Table of Contents

 

Stroke is a leading cause of morbidity and mortality in children. The etiologies, risk factors, and presentation of stroke differ from those of adults, and the diagnosis of stroke is often delayed in children. The management of pediatric stroke can be challenging because there are few data to support the efficacy of interventions. This issue reviews the most common causes of pediatric stroke, provides guidance for distinguishing stroke from stroke mimics, discusses the indications for diagnostic studies, and offers evidence-based recommendations for treatment in the emergency department. You will learn:

Common causes of pediatric arterial ischemic stroke (eg, arteriopathies, cardiac etiologies, prothrombotic states, and systemic disorders) and hemorrhagic stroke (eg, arteriovenous malformations, cavernous malformations, aneurysms, and tumors)

How to differentiate between stroke and common stoke mimics, such as migraine

Risk factors and physical examination findings that can help narrow the differential diagnosis, including key features of the presentation of pediatric stroke that are different than those of adults with stroke

Which laboratory studies and imaging modalities should be used to evaluate for stroke or stroke mimics, and which should be ordered after stroke is confirmed

Evidence-based recommendations for management of arterial ischemic stroke and hemorrhagic stroke in pediatric patients in the emergency department

1. Abstract
2. Case Presentations
3. Introduction
4. Critical Appraisal of the Literature
5. Etiology and Pathophysiology
   1. Ischemic Stroke
      1. Arteriopathies
      2. Cardiac Etiologies
      3. Prothrombotic States
      4. Systemic Disorders
   2. Cerebral Sinus Venous Thrombosis
   3. Hemorrhagic Stroke
6. Differential Diagnosis
7. Prehospital Care
8. Emergency Department Evaluation
   1. History
   2. Physical Examination
9. Diagnostic Studies
10. Treatment
    1. Ischemic Stroke
       1. Arterial Ischemic Stroke
       2. Thrombolytics
       3. Mechanical Thrombectomy
       4. Sickle Cell Disease
       5. Summary
    2. Hemorrhagic Stroke
11. Special Populations
    1. Patients With Sickle Cell Disease
    2. Neonates
12. Controversies and Cutting Edge
    1. Therapies for Pediatric Stroke
    2. Pediatric Stroke Protocols
13. Disposition
14. Summary
15. Time- and Cost-Effective Strategies
16. Risk Management Pitfalls in the Management of Pediatric Stroke
17. Case Conclusions
18. Clinical Pathway for Management of Pediatric Stroke
19. Tables and Figures
    1. Table 1. Hypercoagulable States Associated With Pediatric Arterial Ischemic Stroke
    2. Table 2. Differential Diagnosis for Pediatric Stroke
    3. Table 3. Pediatric National Institutes of Health Stroke Scale (PedNIHSS)
    4. Table 4. Medications for Ischemic Stroke
    5. Table 5. Antithrombotic Medication Reversal Agents
    6. Figure 1. Moyamoya Syndrome on Magnetic Resonance Angiogram
20. References

Abstract

Although pediatric stroke is rare, it is a leading cause of morbidity and mortality in children. The diagnosis of stroke is often delayed in children, which can contribute to death and disability. Management of pediatric stroke is challenging because there are few data to support the efficacy of interventions, and management is based on society guidelines and expert opinion, as well as extrapolation from adult stroke management. This issue reviews the most common causes of pediatric stroke, provides guidance for distinguishing stroke from stroke mimics, discusses the indications for laboratory studies and imaging modalities, and offers evidence-based recommendations for treatment.

Case Presentations

A 7-year-old boy is brought in by ambulance after a witnessed generalized seizure lasting 2 minutes at home. He has no history of prior seizures. Upon arrival to the ED, he appears postictal and is moving all of his extremities. His blood glucose is 110 mg/dL. His vital signs are: temperature, 36.9°C (98.5°F); heart rate, 60 beats/min; blood pressure, 110/70 mm Hg; respiratory rate, 14 breaths/min; and oxygen saturation, 98% on room air. The boy vomits while the nurse is trying to obtain IV access. Per the mother, the boy has been receiving chemotherapy for lymphoma and was complaining of a headache earlier in the day. He has no history of intrathecal chemotherapy. The mother does not think he had any head trauma recently. You know that the child needs brain imaging, but you are uncertain which imaging would be most useful…

In the next room, you see a 5-year-old boy with sickle cell disease who was brought to the ED by his father. The father states that 1 hour prior to arrival, the boy started stumbling while walking. The father says he didn’t think much of it until he noticed the child's speech was slurred. The father also says he thinks his son’s face looks different on 1 side, though you cannot appreciate facial asymmetry on examination. The boy has 3 out of 5 strength of the left arm and leg, as well as dysarthria. He is alert and denies headache or visual changes. The rest of the neurological examination seems normal. The boy’s vital signs are unremarkable except for mild elevation of blood pressure. You are concerned about a stroke and begin to think about what tests to order as well as which specialists to consult before initiating treatment...

You then see a 2-year-old girl who was brought to the ED by her parents after she fell forward with a toothbrush in her mouth. The mother removed the toothbrush from the unconscious child’s mouth and noted blood on the toothbrush as well as in the child’s mouth. Although the child was unresponsive for 30 seconds after the event, no seizure-like activity was noted. On presentation, the patient is alert with normal mental status and normal vital signs. She has no obvious intraoral trauma, abnormal voice, or stridor, and she has a normal neurological examination for her age. Given the loss of consciousness and the report of blood on the toothbrush despite no oral laceration seen, you decide to obtain a CT angiogram of the neck. The CT angiogram shows a dissection of the left internal carotid artery and subcutaneous air in the area. You consider what treatments to initiate, which specialist to consult, whether further imaging is needed, and what should be the disposition of this child...

Introduction

Stroke is typically thought of as a disease that occurs in older adults with risk factors for atherosclerosis. Stroke also occurs in the pediatric population, but the etiologies, risk factors, and presentation of stroke differ from those of adults. Stroke is more common in neonates than in children, and will be discussed separately, as the risk factors, treatment, and outcomes differ from those of older infants and children (see the “Neonates” section.).^1,2

Annually, stroke affects 1 to 2 children per 100,000 children,^1,3 and it is among the top 10 causes of pediatric mortality, with a mortality rate of up to 10% for arterial ischemic stroke (AIS) and 25% for hemorrhagic stroke.^4,5 Despite potential neuroplasticity, two-thirds of children will have persistent neurological deficits after a stroke.¹

There is usually an excessive delay in the diagnosis of pediatric stroke, which may contribute to morbidity and mortality. A retrospective study of children with AIS in an urban center found a median of 22.7 hours from symptom onset to diagnosis of stroke and 12.7 hours from hospital presentation to the time of diagnosis. On initial assessment, the diagnosis was suspected in only 38% of children.⁶ Another study found that physicians documented a suspicion of stroke in only 26% of children with AIS.⁷ Multiple studies have found that children with acute-onset neurological symptoms are most often brought to the emergency department (ED) by private vehicle rather than by ambulance.^6,8 The delay in diagnosis is likely multifactorial, in part due to clinicians’ unfamiliarity with pediatric stroke and a bias for diagnosing more common stroke mimics. A clinician who does not know the different etiologies of stroke in children may not identify the risk factors. Children also present differently from adults with stroke. Children are more likely to have seizure and altered mental status with stroke, which generates a large list of differential diagnoses.^1,6

Management of pediatric stroke is challenging because there are few data to support the efficacy of interventions, and management is based on society guidelines and expert opinion (with the exception of children with sickle cell disease). Management of stroke in children is also extrapolated from adult stroke management even though the pathophysiology and etiologies of stroke in children differ significantly from adults.

This issue of Pediatric Emergency Medicine Practice reviews common causes of pediatric stroke, offers guidance on how to distinguish stroke from its mimics, discusses the indications for imaging modalities, and provides evidence-based treatment recommendations.

Critical Appraisal of the Literature

A literature search was performed in MEDLINE^® and the Cochrane Database of Systematic Reviews using the search terms pediatric stroke, pediatric stroke management, and hemorrhagic stroke pediatric presentation management. Results were limited to studies involving children aged 0 to 18 years, those with full text in English, and those involving human subjects. References within the articles were also reviewed to identify additional articles for inclusion. Titles and abstracts were reviewed for relevance to the topic, and 70 articles were chosen for inclusion.

Several pediatric stroke registries, prospective cohorts, and retrospective cohorts are reported in the literature.^1,6,8-18 Until about 10 years ago, there were only case reports of medical interventions for pediatric stroke. Evidence for surgical interventions and mechanical thrombectomy is still based mainly on case reports.^19-22 There are no completed prospective controlled trials of anticoagulation, antiplatelet medication, or thrombolysis for AIS in children, though society guidelines support the use of anticoagulation and antiplatelets, based on the observed safety of these interventions in cohort studies.^3,23

Risk Management Pitfalls in the Management of Pediatric Stroke

2. “I obtained a CT scan instead of an MRI because it’s too difficult to obtain an MRI in the ED, and it won’t give me management-changing information.”

Though CT scan may yield important diagnostic information, MRI is the preferred modality for pediatric stroke. MRI can better detail AIS and CSVT in addition to common stroke mimics. Delaying MRI delays definitive diagnosis, treatment, and possible prevention of future stroke.

5. “This patient was last well 2 hours ago, and he has a PedNIHSS score of 10. The CT scan showed no hemorrhage, so I don’t need to involve neurology prior to giving tPA.”

While some specialists may recommend thrombolytics in pediatric AIS, emergency clinicians should never make this decision on their own. tPA may be reasonable in some situations under the guidance of a neurologist with experience treating pediatric stroke. Vascular imaging that demonstrates complete or partial occlusion of the vessel is required, in addition to other radiologic, laboratory, and clinical criteria. The safety and efficacy of thrombolytics in children have not been studied adequately.

10. “I was concerned the patient had intracerebral hemorrhage, so I rushed him to the CT scanner before wasting time with IV placement or other resuscitation.”

While it is important to rapidly diagnose and contact neurosurgery in the case of a hemorrhagic stroke, it is also important to prevent secondary brain injury from causes such as hypoxia or hypotension/hypertension. Interventions such as IV placement and supplemental oxygen or intubation should be performed to stabilize the patient prior to obtaining imaging.

Tables and Figures

References

Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report.

To help the reader judge the strength of each reference, pertinent information about the study is included in bold type following the reference, where available. In addition, the most informative references cited in this paper, as determined by the author, are highlighted.

1. deVeber GA, Kirton A, Booth FA, et al. Epidemiology and outcomes of arterial ischemic stroke in children: the Canadian Pediatric Ischemic Stroke Registry. Pediatr Neurol. 2017;69:58-70. (Prospective national population-based cohort; 1129 children)
2. Lehman LL, Rivkin MJ. Perinatal arterial ischemic stroke: presentation, risk factors, evaluation, and outcome. Pediatr Neurol. 2014;51(6):760-768. (Review article)
3. Ferriero DM, Fullerton HJ, Bernard TJ, et al. Management of stroke in neonates and children: a scientific statement from the American Heart Association/American Stroke Association. Stroke. 2019;50(3):e51-e96. (Review article, AHA guidelines)
4. Jordan LC, Hillis AE. Hemorrhagic stroke in children. Pediatr Neurol. 2007;36(2):73-80. (Review article)
5. Simma B, Holiner I, Luetschg J. Therapy in pediatric stroke. Eur J Pediatr. 2013;172(7):867-875. (Review article)
6. Rafay MF, Pontigon AM, Chiang J, et al. Delay to diagnosis in acute pediatric arterial ischemic stroke. Stroke. 2009;40(1):58-64. (Prospective cohort; 209 children)
7. Srinivasan J, Miller SP, Phan TG, et al. Delayed recognition of initial stroke in children: need for increased awareness. Pediatrics. 2009;124(2):e227-e234. (Retrospective chart review; 107 patients)
8. Mackay MT, Chua ZK, Lee M, et al. Stroke and nonstroke brain attacks in children. Neurology. 2014;82(16):1434-1440. (Prospective cohort study; 287 children)
9. Mackay MT, Wiznitzer M, Benedict SL, et al. Arterial ischemic stroke risk factors: the International Pediatric Stroke Study. Ann Neurol. 2011;69(1):130-140. (International Pediatric Stroke Study, multicenter observational cohort; 676 children)
10. Abend NS, Beslow LA, Smith SE, et al. Seizures as a presenting symptom of acute arterial ischemic stroke in childhood. J Pediatr. 2011;159(3):479-483. (Single-center prospective stroke registry; 60 children)
11. Amlie-Lefond C, Bernard TJ, Sebire G, et al. Predictors of cerebral arteriopathy in children with arterial ischemic stroke: results of the International Pediatric Stroke Study. Circulation. 2009;119(10):1417-1423. (International Pediatric Stroke Study, multicenter observational cohort; 667 children)
12. Ding D, Starke RM, Kano H, et al. International multicenter cohort study of pediatric brain arteriovenous malformations. Part 1: Predictors of hemorrhagic presentation. J Neurosurg Pediatr. 2017;19(2):127-135. (Multicenter retrospective cohort study; 357 children)
13. Fullerton HJ, Wintermark M, Hills NK, et al. Risk of recurrent arterial ischemic stroke in childhood: a prospective international study. Stroke. 2016;47(1):53-59. (Prospective cohort study; 355 children)
14. Grunt S, Mazenauer L, Buerki SE, et al. Incidence and outcomes of symptomatic neonatal arterial ischemic stroke. Pediatrics. 2015;135(5):e1220-e1228. (Prospective cohort study; 100 neonates)
15. Jordan LC, Johnston SC, Wu YW, et al. The importance of cerebral aneurysms in childhood hemorrhagic stroke: a population-based study. Stroke. 2009;40(2):400-405. (Retrospective cohort study; 116 children)
16. Liu J, Wang D, Lei C, et al. Etiology, clinical characteristics and prognosis of spontaneous intracerebral hemorrhage in children: a prospective cohort study in China. J Neurol Sci. 2015;358(1-2):367-370. (Prospective cohort study; 70 children)
17. Shellhaas RA, Smith SE, O’Tool E, et al. Mimics of childhood stroke: characteristics of a prospective cohort. Pediatrics. 2006;118(2):704-709. (Prospective cohort; 143 patients)
18. Wintermark M, Hills NK, deVeber GA, et al. Arteriopathy diagnosis in childhood arterial ischemic stroke: results of the vascular effects of infection in pediatric stroke study. Stroke. 2014;45(12):3597-3605. (Prospective cohort; 355 cases)
19. Bodey C, Goddard T, Patankar T, et al. Experience of mechanical thrombectomy for paediatric arterial ischaemic stroke. Eur J Paediatr Neurol. 2014;18(6):730-735. (Case series of mechanical thrombectomy; 4 children)
20. Tabone L, Mediamolle N, Bellesme C, et al. Regional pediatric acute stroke protocol: initial experience during 3 years and 13 recanalization treatments in children. Stroke. 2017;48(8):2278-2281. (Retrospective chart review; 13 children)
21. Gerstl L, Olivieri M, Heinen F, et al. Successful mechanical thrombectomy in a three-year-old boy with cardioembolic occlusion of both the basilar artery and the left middle cerebral artery. Eur J Paediatr Neurol. 2016;20(6):962-965. (Case report of mechanical thrombectomy)
22. Tatum J, Farid H, Cooke D, et al. Mechanical embolectomy for treatment of large vessel acute ischemic stroke in children. J Neurointerv Surg. 2013;5(2):128-134. (Case series of mechanical embolectomy; 4 cases)
23. Monagle P, Chan AKC, Goldenberg NA, et al. Antithrombotic therapy in neonates and children: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e737S-e801S. (Review article, American College of Chest Physicians guidelines)
24. Earley CJ, Kittner SJ, Feeser BR, et al. Stroke in children and sickle-cell disease: Baltimore-Washington Cooperative Young Stroke Study. Neurology. 1998;51(1):169-176. (Retrospective chart review; 35 children)
25. Gumer LB, Del Vecchio M, Aronoff S. Strokes in children: a systematic review. Pediatr Emerg Care. 2014;30(9):660-664. (Systematic literature review; 1455 children)
26. Roach ES, Golomb MR, Adams R, et al. Management of stroke in infants and children: a scientific statement from a Special Writing Group of the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young. Stroke. 2008;39(9):2644-2691. (Review article, AHA guidelines)
27. Scott RM, Smith ER. Moyamoya disease and moyamoya syndrome. N Engl J Med. 2009;360(12):1226-1237. (Review article)
28. Fullerton HJ, Johnston SC, Smith WS. Arterial dissection and stroke in children. Neurology. 2001;57(7):1155-1160. (Systematic literature review; 118 patients)
29. Zadro R, Herak DC. Inherited prothrombotic risk factors in children with first ischemic stroke. Biochem Med (Zagreb). 2012;22(3):298-310. (Review article)
30. Rogers P, Pan WJ, Drachtman RA, et al. A stroke mimic: methotrexate-induced neurotoxicity in the emergency department. J Emerg Med. 2017;52(4):559-561. (Case report)
31. Sebire G, Tabarki B, Saunders DE, et al. Cerebral venous sinus thrombosis in children: risk factors, presentation, diagnosis and outcome. Brain. 2005;128(Pt 3):477-489. (Retrospective chart review; 42 children)
32. Huang J, McGirt MJ, Gailloud P, et al. Intracranial aneurysms in the pediatric population: case series and literature review. Surg Neurol. 2005;63(5):424-432. (Case series; 19 cases)
33. Al-Jarallah A, Al-Rifai MT, Riela AR, et al. Nontraumatic brain hemorrhage in children: etiology and presentation. J Child Neurol. 2000;15(5):284-289. (Retrospective review; 68 children)
34. Vasconcelos MM, Vasconcelos LGA, Brito AR. Assessment of acute motor deficit in the pediatric emergency room. J Pediatr (Rio J). 2017;93 Suppl 1:26-35. (Review article)
35. Mackay MT, Yock-Corrales A, Churilov L, et al. Differentiating childhood stroke from mimics in the emergency department. Stroke. 2016;47(10):2476-2481. (Prospective cohort; 280 children)
36. Ladner TR, Mahdi J, Gindville MC, et al. Pediatric acute stroke protocol activation in a children’s hospital emergency department. Stroke. 2015;46(8):2328-2331. (Retrospective chart review; 124 stroke alerts)
37. Mackay MT, Lee M, Yock-Corrales A. Differentiating arterial ischemic stroke from migraine in the pediatric emergency department. Dev Med Child Neurol. 2018;30(11):1117-1122. (Comparison of children with migraine and AIS)
38. Hills NK, Sidney S, Fullerton HJ. Timing and number of minor infections as risk factors for childhood arterial ischemic stroke. Neurology. 2014;83(10):890-897. (Case-control study; 102 cases)
39. Hills NK, Johnston SC, Sidney S, et al. Recent trauma and acute infection as risk factors for childhood arterial ischemic stroke. Ann Neurol. 2012;72(6):850-858. (Nested case-control study; 126 cases)
40. Beslow LA, Jordan LC. Pediatric stroke: the importance of cerebral arteriopathy and vascular malformations. Childs Nerv Syst. 2010;26(10):1263-1273. (Review article)
41. Fox CK, Sidney S, Fullerton HJ. Community-based case-control study of childhood stroke risk associated with congenital heart disease. Stroke. 2015;46(2):336-340. (Case-control study; 412 cases)
42. Kyrnetskiy EE, Kun LE, Boop FA, et al. Types, causes, and outcome of intracranial hemorrhage in children with cancer. J Neurosurg. 2005;102(1 Suppl):31-35. (Retrospective chart review; 51 children)
43. Mackay MT, Monagle P, Babl FE. Brain attacks and stroke in children. J Paediatr Child Health. 2016;52(2):158-163. (Review article)
44. Zimmer JA, Garg BP, Williams LS, et al. Age-related variation in presenting signs of childhood arterial ischemic stroke. Pediatr Neurol. 2007;37(3):171-175. (Retrospective chart review; 76 children)
45. Kumar R, Shukla D, Mahapatra AK. Spontaneous intracranial hemorrhage in children. Pediatr Neurosurg. 2009;45(1):37-45. (Retrospective chart review; 50 patients)
46. Neville K, Lo W. Sensitivity and specificity of an adult stroke screening tool in childhood ischemic stroke. Pediatr Neurol. 2016;58:53-56. (Retrospective study of stroke screening tool; 53 children)
47. Elbers J, Wainwright MS, Amlie-Lefond C. The pediatric stroke code: early management of the child with wtroke. J Pediatr. 2015;167(1):19-24. (Expert recommendations)
48. Ichord RN, Bastian R, Abraham L, et al. Interrater reliability of the Pediatric National Institutes of Health Stroke Scale (PedNIHSS) in a multicenter study. Stroke. 2011;42(3):613-617. (Prospective cohort study; 25 children)
49. Mirsky DM, Beslow LA, Amlie-Lefond C, et al. Pathways for neuroimaging of childhood stroke. Pediatr Neurol. 2017;69:11-23. (Review article, expert guidelines)
50. Strater R, Kurnik K, Heller C, et al. Aspirin versus low-dose low-molecular-weight heparin: antithrombotic therapy in pediatric ischemic stroke patients: a prospective follow-up study. Stroke. 2001;32(11):2554-2558. (Prospective, nonrandomized intervention study; 135 children)
51. Schechter T, Kirton A, Laughlin S, et al. Safety of anticoagulants in children with arterial ischemic stroke. Blood. 2012;119(4):949-956. (Prospective cohort; 123 cases)
52. Monagle P, Michelson AD, Bovill E, et al. Antithrombotic therapy in children. Chest. 2001;119(1 Suppl):344S-370S. (Review article)
53. Bigi S, Dulcey A, Gralla J, et al. Feasibility, safety and outcome of recanalisation treatment in childhood stroke. Ann Neurol. 2018. (Retrospective study; 150 patients)
54. Amlie-Lefond C, deVeber G, Chan AK, et al. Use of alteplase in childhood arterial ischaemic stroke: a multicentre, observational, cohort study. Lancet Neurol. 2009;8(6):530-536. (Descriptive study of tPA use in the International Pediatric Stroke Study and case reports; 15 children)
55. Gupta AA, Leaker M, Andrew M, et al. Safety and outcomes of thrombolysis with tissue plasminogen activator for treatment of intravascular thrombosis in children. J Pediatr. 2001;139(5):682-688. (Case series; 80 children)
56. See AP, Kochis MA, Khandelwal P, et al. Considerations in applying a new stent retriever in pediatric endovascular cerebral thrombectomy for acute ischemic stroke. Pediatr Neurosurg. 2016;51(5):263-268. (Case report)
57. Bose A, Henkes H, Alfke K, et al. The Penumbra System: a mechanical device for the treatment of acute stroke due to thromboembolism. AJNR Am J Neuroradiol. 2008;29(7):1409-1413. (Prospective single-arm intervention study; 23 subjects)
58. Grunwald IQ, Walter S, Shamdeen MG, et al. New mechanical recanalization devices - the future in pediatric stroke treatment? J Invasive Cardiol. 2010;22(2):63-66. (Case series; 3 cases)
59. Webb J, Kwiatkowski JL. Stroke in patients with sickle cell disease. Expert Rev Hematol. 2013;6(3):301-316. (Review article)
60. Lo WD. Childhood hemorrhagic stroke: an important but understudied problem. J Child Neurol. 2011;26(9):1174-1185. (Review article)
61. Heffren J, McIntosh AM, and Reiter PD. Nimodipine for the prevention of cerebral vasopasm after subarachnoid hemorrhage in 12 children. Pediatr Neurol. 2015;52(3):356-360. (Retrospective chart review; 12 patients)
62. United States Food and Drug Administration. Highlights of prescribing information. Levenox (enoxaparin sodium injection) for subcutaneous and intravenous use. Accessed October 15, 2019. (FDA prescribing information)
63. Bruno CJ, Beslow LA, Witmer CM, et al. Haemorrhagic stroke in term and late preterm neonates. Arch Dis Child Fetal Neonatal Ed. 2014;99(1):F48-F53. (Prospective cohort from a single center registry; 42 neonates)
64. Cole L, Dewey D, Letourneau N, et al. Clinical characteristics, risk factors, and outcomes associated with neonatal hemorrhagic stroke: a population-based case-control study. JAMA Pediatr. 2017;171(3):230-238. (Population-based, nested case-control study; 86 cases)
65. Sandberg DI, Lamberti-Pasculli M, Drake JM, et al. Spontaneous intraparenchymal hemorrhage in full-term neonates. Neurosurgery. 2001;48(5):1042-1048. (Retrospective chart review; 11 neonates)
66. Rivkin MJ, deVeber G, Ichord RN, et al. Thrombolysis in pediatric stroke study. Stroke. 2015;46(3):880-885. (International phase 1 cohort study of thrombolysis)
67. Shack M, Andrade A, Shah-Basak PP, et al. A pediatric institutional acute stroke protocol improves timely access to stroke treatment. Dev Med Child Neurol. 2017;59(1):31-37. (Pre/post intervention study; 321 children)
68. DeLaroche AM, Sivaswamy L, Farooqi A, et al. Pediatric stroke clinical pathway improves the time to diagnosis in an emergency department. Pediatr Neurol. 2016;65:39-44. (Pre/post intervention study; 36 patients)
69. Fox CK, Johnston SC, Sidney S, et al. High critical care usage due to pediatric stroke: results of a population-based study. Neurology. 2012;79(5):420-427. (Retrospective review; 256 children)
70. Beslow LA, Dowling MM, Hassanein SMA, et al. Mortality after pediatric arterial ischemic stroke. Pediatrics. 2018;141(5). (Retrospective analysis of International Pediatric Stroke Study registry; 915 neonates and 2273 children)