging with the goal of standardizing neuroimaging protocols across Australian pediatric institutions. Diagnosis must be confirmed on brain imaging in chil- dren before considering reperfusion therapies (Figures 1 and 2) as stroke is an uncommon cause of focal neurological symptoms, accounting for less than one- third of cases.26,28,32 There are arguments for and against computed tomography (CT) and magnetic res- onance imaging modalities in suspected childhood stroke. The advantages of CT are that most children will not require sedation and it is readily available in most emergency departments. However, these benefits are largely outweighed by the evidence showing that CT has poor sensitivity for early detection of ischemic infarction resulting in a delayed diagnosis.22,24,27,37 Thus, magnetic resonance imaging (MRI), with diffu- sion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) sequences, is recommended as the imaging modality of choice for suspected AIS (Figure 2). In contrast, CT imaging and MRI gradient echo sequences (such as susceptibility-weighted imaging) are equally sensitive for the detection of intraparench- ymal blood. Therefore, where signs and symptoms sug- gest hemorrhagic stroke, and access to sedation or MRI is delayed, a CT can be performed. Accessing urgent MRI is a major challenge in the pediatric emergency department, particularly with the added requirement for sedation in younger children. As the use of reperfusion therapies are highly time- Section 1: Recommendations for the clinical identification of stroke Children presenting with sudden onset of the following symptoms are at high risk of stroke and should undergo immediate neurological assessment and consideration of urgent neuroimaging: (i) focal weakness, (ii) visual or speech disturbances, (iii) limb incoordination or ataxia, (iv) altered mental status, (v) headache, (vi) signs of raised intracranial pressure, or (vii) seizures with additional neurological symptoms. Level of evidence (III). In children presenting with neurological symptoms or signs relevant for stroke, the use of adult stroke recognition tools to differentiate childhood stroke from its mimics are not recommended in their current form. Level of evidence (III-2). In all children between the ages of 2 and 18 years, stroke severity should be assessed upon arrival to the hospital using the Pediatric National Institute of Health Stroke Scale to facilitate ongoing management. Level of evidence (III, CBR) International Journal of Stroke, 14(1) 96 International Journal of Stroke 14(1)
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  dependent, rapid MRIprotocols to accurately diagno- sis stroke are imperative. Therefore, a rapid protocol (of approximately 10–15 min, depending on MRI cap- abilities) is proposed, based on a review of literature and expert opinion, for children presenting within the windows for reperfusion therapies, and a full diagnostic protocol for those presenting beyond these times (Figure 2). Figure 1. Quick Reference Guide for the diagnosis and acute management of childhood stroke. MRI: magnetic resonance imaging; CT: computed tomography; CTA, CT angiography; PPSC: primary pediatric stroke center; MMCAI: malignant middle cerebral artery infarction; ICH: intracranial hemorrhage; ICP: intracranial pressure. International Journal of Stroke, 14(1) Medley et al. 97
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  Section 3: Investigationsto determine underlying stroke etiology Investigations to determine underlying etiology guide prognostication and treatments to reduce risk of stroke recurrence. While the level of evidence is low, studies are consistent in demonstrating an association between arteriopathies and initial AIS1,2,12,38–48 and recurrent events.7,13,49,50 Unilateral focal cerebral arter- iopathy, dissection, and Moyamoya disease are the Section 2: Neuroimaging recommendations for diagnosing arterial ischemic and hemorrhagic stroke In children with suspected AIS, urgent brain MRI should be performed as the diagnostic imaging modality of choice. Level of evidence (I (adult), III-2–IV pediatric). In children undergoing MRI for suspected AIS within time frames for reperfusion therapies, a rapid imaging protocol including (i) axial DWI/ ADC, (ii) axial gradient echo (such as SWI) for detection of hemorrhage, (iii) axial fast spin echo or turbo spin T2, (iv) consideration of fluid-attenuated inversion recovery if greater than 1 year of age, (v) axial T1, and (vi) time of flight MRA, to inform ongoing management, is recommended. Level of evidence (III-2, VI). In children with suspected AIS where urgent MRI is not possible, CT imaging, including CTA and CT perfusion, can be considered as an alternative, particularly in older teenagers. Level of evidence (CBR). In children with suspected hemorrhagic stroke, urgent brain MRI or CT should be performed. Level of evidence (III-3). Figure 2. Imaging pathway for suspected childhood stroke (29 days to 18 years of age). MRI: magnetic resonance imaging; DWI: diffusion-weighted images; ADC: apparent diffusion coefficient; SWI: susceptibility-weighted images; FSE: fast spin echo; TSE: turbo spin echo; FLAIR: fluid-attenuated inversion recovery; TOF: time of flight; MRA: magnetic resonance angiography; PPSC: primary pediatric stroke center; CT: computed tomography; CTA: computed tomography angiography. *Time may vary between scanners. yIn children with alternative diagnoses, if attaining subsequent imaging will be difficult/traumatic (e.g. young children or those with intellectual disability) consideration should be given to complete a full diagnostic scan to elucidate etiology. z E.g. investigations for specific arteriopathies may include (i) intracranial arteriopathy using vessel wall imaging (axial/coronal pre and postcontrast T1 weighted imaging) or (ii) cervical dissection via contrast MRA and axial/coronal fat saturated pre and postcontrast T1. § There are substantial difficulties associated with delivering contrast in young children, particularly using pump injection in the absence of general anaesthetic, and the skill required to attain images without movement error, teenagers 13–18 years of age. Note: Sequences are a guide and should be at discretion of the neuroradiologist. International Journal of Stroke, 14(1) 98 International Journal of Stroke 14(1)
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  most commonly identifiedsubtypes of arteriopa- thies.51,52 Vascular imaging, which is essential to diag- nosis, should preferably be performed as part of the initial diagnostic imaging study. Cardiac disorders also account for a significant pro- portion of childhood strokes.12,53 This cohort is an important target for primary prevention, as diagnosis is usually known prior to the stroke event. Congenital heart defects, particularly complex cyanotic lesions, account for the majority of clinically recognized strokes.39,40 A case–control study of 412 children reported a 19-fold increased stroke risk in children aged >28 days with congenital heart disease. The risk was even greater for children with a history of cardiac surgery although many events were unrelated to or occurred more than five years from surgery.41 In mixed congenital heart disease cohort studies, the incidence of preoperative stroke ranges from 10 to 31%.1,2,12,38 Case–control and cohort studies indicate that infec- tion is associated with an increased risk of childhood stroke. Varicella infection was first implicated as a risk factor for childhood stroke almost 20 years ago.54,55 The multinational VIPS study found that infection in the week prior to stroke was associated with a 6.3-fold increased risk of AIS.56 Serological investigations of the same cohort demonstrated higher rates of acute herpes simplex and varicella infection in children with stroke, compared to controls.57 An association between iron deficiency and child- hood stroke has been demonstrated in two case–control studies.58,59 Meta analyses suggest that prothrombotic factors including Factor V Leiden, prothrombin G20210A, methyl tetrahydrofolate reductase, lipopro- tein (a), protein C deficiency, antiphospholipid antibo- dies, and lupus anticoagulant may also be associated with childhood stroke. However, the evidence is incon- sistent and inconclusive. Interpretations of findings are influenced by methodological limitations including lack of concurrent controls, highly selected patient popula- tions, the use of adult reference ranges, which do not consider developmental differences in hemostatic fac- tors, and failure to confirm abnormalities on follow- up testing. The evidence for serum biomarkers, such as D-dimer and C-reactive protein, serum amyloid A, myeloperoxidase, and tumor necrosis factor alpha, is also limited by small sample sizes, lack of data on reproducibility, and limited follow up data. Section 4: Code Stroke protocols and primary pediatric stroke center care Two studies26,27 have demonstrated the benefit of an Emergency Department acute Code Stroke protocols with (i) reduced time to secondary preventative treat- ment, (ii) increased usage of, and shorter time to MRI as first imaging modality, and (iii) improved access to reperfusion therapies. Developed here is a Quick Reference guide to the diagnosis and acute manage- ment of childhood stroke that can be implemented to reduce time to diagnosis (Figure 1). There are, however, no data to directly demonstrate the benefit of pediatric stroke units. Australian adult stroke units are defined Section 3: Investigations for suspected or confirmed childhood stroke Upon presentation, all children should undergo the following pathology: full blood count with differential, basic biochemistry (urea, creatinine, electrolytes, glucose), and a coagulation screen (international normalized ratio/prothrombin time, activated partial thromboplastin time, fibrinogen). Level of evidence (CBR). Vascular imaging (MR or CT angiography) of the intracranial and neck vessels is recommended in all children with confirmed AIS. Level of evidence (II–IV). Ongoing radiological surveillance is recommended in children with cervical or cranial arteriopathies, due to the association with increased risk of recurrent events. Level of evidence (II–IV). Conventional angiography may be considered in cases where diagnostic uncertainties persist following MR or CT angiography. Level of evidence (III). Echocardiography and ECG should be performed in all children with AIS. Level of evidence (III–IV). A full blood count and iron studies should be performed in all children with suspected stroke at presentation. Level of evidence (III–IV). Investigation of prothrombotic makers (anticardiolipin Ab(ACLA), lupus anticoagulant, antithrombin, protein C, protein S, activated protein C resistance, Factor V Leiden, prothrombin G20210A, and MTHFR TT677 mutations) and serum homocysteine is reasonable in children with radiologically confirmed stroke, where etiology remains to be fully elucidated. Level of evidence (I–IV). A history of recent infection (within the preceding six months), particularly varicella infection should be sought in children with suspected or confirmed stroke. Level of evidence (II–III3). In children with AIS measurement of biomarkers CRP, D-dimer and serum amyloid, and myeloperoxidase are unlikely to influence manage- ment directly. There is insufficient evidence to support testing for more specific serum biomarkers for inflammation, systemic vasculitides, or genetic polymorphisms. Level of evidence (II–III-3). International Journal of Stroke, 14(1) Medley et al. 99
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  by a minimumset of criteria and services and are cate- gorized into comprehensive stroke centers and primary stroke centers.60 Presented here are consensus-based recommendations for the required service elements to facilitate certification of a hospital as a Primary Pediatric Stroke Center (PPSC, Table 1), drawing on key components of adult primary and comprehensive stroke centers. The development of PPSC’s across Table 1. Elements of service for pediatric stroke care centers Element of service Primary pediatric stroke centera Organized prehospital services 7 Coordinated emergency department systems (e.g. code stroke) 3b Coordinated regional stroke systems (includes protocols for hospital bypass, transfer to stroke centers) 3b Onsite CT brain imaging (24/7) 3 Advanced imaging capability (e.g. MRI/MRA, catheter angiography) 3 (24/7) On-site neurosurgical services (e.g. for hemicraniectomy due to large middle cerebral artery infarcts) 3c Delivery of intravenous tissue plasminogen activator (tPA) Optional Ability to provide acute monitoring up to 72 h 3 Dedicated stroke coordinator position 3d Dedicated medical lead 3 Access to ICU 3 Provision of telehealth services for acute assessment and treatment Optional Coordination with rehabilitation service providers 3 Routine involvement of carers in rehabilitation process 3 Routine use of guidelines, care plans and protocols 3b Access and collaboration with other services (cardiology, palliative care, vascular) Optional Regional responsibility Commonly Parent/carer and children provided with appropriate level of literature 3 Table adapted from National Acute Stroke Services Framework 2015.60 a Consensus based recommendations on the elements of service relevant to childhood stroke to qualify as a primary pediatric stroke center. b Upon successful implementation of guideline recommendations. c If neurosurgical services are not available, the institution should have developed transfer protocols. d If a stroke coordinator not available, institution should have a dedicated medical lead who has a primary focus on stroke (stroke center director). Section 4: Recommendations for primary pediatric stroke center care All children with stroke should be admitted to pediatric centers meeting criteria for a primary pediatric stroke center. Level of evidence (Adult I). Parents/carers and children should be provided with the appropriate level of stroke literature. Level of evidence (CBR, IV). International Journal of Stroke, 14(1) 100 International Journal of Stroke 14(1)
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  Australia will helpdetermine whether children obtain similar benefits from dedicated stroke units as adults. The variations between adult primary centers criteria, and those recommended for children, are explained by differences in pathophysiology, presentation, fre- quency, staffing constraints, and international recom- mendations from leading pediatric stroke institutions. Section 5: Reperfusion interventions, antithrombotic, immunotherapies, and management of raised intracranial pressure Reperfusion therapies. Intravenous and endovascular thrombolytic therapies have revolutionized the manage- ment of ischemic stroke in adults, reducing the severity of disability and mortality rates. For adults, the recom- mendations for eligibility and efficacy of interventions are based on multiple large randomized controlled trials. There are no such trials in children, and thrombo- lytic agents are not approved by the Therapeutic Goods Administration for use in Australian children. Despite this lack of evidence, there are growing numbers of inter- national publications reporting use of these interven- tions. Thus, there is a strong impetus for development of primary pediatric stroke centers, and formulation of pediatric protocols with clear guidelines around eligi- bility and exclusion criteria, to allow some children to access off-label treatment, whilst minimizing risk of complications. A total of 67 studies reporting intravenous thrombo- lytic or endovascular therapy in children were reviewed for the Guideline, including one case–control study and case reports for 82 children. Treatments administered included (i) IV–tPA alone in 28 children, (ii) IA–tPA alone in 13 children, (iii) IA–urokinase alone in 8 or IA–streptokinase alone in 1 child, (iv) endovascular therapy with mechanical clot retrieval alone in 22 chil- dren, or in combination with (v) IV–tPA (n ¼ 5), (vi) IA–tPA (n ¼ 3), or (vii) IA–urokinase (n ¼ 2) children. The median age of treated children was 10 years; the youngest patient was 2.5 months and only 13% were less than five years. The anterior circulation was affected in the majority of cases. Cardiac embolism was the most commonly identified stroke mechanism, in 42% of children, followed by dissection in 12%, other/nonspecified arteriopathies 5%; no etiology was identified in 29% of cases. The effect of interventions is difficult to interpret due to variations in reporting of baseline data, outcomes at follow-up, and description or severity of deficits. Twenty percent of children were neurologically normal at discharge but 4% died. The evidence for use of IA–tPA and endovascular therapy in childhood AIS is inconsistent largely due to heterogeneity in stroke etiology, age, time to treatment, stroke severity, imaging findings, and reporting of out- comes and adverse events. Anticoagulation and antiplatelet therapy. The American College of Chest Physicians Clinical Guideline on Antithrombotic Therapy in Neonates and Children, pub- lished in 2012, presents specific recommendations for AIS. New evidence published since 2012 was reviewed for the Australian Childhood Stroke Guideline, and rec- ommendations are provided for the timing and use of anticoagulation, antiplatelet, and steroid therapy in chil- dren with radiologically confirmed ischemic stroke. Despite the absence of controlled trials, there is a body of literature supporting the safety of using antic- oagulation and antiplatelet therapy in children with stroke61–70 and suggested eligibility and protocol when considering use of IV–tPA in children with stroke as a part of the thrombolysis in pediatric stroke study.71 In review of the literature, eight studies were identified describing the use of anticoagulation or antiplatelet ther- apy in children with AIS, of varying etiologies, including a systematic review,63 five cohort studies,64,66–70 and a case series.65 Three of these studies compared treated and untreated cases.65–67 While there are limited data, it is reasonable to assume safety of anticoagulation and antiplatelet ther- apy, based on current findings unable to find an increased risk of bleeding. Evidence regarding the role of antithrombotic therapy in recurrent stroke is varied, but may suggest benefit of treating with unfractionated heparin, compared to aspirin or no treatment.69 In the absence of consistent high-quality evidence, one approach is to administer anticoagulation upon exclu- sion of hemorrhage until the exclusion of dissection or embolism as a cause of stroke.72 The rationale is to reduce the risk of recurrent stroke while investigating for etiology. An alternative argument suggests initial use of Aspirin, because the potentially increased risk of bleeding should be considered and that formal antic- oagulation should only be administered after embolism or dissection as proven.73 The biological rationale in favor of initial heparinization is that recurrent strokes are most likely to occur within the first 48–72 hours if there is dissection or embolus. Steroid therapy. Current or past infection or inflamma- tory disease may be associated with increased risk of stroke. Two papers that addressed the use of steroids in childhood AIS were identified.74,75 A systematic review of 32 observational studies and two trials involving 152 children provided weak evidence for the benefits of ster- oid treatment in childhood AIS, in the context of tuber- culous or bacterial meningitis, and some subtypes of arteriopathy. It was noted, however, that the studies reviewed had no internal controls or comparison International Journal of Stroke, 14(1) Medley et al. 101
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  groups. The authorsconcluded that there was little robust evidence either in favor or against the use of immunotherapy in childhood AIS. Intracranial pressure and decompressive craniectomy for acute arterial stroke. In the pediatric population data suggests that 1–12% of children with AIS develop malignant middle cerebral artery infraction (MMCAI) and raised intracranial pressure.76–78 The most import- ant indicators for raised intracranial pressure with both supra and infratentorial infarcts are deteriorating level of consciousness and the worsening of neurologic dysfunction. Seizures longer than 5 minutes and more severe neurologic dysfunction—measured as higher ini- tial PedNIHSS scores (>7.5) are independent pre- dictors of developing MMCAI syndrome.79 Adult data are high-quality, extensive, and support- ive of decompressive craniectomy for MMCAI with four systematic reviews80–83 reporting marked reduc- tion in mortality compared to medical treatment alone and overall improved disability measured by Modified Rankin Scale. There are no controlled trials of decompressive craniectomy in pediatric stroke patients, with data confined to retrospective series or Recommendations for reperfusion interventions, antithrombotic, immunotherapies, and management of raised intracranial pressure Reperfusion therapies. IV–tPA may be appropriate in specific children. Consensus on potential eligibility criteria include (i) 2 to 17 years of age, (ii) radiologically confirmed arterial stroke with absence of hemorrhage, (iii) pediatric stroke severity score 4 and 24, and (iv) treatment can be administrated within 4.5 h from known symptom onset. However, the absence of high-quality evidence means that benefit over harm to these children cannot be accurately assessed. Level of evidence (III, IV). Administration of IV–tPA in children with confirmed stroke should not be considered where the time from symptom onset is unknown or greater than 4.5 h. Level of evidence (I–III). Where administration of IV–tPA is being considered for children with stroke, eligibility and protocols should align with previously developed international consensus-based standards and adult protocols where appropriate (e.g. in teenagers 13–18 years). Level of evidence (CBR). Endovascular therapies may be appropriate in some children meeting adult eligibility criteria, defined as radiologically diagnosed ischemic stroke caused by large vessel occlusion and where treatment can be initiated within 6 h since onset of stroke symptoms. The absence of high quality pediatric evidence, together with differences in underlying pathophysiology, means that benefit over harm for children cannot be accurately assessed. Level of evidence (III-2, IV). In children with stroke where time of onset of symptoms is unknown or greater than 6 h, adult evidence suggests that endovascular therapy inclusive of IA–tPA and mechanical clot retrieval should not be considered. Level of evidence (Adult II). Anticoagulation and antiplatelet therapy are safe in children with AIS after the exclusion of hemorrhage. Level evidence (III, IV). In children with AIS, anticoagulation should not be administered within 24 h of receiving neurovascular intervention. Level evidence (adult I). For all children with AIS, after exclusion of hemorrhage, unfractionated heparin, low molecular weight heparin, or Aspirin is recommended as an initial therapy until the exclusion of dissection and embolic causes. Adapted from72 In children where an AIS is NOT caused by cardioembolism or dissection, daily aspirin is recommended for a minimum of 2 years. Adapted from72 In children with AIS, secondary to cardioembolism treatment with low molecular weight heparin or Vitamin K antagonist is recommended for a minimum of three months. Adapted from72 In children with AIS secondary to dissection, treatment with low molecular weight heparin or Vitamin K antagonist is recommended for a minimum of 6 weeks. Ongoing treatment should be dependent on neuroradiological assessment of stenosis severity and recurrent ischemic episodes. Adapted from72 Steroids. In children where the cause of AIS is NOT cardioembolic or dissection, the addition of steroids to antiplatelet therapy may be considered in some subgroups of children with infection and arteriopathy related etiologies. Level of evidence (I–IV). Adapted from72 Intracranial pressure. Early recognition of the minority of pediatric patients with acute stroke who may develop raised intracranial pressure should prompt initial supportive care and early neurosurgical referral for consideration of decompressive craniectomy. Level of evidence (IV). Decompressive craniectomy should be considered for children with malignant ischemic MCA (or ICA) territory infarction. Level of evidence (III, IV). Suboccipital decompressive craniectomy should be considered for children with posterior circulation ischemic strokes and raised intracranial pressure or decreasing level of consciousness. Level of evidence (IV). Decompressive craniectomy may be considered 24 h after treatment with intravenous thrombolytic therapy (e.g. tPA). Level of evidence (IV). Placement of an intracranial pressure monitor and subsequent time to assess pressure should not delay decompressive craniectomy. Level of evidence (CBR). Placement of an intracranial pressure measuring device at the time of decompressive craniectomy should be considered for pediatric patients. Level of evidence (CBR, IV). Elevation of the head of the bed to 30–45 is recommended after decompressive craniectomy. Level of evidence (Adult, I). International Journal of Stroke, 14(1) 102 International Journal of Stroke 14(1)
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  case studies.76,78,79,84–88 Collectively, lowquality evi- dence suggests that morbidity and mortality outcomes after decompressive craniectomy for MMCAI and raised intracranial pressure may be better for children than adults, recognizing the issue of publication bias toward positive outcomes. Only one relevant pediatric paper was identified reporting outcomes following pos- terior fossa decompression for posterior circulation stroke.89 Clinical considerations The most important issue faced by the Guideline writ- ing group was the low quality of evidence in pediatric stroke, with few case–control or cohort studies to guide recommendations for clinical recognition, neuroima- ging, and investigation of underlying etiologies, and no randomized controlled trials to guide recommenda- tions for acute and secondary prevention therapies. It will not be possible to improve outcomes for chil- dren affected by stroke without minimizing extent of brain injury. This requires better clinical recognition of stroke symptoms among carers, emergency medical ser- vices and pediatric physicians, more rapid radiological confirmation or diagnosis, and initiating interventions to restore perfusion and to minimize secondary injury. The guideline committee felt that implementation of a stan- dardized approach to diagnosis and management of childhood stroke would be unattainable if recommenda- tions were largely based on consensus statements. Despite limited evidence, the guideline writing group decided, prior to reviewing the evidence, that it was appropriate to assign strong GRADE recommendations for questions where there was potential benefit (based on clear evidence from adults and lower quality evidence in children) and almost no harm in children, and that weak recommendations were appropriate where it was less clear that benefit outweighed harm. Summary The purpose of the Guideline is to provide recommenda- tions for the diagnosis and acute management of child- hood stroke in order to reduce variation in care across pediatric centers, to reduce time to diagnosis and treat- ment, and to facilitate the development of a national collaborative research network and stroke registry. The Guideline is aimed at pediatric health professionals working in secondary and tertiary level acute pediatric centers. It is anticipated that administrators, funders, and policy makers who manage and deliver care for children with stroke will also End the Guideline useful. Effective implementation requires engagement of clinicians, hospital administrators, government, research funding organizations, and stroke advocacy groups. Priorities include (i) coordinated regional stroke systems of care with predefined protocols for hospital bypass to accredited primary stroke centers with the capability to offer reperfusion therapies, (ii) multidisciplinary pediatric stroke teams, and (iii) devel- opment of institutional pediatric Stroke Code protocols which include rapid imaging protocols, validated clin- ical decision support tools, and parallel work practices to increase efficiencies. Narrowing the gaps in knowledge between adults and children is of vital importance. Improving the evi- dence for key interventions which have transformed outcomes for adults, such as stroke units, intravenous thrombolysis, and reperfusion therapies, is particularly important. Audits that capture data on timelines of care, access to acute interventions, adherence to recom- mended inclusion and exclusion criteria, treatment complications of treatment, and functional outcomes using validated outcome measures will allow for bench- marking of practice across centers. Appointment of a key worker (ideally a stroke nurse/coordinator) will ensure data collection for national auditing as well as providing appropriate information and support to chil- dren and their families affected by stroke. It is also clear there is a need for high-quality multi- center research across many areas of childhood stroke. Developing a national pediatric registry with common data elements and centralized data collection will be required to elucidate incidence, standardize reporting, and measure implementation of the guideline. Other research priorities include an economic analysis of life- time cost of pediatric stroke in Australian children and determination of the accuracy of diagnosing arterial ischemic and hemorrhagic stroke using standardized diagnostic protocols. Acknowledgements The Murdoch Children’s Research Institute gratefully acknowledges funding support from the Ian Potter Foundation, and as part of the external consultation process, reviews by Associate Professors Franz Babl and Richard Leventer and Professor Stacy Goergen. The endorsement from the Stroke Foundation of Australia, and the Australian and New Zealand Childhood Stroke Society is also acknowledged. Declaration of conflicting interests The author(s) declared the following potential conflicts of inter- est with respect to the research, authorship, and/or publication of this article: TM and MM contributed to all aspects of the guideline development, including conducting the evidence searches, data analysis, completing the evidence summaries sup- porting the recommendations, drafting and editing the guide- line, coordinating the external consultation process, and final approval of the guideline. All other members contributed by reviewing and grading evidence, discussions by meetings, International Journal of Stroke, 14(1) Medley et al. 103
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  writing and collectivelyfinalizing the wording of all recommendations. Funding The author(s) disclosed receipt of the following financial sup- port for the research, authorship, and/or publication of this article: The Murdoch Children’s Research Institute gratefully acknowledges funding support from the Ian Potter Foundation. ORCID iD Tanya L Medley http://orcid.org/0000-0002-9505-6634 Ian Andrews http://orcid.org/0000-0002-9852-4755 Russell C Dale http://orcid.org/0000-0002-0109-8877 References 1. Mallick AA, Ganesan V, Kirkham FJ, et al. Childhood arterial ischaemic stroke incidence, presenting features, and risk factors: a prospective population-based study. Lancet Neurol 2014; 13: 35–43. 2. Steinlin M, Pfister I, Pavlovic J, et al. 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