Volume 9, Issue 1 (1-2021)                   J. Pediatr. Rev 2021, 9(1): 47-52 | Back to browse issues page

XML Print

Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:
Shahmirzaei S, Majidi F, Elfil M, Eldokmak M, Baratloo A R. A Review on Emergency Management of Pediatric Acute Ischemic Stroke. J. Pediatr. Rev 2021; 9 (1) :47-52
URL: http://jpr.mazums.ac.ir/article-1-313-en.html
A Review on Emergency Management of Pediatric Acute Ischemic Stroke
Shaghayegh Shahmirzaei1 , Fazeleh Majidi2 , Mohamed Elfil3 , Mohamed Eldokmak4 , Ali Reza Baratloo 5
1- Multiple Sclerosis Research Center, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran.
2- Research Development Center, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran.
3- Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, NE, USA.
4- Department of Neurology, SUNY Downstate Health Sciences University, Brooklyn, NY, USA.
5- Prehospital and Hospital Emergency Research Center, Tehran University of Medical Sciences, Tehran, Iran. , alirezabaratloo@yahoo.com
Keywords: Cerebrovascular disorders, Disease management, Pediatrics, Stroke, Emergency management
Full-Text [PDF 383 kb]   (1459 Downloads)     |   Abstract (HTML)  (2966 Views)
Full-Text:   (580 Views)

1. Context

The World Health Organization (WHO) has defined stroke as “a sudden non-convulsive loss of neurological function due to an ischemic or hemorrhagic intracranial vascular event” (1, 2). Although the disease is well-defined in the adult population, there are considerable gaps in the topic of Pediatric Acute Ischemic Stroke (P-AIS) (3, 4). With the prevalence of 1.2 to 5.11 per 100000 children/year in developed countries, P-AIS is considered a rare health event (5, 6). The differences in the reported incidence of P-AIS in different studies might arise from the discrepancies in the age of the included populations, as the incidence of P-AIS amongst the neonates (birth to 28 days) is much higher than the incidence in children (29 days to 18 years) (6).
Cerebrovascular diseases have significant importance due to their high morbidity and mortality rates. Indeed, they have been reported amongst the top 10 leading causes of pediatric mortality in the United States (7). P-AIS patients can suffer long-term, sometimes even lifelong complications, such as permanent cognitive and motor disabilities. These complications emphasize early diagnosis and management of P-AIS (8, 9). Based on current literature, there is no consensus regarding the proper emergency management of P-AIS. Also, there are lots of considerable controversies in this regard. Therefore, the current review was conducted to provide a more comprehensive discussion on this topic.

2. Evidence Acquisition

We searched the PubMed database using the terms “pediatrics”, “stroke”, and “recombinant tissue plasminogen activator”. By reviewing the titles and abstracts, we selected all English language papers on P-AIS management published after 2000. Two investigators were assessed eligible articles in respect of relevance to the topic. Then the full-texts of selected papers were further studied.
Furthermore, an expert panel performed a critical appraisal to summarize the findings and make them applicable. Finally, the extracted data were categorized under proper subheadings, and the manuscript was prepared. Then, the complete manuscript was reviewed, revised, and approved by all of the authors.

3. Results

Etiology and the underlying diseases
Several classification systems have been reported regarding P-AIS, but none of them has been universally accepted. Three subtypes have been proposed by the International Pediatric Stroke Study (IPSS): Arteriopathy, cardioembolic, other or undetermined (10). The most common known etiologies of P-AIS that may even accompany with recurrence stroke are sickle cell disease, cardiac disease, antiphospholipid antibodies, metabolic and mitochondrial disorders, elevated lipoprotein A, protein C deficiency, and vasculopathy (7, 11-13). Risk factors for P-AIS are not well understood, but thrombophilia, sickle cell anemia, and infection are among the most studied ones (14).
Clinical presentation
P-AIS symptoms include headache, vomiting, vertigo, ataxia, altered level of consciousness, apnea, hypotonia, seizures, which in most cases are not typical for a stroke. Unlike adults, most children presenting with acute-onset focal neurological symptoms suffer from stroke mimics. Many conditions, including migraine, seizures, Todd’s paralysis after focal seizures, conversion disorders, tumors, demyelinating diseases, can mimic stroke presentations in children; migraine is the most common one to simulate P-AIS clinical manifestations (15-18).
Diagnosis
Because of similar symptoms in both stroke and the previously mentioned diseases, making a definite P-AIS diagnosis is difficult. Considering early complications such as cerebral edema and “stroke mimics” are crucial to get better results (14). Some clues can help distinguishing stroke from such diseases, including children’s well-being during the prior week to the clinical presentation of acute ischemic stroke, their inability to walk, and weakness in the face and arm (17, 19). There is a very limited time window for evaluating and diagnosing AIS in children, outlining the importance of a guideline in this regard. To the best of our knowledge, at present, there is no published consensus guideline on this subject. Non-enhanced Computed Tomography (CT) helps distinguishing hemorrhage from AIS, but it is not always helpful in the hyperacute state (20). Magnetic Resonance Imaging (MRI) is more sensitive and specific in diagnosis, but it is not available in all centers, especially in centers with no pediatric stroke protocols (21).
Management 
In contrast to adult stroke, P-AIS management is mostly based on expert opinions, case reports, and a few non-randomized trials (1). Overall, management should focus on removing the clot in the vessels (primarily) and treating the underlying causes. As in adults, there are two management options for P-AIS: thrombolytic therapy and mechanical thrombectomy. 
Thrombolytic therapy
Excluding case reports and case series, there are two important studies regarding the use of recombinant tissue plasminogen activator (rt-PA) in P-AIS named as International Pediatric Stroke Study (IPSS) and Thrombolysis in Pediatric Stroke Study (TIPS). 
IPSS is a prospective multi-center cohort study conducted from 2003 until 2007 in which 687 patients with P-AIS with a mean age of 8.9 years were enrolled. Fifteen patients were treated with rt-PA, either intravenously or intra-arterially. Their mean time to treatment was 3.3 hours in the intravenous group and 4.5 hours in the intra-arterial one. The patients were administered a total dose of 0.02–0.9 mg/kg. Out of 15 treated patients with rt-PA, 2 died. The causes of death in both were reported to be unrelated to rt-PA administration. Out of 13 survivors, 4 had brain hemorrhage yet remained asymptomatic, 9 had neurological deficits at the time of discharge, and neurological symptoms resolved in only 1 patient (22).
The TIPS trial assessed the safety and the optimal dosage of rt-PA. The rationale of the TIPS trial has argued that the use of rt-PA outside therapeutic windows defined for adults and the different fibrinolysis pathways in pediatrics have a considerable impact on the outcomes. For instance, higher levels of tissue plasminogen activator inhibitor-1 and lower endogenous plasminogen levels necessitate higher doses of rt-PA in pediatrics. Considering these factors, TIPS was started in 2012 but got terminated after 1 year due to poor enrollment. Out of 43 patients identified as P-AIS, only 1 met their designated criteria for rt-PA administration (23).
The Australian Childhood Stroke Advisory Committee guidelines provide a weak recommendation on the use of rt-PA in P-AIS patients of 2-17 years old, with pediatric stroke severity score between 4 and 24, lack of bleeding, and the ability to start the treatment in 4.5 hours of symptoms onset (level of evidence: III, IV). These guidelines advise strongly against the use of rt-PA after 4.5 hours from the onset of symptoms (Level of evidence: I-III) (24).
The “Canadian Best Practice Recommendations for Stroke Care” recommends that all patients should be evaluated for their eligibility for thrombolytic therapy if there is the possibility to initiate the treatment within 4.5 hours of symptom onset. The recommended door-to-needle time for intravenous alteplase is less than 60 minutes (Evidence level C) (25). Rajani et al. argued that making arterial occlusion a mandatory criterion for P-AIS would result in children being denied a potentially lifesaving treatment (26).
Thrombectomy
To our knowledge, no published clinical trials exist considering mechanical interventions in P-AIS. Case series on this subject may seem to have a bias since unsuccessful interventions are unlikely to get published. However, 2018 American guidelines for endovascular therapy recommend stent retrievers as a reasonable method for some children under 18 with large-vessel occlusion (27). They also recommend starting the treatment 6 hours from the onset of the symptoms. The limitations include the difference between vessel size in children and adults that make some clot retrieval devices out of use. Besides, stroke mechanisms differ in children from adults, mostly focal cerebral arteriopathy, sickle cell arteriopathy, and moyamoya, which are not amenable to thrombectomy (21, 28, 29).
Outcome
Recent evidence has suggested that the existence of multiple risk factors is associated with worse outcomes. Therefore, metabolic, hematologic, and angiographic studies should be carried out to evaluate further risk factors. Other risk factors include a history of head trauma, developmental delay, headaches, fever, family history of bleeding disorders, etc. Based on these findings, neuroimaging, echocardiography, and metabolic and hematologic studies may be indicated.

4. Conclusions

Although thrombolytic therapy is recommended in P-AIS, since most cases are diagnosed outside the therapeutic window, this treatment is practically impossible, so they are candidates for mechanical interventions. On the other hand, a proper device may not be available to fit the size of the younger children’s vasculature.

Ethical Considerations

Compliance with ethical guidelines

There were no ethical considerations to be considered in this research.

Funding

This research did not receive any grant from funding agencies in the public, commercial, or non-profit sectors. 

Authors' contributions

All authors equally contributed to preparing this article.

Conflicts of interest

The authors declared no conflict of interest.

Acknowledgments

The authors would like to thank consultants of the Research Development Center of Sina Hospital for their assistance.


 

References

  1. Carpenter J, Tsuchida T, Lynch JK. Treatment of arterial ischemic stroke in children. Expert Review of Neurotherapeutics. 2007; 7(4):383-92. [DOI:10.1586/14737175.7.4.383] [PMID]
  2. Baratloo A, Forouzanfar MM, Hashemi B, Safari S, Kasmaei HD, Rouhipour A, et al. Tissue plasminogen activator: A literature review. Archives of Neuroscience. 2016; 3(1):e30452. [DOI:10.5812/archneurosci.30452]
  3. DeVeber G. In pursuit of evidence-based treatments for paediatric stroke: The UK and Chest guidelines. The Lancet Neurology. 2005; 4(7):432-6. [DOI:10.1016/S1474-4422(05)70120-4]
  4. Sébire G, Fullerton H, Riou E, deVeber G. Toward the definition of cerebral arteriopathies of childhood. Current Opinion in Pediatrics. 2004; 16(6):617-22. [DOI:10.1097/01.mop.0000144441.29899.20] [PMID]
  5. Fullerton HJ, Wu YW, Zhao S, Johnston SC. Risk of stroke in children: Ethnic and gender disparities. Neurology. 2003; 61(2):189-94. [DOI:10.1212/01.WNL.0000078894.79866.95] [PMID]
  6. deVeber GA, Kirton A, Booth FA, Yager JY, Wirrell EC, Wood E, et al. Epidemiology and outcomes of arterial ischemic stroke in children: The Canadian Pediatric Ischemic Stroke Registry. Pediatric Neurology. 2017; 69:58-70. [DOI:10.1016/j.pediatrneurol.2017.01.016] [PMID]
  7. Sofronas M, Ichord RN, Fullerton HJ, Lynch JK, Massicotte MP, Willan AR, et al. Pediatric stroke initiatives and preliminary studies: What is known and what is needed? Pediatric Neurology. 2006; 34(6):439-45. [DOI:10.1016/j.pediatrneurol.2005.10.016] [PMID]
  8. Cremer S, Berliner Y, Warren D, Jones AE. Successful treatment of pediatric stroke with recombinant tissue Plasminogen Activator (rt-PA): A case report and review of the literature. Canadian Journal of Emergency Medicine. 2008; 10(6):575-8. https://www.cambridge.org/core/journals/canadian-journal-of-emergency-medicine/article
  9. de Veber GA, Mac Gregor D, Curtis R, Mayank S. Neurologic outcome in survivors of childhood arterial ischemic stroke and sinovenous thrombosis. Journal of Child Neurology. 2000; 15(5):316-24. [DOI:10.1177/088307380001500508] [PMID]
  10. Mackay MT, Wiznitzer M, Benedict SL, Lee KJ, deVeber GA, Ganesan V, et al. Arterial ischemic stroke risk factors: The international pediatric stroke study. Annals of Neurology. 2011; 69(1):130-40. [DOI:10.1002/ana.22224] [PMID]
  11. Simma B, Höliner I, Luetschg J. Therapy in pediatric stroke. European Journal of Pediatrics. 2013; 172(7):867-75. [DOI:10.1007/s00431-012-1863-9] [PMID]
  12. Lynch JK, Hirtz DG, De Veber G, Nelson KB. Report of the National Institute of Neurological Disorders and Stroke workshop on perinatal and childhood stroke. Pediatrics. 2002; 109(1):116-23. [DOI:10.1542/peds.109.1.116] [PMID]
  13. Kirton A, Deveber G. Therapeutic approaches and advances in pediatric stroke. NeuroRx. 2006; 3(2):133-42. [DOI:10.1016/j.nurx.2006.01.003] [PMID] [PMCID]
  14. Paediatric Stroke Working Group, Royal College of Physicians of London. Clinical Effectiveness, Evaluation Unit. Stroke in childhood: Clinical guidelines for diagnosis, management and rehabilitation. Royal College of Physicians; 2004. https://www.rcpch.ac.uk/resources/stroke-childhood-clinical-guideline-diagnosis-management-rehabilitation
  15. Shellhaas RA, Smith SE, O’Tool E, Licht DJ, Ichord RN. Mimics of childhood stroke: Characteristics of a prospective cohort. Pediatrics. 2006; 118(2):704-9. [DOI:10.1542/peds.2005-2676] [PMID]
  16. Mackay MT, Chua ZK, Lee M, Yock-Corrales A, Churilov L, Monagle P, et al. Stroke and nonstroke brain attacks in children. Neurology. 2014; 82(16):1434-40. [DOI:10.1212/WNL.0000000000000343] [PMID]
  17. Mackay MT, Yock-Corrales A, Churilov L, Monagle P, Donnan GA, Babl FE. Differentiating childhood stroke from mimics in the emergency department. Stroke. 2016; 47(10):2476-81. [DOI:10.1161/STROKEAHA.116.014179] [PMID] [PMCID]
  18. DeLaroche AM, Sivaswamy L, Farooqi A, Kannikeswaran N. Pediatric stroke and Its mimics: limitations of a pediatric stroke clinical pathway. Pediatric Neurology. 2018; 80:35-41. [DOI:10.1016/j.pediatrneurol.2017.10.005] [PMID]
  19. Mackay M T, Yock-Corrales A, Churilov L, Monagle P, Donnan G A, Babl F E. Accuracy and reliability of stroke diagnosis in the pediatric emergency department. Stroke. 2017; 48(5):1198-202. [DOI:10.1161/STROKEAHA.116.015571] [PMID]
  20. Jain SV, Morton LD. Ischemic stroke and excellent recovery after administration of intravenous tissue plasminogen activator. Pediatric Neurology. 2008; 38(2):126-9. [DOI:10.1016/j.pediatrneurol.2007.10.006] [PMID]
  21. Lehman L L, Beslow L A, Steinlin M, Kossorotoff M, Mackay M T. What will improve pediatric acute stroke care? Stroke. 2019; 50(2):249-56. [DOI:10.1161/STROKEAHA.118.022881] [PMID]
  22. Amlie-Lefond C, deVeber G, Chan A K, Benedict S, Bernard T, Carpenter J, et al. Use of alteplase in childhood arterial ischaemic stroke: A multicentre, observational, cohort study. The Lancet Neurology. 2009; 8(6):530-6. [DOI:10.1016/S1474-4422(09)70106-1]
  23. Rivkin M J, deVeber G, Ichord RN, Kirton A, Chan A K, Hovinga C A, et al. Thrombolysis in pediatric stroke study. Stroke. 2015; 46(3):880-5. [DOI:10.1161/STROKEAHA.114.008210] [PMID] [PMCID]
  24. Medley TL, Miteff C, Andrews I, Ware T, Cheung M, Monagle P, et al. Australian clinical consensus guideline: The diagnosis and acute management of childhood stroke. International Journal of Stroke. 2019; 14(1):94-106. [DOI:10.1177/1747493018799958] [PMID]
  25. Lindsay P, Bayley M, Hellings C, Hill M, Woodbury E, Phillips S. Canadian best practice recommendations for stroke care (updated 2008). Canadian Medical Association Journal. 2008; 179(12):S1-S25. [DOI:10.1503/cmaj.081148.R2] [PMCID]
  26. Rajani NK, Pearce K, Campion T, Salpietro V, Planells M, Chong W, et al. Pediatric stroke: Current diagnostic and management challenges. Quantitative Imaging in Medicine and Surgery. 2018; 8(10):984-91. [DOI:10.21037/qims.2018.11.09] [PMID] [PMCID]
  27. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, et al. 2018 guidelines for the early management of patients with acute ischemic stroke: A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2018; 49(3):e46-e99. [DOI:10.1161/STR.0000000000000163]
  28. Fullerton HJ, Hills NK, Elkind MS, Dowling MM, Wintermark M, Glaser CA, et al. Infection, vaccination, and childhood arterial ischemic stroke: Results of the VIPS study. Neurology. 2015; 85(17):1459-66. [DOI:10.1212/WNL.0000000000002065] [PMID] [PMCID]
  29. Wintermark M, Hills NK, DeVeber GA, Barkovich AJ, Elkind MS, Sear K, et al. Arteriopathy diagnosis in childhood arterial ischemic stroke: Results of the vascular effects of infection in pediatric stroke study. Stroke. 2014; 45(12):3597-605. [DOI:10.1161/STROKEAHA.114.007404] [PMID] [PMCID]

 

Type of Study: Review Article | Subject: Neurology
Received: 2020/03/11 | Accepted: 2020/09/24 | Published: 2021/01/1
Add your comments about this article : Your username or Email:
CAPTCHA
Send email to the article author

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

© 2024 CC BY-NC 4.0 | Journal of Pediatrics Review

Designed & Developed by : Yektaweb