Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Primer
  • Published:

Childhood stroke

Abstract

Stroke is an important cause of neurological morbidity in children; most survivors have permanent neurological deficits that affect the remainder of their life. Stroke in childhood, the focus of this Primer, is distinguished from perinatal stroke, defined as stroke before 29 days of age, because of its unique pathogenesis reflecting the maternal–fetal unit. Although approximately 15% of strokes in adults are haemorrhagic, half of incident strokes in children are haemorrhagic and half are ischaemic. The causes of childhood stroke are distinct from those in adults. Urgent brain imaging is essential to confirm the stroke diagnosis and guide decisions about hyperacute therapies. Secondary stroke prevention strongly depends on the underlying aetiology. While the past decade has seen substantial advances in paediatric stroke research, the quality of evidence for interventions, such as the rapid reperfusion therapies that have revolutionized arterial ischaemic stroke care in adults, remains low. Substantial time delays in diagnosis and treatment continue to challenge best possible care. Effective primary stroke prevention strategies in children with sickle cell disease represent a major success, yet barriers to implementation persist. The multidisciplinary members of the International Pediatric Stroke Organization are coordinating global efforts to tackle these challenges and improve the outcomes in children with cerebrovascular disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Major aetiologies of haemorraghic and ischaemic stroke in childhood.
Fig. 2: Common aetiologies of childhood arterial ischaemic stroke.
Fig. 3: Major signalling pathways and genes involved in vascular malformations that cause the majority of childhood ICH.
Fig. 4: Diagnostic clues for haemorrhagic and ischaemic childhood stroke.
Fig. 5: Treatment algorithm for acute childhood stroke.
Fig. 6: Example of a case with successful mechanical thrombectomy in a 9-year-old boy with left-sided hemiparesis.
Fig. 7: Paediatric stroke trajectories.

Similar content being viewed by others

References

  1. Eeg-Olofsson, O. & Ringheim, Y. Stroke in children. Clinical characteristics and prognosis. Acta Paediatr. 72, 391–395 (1983).

    Article  CAS  Google Scholar 

  2. Broderick, J., Talbot, G. T., Prenger, E., Leach, A. & Brott, T. Stroke in children within a major metropolitan area: the surprising importance of intracerebral hemorrhage. J. Child. Neurol. 8, 250–255 (1993).

    Article  CAS  PubMed  Google Scholar 

  3. Zahuranec, D. B., Brown, D. L., Lisabeth, L. D. & Morgenstern, L. B. Is it time for a large, collaborative study of pediatric stroke? Stroke 36, 1825–1829 (2005).

    Article  PubMed  Google Scholar 

  4. Steinlin, M. et al. The first three years of the Swiss Neuropaediatric Stroke Registry (SNPSR): a population-based study of incidence, symptoms and risk factors. Neuropediatrics 36, 90–97 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Chung, B. & Wong, V. Pediatric stroke among Hong Kong Chinese subjects. Pediatrics 114, e206–e212 (2004).

    Article  PubMed  Google Scholar 

  6. Grunt, S. et al. Incidence and outcomes of symptomatic neonatal arterial ischemic stroke. Pediatrics 135, e1220–e1228 (2015).

    Article  PubMed  Google Scholar 

  7. Mallick, A. A. & O’Callaghan, F. J. Prospective studies of the incidence of pediatric arterial ischaemic stroke. Blood Cells Mol. Dis. 69, 101 (2018).

    Article  PubMed  Google Scholar 

  8. Giroud, M. et al. Cerebrovascular disease in children under 16 years of age in the city of Dijon, France: a study of incidence and clinical features from 1985 to 1993. J. Clin. Epidemiol. 48, 1343–1348 (1995).

    Article  CAS  PubMed  Google Scholar 

  9. Earley, C. J. et al. Stroke in children and sickle-cell disease: Baltimore-Washington Cooperative Young Stroke Study. Neurology 51, 169–176 (1998).

    Article  CAS  PubMed  Google Scholar 

  10. Agrawal, N., Johnston, S. C., Wu, Y. W., Sidney, S. & Fullerton, H. J. Imaging data reveal a higher pediatric stroke incidence than prior US estimates. Stroke 40, 3415–3421 (2009). This study demonstrates the relatively low sensitivity of billing codes for paediatric stroke, suggesting that studies that use administrative data to estimate the incidence of paediatric stroke probably underestimate the number of incident cases.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Barnes, C., Newall, F., Furmedge, J., Mackay, M. & Monagle, P. Arterial ischaemic stroke in children. J. Paediatr. Child. Health 40, 384–387 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Krishnamurthi, R. V. et al. Stroke prevalence, mortality and disability-adjusted life years in children and youth aged 0-19 years: data from the global and regional burden of stroke 2013. Neuroepidemiology 45, 177–189 (2015).

    Article  PubMed  Google Scholar 

  13. Kirkham, F. J. & Lagunju, I. A. Epidemiology of stroke in sickle cell disease. J. Clin. Med. 10, 4232 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Adams, R. J. et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial doppler ultrasonography. N. Engl. J. Med. 339, 5–11 (1998).

    Article  CAS  PubMed  Google Scholar 

  15. Fullerton, H. J., Adams, R. J., Zhao, S. & Johnston, S. C. Declining stroke rates in Californian children with sickle cell disease. Blood 104, 336–339 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Marks, L. J. et al. Stroke prevalence in children with sickle cell disease in sub-Saharan Africa: a systematic review and meta-analysis. Glob. Pediatr. Health 5, 2333794X18774970 (2018).

    PubMed  PubMed Central  Google Scholar 

  17. Lagunju, I. O. et al. Annual stroke incidence in Nigerian children with sickle cell disease and elevated TCD velocities treated with hydroxyurea. Pediatr. Blood Cancer 66, e27252 (2019).

    Article  PubMed  Google Scholar 

  18. Abdullahi, S. U. et al. Primary prevention of stroke in children with sickle cell anemia in sub-Saharan Africa: rationale and design of phase III randomized clinical trial. Pediatr. Hematol. Oncol. 38, 49–64 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Fullerton, H. J., Wu, Y. W., Zhao, S. & Johnston, S. C. Risk of stroke in children: ethnic and gender disparities. Neurology 61, 189–194 (2003).

    Article  PubMed  Google Scholar 

  20. Riikonen, R. & Santavuori, P. Hereditary and acquired risk factors for childhood stroke. Neuropediatrics 25, 227–233 (1994).

    Article  CAS  PubMed  Google Scholar 

  21. Heller, C., Becker, S., Kreuz, W. & Scharrer, I. Prothrombotic risk factors in childhood stroke and venous thrombosis. Eur. J. Pediatr. 158 (Suppl. 3), 117–121 (1999).

    Article  Google Scholar 

  22. Lee, Y. Y. et al. Risk factors and outcomes of childhood ischemic stroke in Taiwan. Brain Dev. 30, 14–19 (2008).

    Article  PubMed  Google Scholar 

  23. Kenet, G. et al. Impact of thrombophilia on risk of arterial ischemic stroke or cerebral sinovenous thrombosis in neonates and children: a systematic review and meta-analysis of observational studies. Circulation 121, 1838–1847 (2010).

    Article  PubMed  Google Scholar 

  24. MacKay, M. T. et al. Arterial ischemic stroke risk factors: the International Pediatric Stroke Study. Ann. Neurol. 69, 130–140 (2011).

    Article  PubMed  Google Scholar 

  25. Hills, N. K., Johnston, S. C., Sidney, S., Zielinski, B. A. & Fullerton, H. J. Recent trauma and acute infection as risk factors for childhood arterial ischemic stroke. Ann. Neurol. 72, 850–858 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Ganesan, V., Prengler, M., McShane, M. A., Wade, A. M. & Kirkham, F. J. Investigation of risk factors in children with arterial ischemic stroke. Ann. Neurol. 53, 167–173 (2003).

    Article  PubMed  Google Scholar 

  27. Golomb, M. R., Fullerton, H. J., Nowak-Gottl, U. & Deveber, G. Male predominance in childhood ischemic stroke: findings from the International Pediatric Stroke Study. Stroke 40, 52–57 (2009).

    Article  PubMed  Google Scholar 

  28. Morrongiello, B. A., McArthur, B. A. & Spence, J. R. Understanding gender differences in childhood injuries: examining longitudinal relations between parental reactions and boys’ versus girls’ injury-risk behaviors. Heal. Psychol. 35, 523–530 (2016).

    Article  Google Scholar 

  29. Normann, S. et al. Role of endogenous testosterone concentration in pediatric stroke. Ann. Neurol. 66, 754–758 (2009).

    Article  CAS  PubMed  Google Scholar 

  30. Fullerton, H. J., Chetkovich, D. M., Wu, Y. W., Smith, W. S. & Johnston, S. C. Deaths from stroke in US children, 1979 to 1998. Neurology 59, 34–39 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Fullerton, H. J., Elkins, J. S. & Johnston, S. C. Pediatric stroke belt: geographic variation in stroke mortality in US children. Stroke 35, 1570–1573 (2004).

    Article  PubMed  Google Scholar 

  32. Hills, N. K., Sidney, S. & Fullerton, H. J. Timing and number of minor infections as risk factors for childhood arterial ischemic stroke. Neurology 83, 890–897 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Fullerton, H. J. et al. Infection, vaccination, and childhood arterial ischemic stroke. Neurology 85, 1459–1466 (2015). An analysis of the prospective case–control VIPS study suggesting that infection may act as a trigger for childhood AIS, while routine vaccinations appear protective.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Günel, M. et al. A founder mutation as a cause of cerebral cavernous malformation in Hispanic Americans. N. Engl. J. Med. 334, 946–951 (1996).

    Article  PubMed  Google Scholar 

  35. Ikezaki, K., Han, D. H., Kawano, T., Inamura, T. & Fukui, M. Epidemiological survey of Moyamoya disease in Korea. Clin. Neurol.Neurosurg. 99 (Suppl. 2), 6–10 (1997).

    Article  Google Scholar 

  36. Wakai, K. et al. Epidemiological features of Moyamoya disease in Japan: findings from a nationwide survey. Clin. Neurol. Neurosurg. 99 (Suppl. 2), 1–5 (1997).

    Article  Google Scholar 

  37. Fox, C. K., Johnston, S. C., Sidney, S. & Fullerton, H. J. High critical care usage due to pediatric stroke: results of a population-based study. Neurology 79, 420–427 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Beslow, L. A. et al. Mortality after pediatric arterial ischemic stroke. Pediatrics 141, e20174146 (2018).

    Article  PubMed  Google Scholar 

  39. Bigi, S. et al. Acute ischemic stroke in children versus young adults. Ann. Neurol. 70, 245–254 (2011).

    Article  PubMed  Google Scholar 

  40. Mallick, A. A. et al. Childhood arterial ischaemic stroke incidence, presenting features, and risk factors: a prospective population-based study. Lancet Neurol. 13, 35–43 (2014).

    Article  PubMed  Google Scholar 

  41. Wintermark, M. et al. Arteriopathy diagnosis in childhood arterial ischemic stroke: results of the Vascular Effects of Infection in Pediatric Stroke study. Stroke 45, 3597–3605 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Asakai, H. et al. Arterial ischemic stroke in children with cardiac disease. Neurology 85, 2053–2059 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Fox, C. K., Sidney, S. & Fullerton, H. J. Community-based case-control study of childhood stroke risk associated with congenital heart disease. Stroke 46, 336–340 (2015).

    Article  CAS  PubMed  Google Scholar 

  44. Jordan, L. C. et al. Neurological complications and outcomes in the Berlin Heart EXCOR® pediatric investigational device exemption trial. J. Am. Heart Assoc. 4, e001429 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Fraser, C. D. et al. Prospective trial of a pediatric ventricular assist device. N. Engl. J. Med. 367, 532–541 (2012).

    Article  CAS  PubMed  Google Scholar 

  46. Chung, M. G. et al. Arterial ischemic stroke secondary to cardiac disease in neonates and children. Pediatr. Neurol. 100, 35–41 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Asakai, H. et al. Risk factors for peri-procedural arterial ischaemic stroke in children with cardiac disease. Pediatr. Cardiol. 38, 1385–1392 (2017).

    Article  PubMed  Google Scholar 

  48. Henzi, B. C. et al. Risk factors for postprocedural arterial ischemic stroke in children with cardiac disease. Stroke 51, e242–e245 (2020).

    Article  PubMed  Google Scholar 

  49. Amlie-Lefond, C. et al. Predictors of cerebral arteriopathy in children with arterial ischemic stroke: results of the International Pediatric Stroke Study. Circulation 119, 1417–1423 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Mineyko, A. et al. Inflammatory biomarkers of pediatric focal cerebral arteriopathy. Neurology 79, 1406–1408 (2012).

    Article  PubMed  Google Scholar 

  51. Buerki, S. E. et al. Inflammatory markers in pediatric stroke: an attempt to better understanding the pathophysiology. Eur. J. Paediatr. Neurol. 20, 252–260 (2016).

    Article  PubMed  Google Scholar 

  52. Eleftheriou, D., Ganesan, V., Hong, Y., Klein, N. J. & Brogan, P. A. Endothelial injury in childhood stroke with cerebral arteriopathy. Neurology 79, 2089–2096 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Eleftheriou, D., Ganesan, V., Hong, Y., Klein, N. J. & Brogan, P. A. Endothelial repair in childhood arterial ischaemic stroke with cerebral arteriopathy. Cerebrovasc. Dis. Extra 5, 68–74 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Wintermark, M. et al. Clinical and imaging characteristics of arteriopathy subtypes in children with arterial ischemic stroke: results of the VIPS study. AJNR Am. J. Neuroradiol. 38, 2172–2179 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Dlamini, N. et al. Intracranial dissection mimicking transient cerebral arteriopathy in childhood arterial ischemic stroke. J. Child. Neurol. 26, 1203–1206 (2011).

    Article  PubMed  Google Scholar 

  56. Perez, F. A., Oesch, G. & Amlie-Lefond, C. M. MRI vessel wall enhancement and other imaging biomarkers in pediatric focal cerebral arteriopathy-inflammatory subtype. Stroke 51, 583–859 (2020).

    Article  Google Scholar 

  57. Stence, N. V. et al. Predicting progression of intracranial arteriopathies in childhood stroke with vessel wall imaging. Stroke 48, 2274–2277 (2017).

    Article  PubMed  Google Scholar 

  58. Braun, K. P. J. et al. The course and outcome of unilateral intracranial arteriopathy in 79 children with ischaemic stroke. Brain 132, 554–557 (2009).

    Google Scholar 

  59. Steinlin, M. et al. Focal cerebral arteriopathy: do steroids improve outcome? Stroke 48, 2375–2382 (2017). This retrospective cohort study changed clinical management of focal cerebral arteriopathy of childhood by suggesting possible efficacy for improving neurological outcomes. A randomized clinical trial is now underway.

    Article  PubMed  Google Scholar 

  60. Gilden, D., Cohrs, R. J., Mahalingam, R. & Nagel, M. A. Varicella zoster virus vasculopathies: diverse clinical manifestations, laboratory features, pathogenesis, and treatment. Lancet Neurol. 8, 731–740 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Hayman, M., Hendson, G., Poskitt, K. J. & Connolly, M. B. Postvaricella angiopathy: report of a case with pathologic correlation. Pediatr. Neurol. 24, 387–389 (2001).

    Article  CAS  PubMed  Google Scholar 

  62. Berger, T. M., Caduff, J. H. & Gebbers, J. O. Fatal varicella-zoster virus antigen-positive giant cell arteritis of the central nervous system. Pediatr. Infect. Dis. J. 19, 653–656 (2000).

    Article  CAS  PubMed  Google Scholar 

  63. Fullerton, H. J., Johnston, S. C. & Smith, W. S. Arterial dissection and stroke in children. Neurology 57, 1155–1160 (2001).

    Article  CAS  PubMed  Google Scholar 

  64. Morel, A. et al. Mechanism of ischemic infarct in spontaneous cervical artery dissection. Stroke 43, 1354–1361 (2012).

    Article  PubMed  Google Scholar 

  65. Brandt, T. et al. Pathogenesis of cervical artery dissections: association with connective tissue abnormalities. Neurology 57, 24–30 (2001).

    Article  CAS  PubMed  Google Scholar 

  66. Debette, S. et al. Familial occurrence and heritable connective tissue disorders in cervical artery dissection. Neurology 83, 2023–2031 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Grond-Ginsbach, C. et al. Genetic imbalance in patients with cervical artery dissection. Curr. Genomics 18, 206–213 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Rollins, N., Braga, B., Hogge, A., Beavers, S. & Dowling, M. Dynamic arterial compression in pediatric vertebral arterial dissection. Stroke 48, 1070–1073 (2017).

    Article  PubMed  Google Scholar 

  69. Fox, C. K. et al. Single-center series of boys with recurrent strokes and rotational vertebral arteriopathy. Neurology 95, e1830–e1834 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Kuriyama, S. et al. Prevalence and clinicoepidemiological features of moyamoya disease in Japan: findings from a nationwide epidemiological survey. Stroke 39, 42–47 (2008).

    Article  PubMed  Google Scholar 

  71. Duan, L. et al. Moyamoya disease in China: its clinical features and outcomes. Stroke 43, 56–60 (2012).

    Article  PubMed  Google Scholar 

  72. Chen, P. C., Yang, S. H., Chien, K. L., Tsai, I. J. & Kuo, M. F. Epidemiology of moyamoya disease in Taiwan: a nationwide population-based study. Stroke 45, 1258–1263 (2014).

    Article  PubMed  Google Scholar 

  73. Uchino, K., Johnston, S. C., Becker, K. J. & Tirschwell, D. L. Moyamoya disease in Washington State and California. Neurology 65, 956–958 (2005).

    Article  PubMed  Google Scholar 

  74. Kuroda, S. & Houkin, K. Moyamoya disease: current concepts and future perspectives. Lancet Neurol. 7, 1056–1066 (2008).

    Article  PubMed  Google Scholar 

  75. Smith, K. R. et al. Identification of a novel RNF213 variant in a family with heterogeneous intracerebral vasculopathy. Int. J. Stroke 9, E26–E27 (2014).

    Article  PubMed  Google Scholar 

  76. Kamada, F. et al. A genome-wide association study identifies RNF213 as the first Moyamoya disease gene. J. Hum. Genet. 56, 34–40 (2011).

    Article  CAS  PubMed  Google Scholar 

  77. Liu, W. et al. Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development. PLoS ONE 6, e22542 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Sun, X. S. et al. The association between the ring finger protein 213 (RNF213) polymorphisms and moyamoya disease susceptibility: a meta-analysis based on case–control studies. Mol. Genet. Genomics 291, 1193–1203 (2016).

    Article  CAS  PubMed  Google Scholar 

  79. Ma, Y. G., Zhang, Q., Yu, L. B. & Zhao, J. Z. Role of ring finger protein 213 in moyamoya disease. Chin. Med. J. 129, 2497–2501 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Cecchi, A. C. et al. RNF213 rare variants in an ethnically diverse population with moyamoya disease. Stroke 45, 3200–3207 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Miskinyte, S. et al. Loss of BRCC3 deubiquitinating enzyme leads to abnormal angiogenesis and is associated with syndromic moyamoya. Am. J. Hum. Genet. 88, 718–728 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Pinard, A. et al. The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy. Genet. Med. 22, 427–431 (2020).

    Article  CAS  PubMed  Google Scholar 

  83. Guey, S., Tournier-Lasserve, E., Hervé, D. & Kossorotoff, M. Moyamoya disease and syndromes: from genetics to clinical management. Appl. Clin. Genet. 8, 49–68 (2015).

    PubMed  PubMed Central  Google Scholar 

  84. Aloui, C. et al. Xq28 copy number gain causing moyamoya disease and a novel moyamoya syndrome. J. Med. Genet. 57, 339–346 (2020).

    Article  CAS  PubMed  Google Scholar 

  85. McCrea, N., Fullerton, H. J. & Ganesan, V. Genetic and environmental associations with pediatric cerebral arteriopathy. Stroke 50, 257–265 (2019).

    Article  PubMed  Google Scholar 

  86. Rea, D. et al. Cerebral arteriopathy in children with neurofibromatosis type 1. Pediatrics 124, e476–e483 (2009).

    Article  PubMed  Google Scholar 

  87. Kainth, D. S., Chaudhry, S. A., Kainth, H. S., Suri, F. K. & Qureshi, A. I. Prevalence and characteristics of concurrent down syndrome in patients with moyamoya disease. Neurosurgery 72, 210–215 (2013).

    Article  PubMed  Google Scholar 

  88. Emerick, K. M. et al. Intracranial vascular abnormalities in patients with Alagille syndrome. J. Pediatric Gastroenterol. Nutr. 49, 99–107 (2005).

    Article  Google Scholar 

  89. Raggio, V. et al. Whole genome sequencing reveals a frameshift mutation and a large deletion in YY1AP1 in a girl with a panvascular artery disease. Hum. Genomics 15, 28 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Carpenter, C. D., Linscott, L. L., Leach, J. L., Vadivelu, S. & Abruzzo, T. Spectrum of cerebral arterial and venous abnormalities in Alagille syndrome. Pediatr. Radiol. 48, 602–608 (2018).

    Article  PubMed  Google Scholar 

  91. Milewicz, D. M. et al. Genetic variants promoting smooth muscle cell proliferation can result in diffuse and diverse vascular diseases: evidence for a hyperplastic vasculomyopathy. Genet. Med. 12, 196–203 (2010).

    Article  CAS  PubMed  Google Scholar 

  92. Stansfield, B. K. et al. Ras-Mek-Erk signaling regulates Nf1 heterozygous neointima formation. Am. J. Pathol. 184, 79–85 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Munot, P., Crow, Y. J. & Ganesan, V. Paediatric stroke: genetic insights into disease mechanisms and treatment targets. Lancet Neurol. 10, 264–274 (2011).

    Article  CAS  PubMed  Google Scholar 

  94. Keylock, A. et al. Moyamoya-like cerebrovascular disease in a child with a novel mutation in myosin heavy chain 11. Neurology 90, 136–138 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Zhou, Q. et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N. Engl. J. Med. 370, 911–920 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Caorsi, R. et al. ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study. Ann. Rheum. Dis. 76, 1648–1656 (2017).

    Article  CAS  PubMed  Google Scholar 

  97. Kato, G. J., Hebbel, R. P., Steinberg, M. H. & Gladwin, M. T. Vasculopathy in sickle cell disease: biology, pathophysiology, genetics, translational medicine, and new research directions. Am. J. Hematol. 84, 618–625 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. DeBaun, M. R. et al. Associated risk factors for silent cerebral infarcts in sickle cell anemia: low baseline hemoglobin, sex, and relative high systolic blood pressure. Blood 119, 3684–3690 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Bae, H. T. et al. Meta-analysis of 2040 sickle cell anemia patients: BCL11A and HBS1L-MYB are the major modifiers of HbF in African Americans. Blood 120, 1961–1962 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Bernard, T. J. et al. Towards a consensus-based classification of childhood arterial ischemic stroke. Stroke 43, 371–377 (2012).

    Article  PubMed  Google Scholar 

  101. Bernard, T. J. et al. Inter-rater reliability of the CASCADE criteria: challenges in classifying arteriopathies. Stroke 47, 2443–2449 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Böhmer, M. et al. Impact of childhood arterial ischemic stroke standardized classification and diagnostic evaluation classification on further course of arteriopathy and recurrence of childhood stroke. Stroke 50, 83–87 (2019).

    Article  Google Scholar 

  103. Dlamini, N., Billinghurst, L. & Kirkham, F. J. Cerebral venous sinus (sinovenous) thrombosis in children. Neurosurg. Clin. North. Am. 21, 511–527 (2010).

    Article  Google Scholar 

  104. deVeber, G. et al. Cerebral sinovenous thrombosis in children. N. Engl. J. Med. 345, 417–423 (2001).

    Article  CAS  PubMed  Google Scholar 

  105. Stam, J. Thrombosis of the cerebral veins and sinuses. N. Engl. J. Med. 352, 1791–1799 (2005).

    Article  CAS  PubMed  Google Scholar 

  106. Ferro, J. M., Canhão, P., Stam, J., Bousser, M. G. & Barinagarrementeria, F. Prognosis of cerebral vein and dural sinus thrombosis: results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Stroke 35, 664–670 (2004).

    Article  PubMed  Google Scholar 

  107. Vecht, L., Zuurbier, S. M., Meijers, J. C. M. & Coutinho, J. M. Elevated factor VIII increases the risk of cerebral venous thrombosis: a case–control study. J. Neurol. 265, 1612–1617 (2018).

    Article  CAS  PubMed  Google Scholar 

  108. Sébire, G. et al. Cerebral venous sinus thrombosis in children: risk factors, presentation, diagnosis and outcome. Brain 128, 477–489 (2005).

    Article  PubMed  Google Scholar 

  109. Tsai, L. K., Jeng, J. S., Liu, H. M., Wang, H. J. & Yip, P. K. Intracranial dural arteriovenous fistulas with or without cerebral sinus thrombosis: analysis of 69 patients. J. Neurol. Neurosurg. Psychiatry 75, 1639–1641 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Morales, H., Jones, B. V., Leach, J. L. & Abruzzo, T. A. Documented development of a dural arteriovenous fistula in an infant subsequent to sinus thrombosis: case report and review of the literature. Neuroradiology 52, 225–229 (2010).

    Article  PubMed  Google Scholar 

  111. Boulouis, G. et al. Nontraumatic pediatric intracerebral hemorrhage. Stroke 50, 3654–3661 (2019).

    Article  PubMed  Google Scholar 

  112. Ferriero, D. M. et al. Management of stroke in neonates and children: a scientific statement from the American Heart Association/American Stroke Association. Stroke 50, e51–e96 (2019). A comprehensive scientific statement summarizing current literature, knowledge gaps and consensus opinions regarding diagnosis and treatment of paediatric stroke.

    Article  PubMed  Google Scholar 

  113. Wang, J. J. et al. Risk factors for arterial ischemic and hemorrhagic stroke in childhood. Pediatr. Neurol. 40, 277–281 (2009).

    Article  PubMed  Google Scholar 

  114. Lawton, M. T. et al. Brain arteriovenous malformations. Nat. Rev. Dis. Prim. 1, 1–20 (2015).

    Google Scholar 

  115. Kim, H., Al-Shahi Salman, R., McCulloch, C. E., Stapf, C. & Young, W. L. Untreated brain arteriovenous malformation: patient-level meta-analysis of hemorrhage predictors. Neurology 83, 590–597 (2014). Individual patient data meta-analysis identifying haemorrhagic presentation and increasing age as independent predictors of haemorrhage in children with bAVMs.

    Article  PubMed  PubMed Central  Google Scholar 

  116. Fullerton, H. J. et al. Long-term hemorrhage risk in children versus adults with brain arteriovenous malformations. Stroke 36, 2099–2104 (2005).

    Article  PubMed  Google Scholar 

  117. Oulasvirta, E. et al. Characteristics and long-term outcome of 127 children with cerebral arteriovenous malformations. Clin. Neurosurg. 84, 151–158 (2019).

    Article  Google Scholar 

  118. Hetts, S. W. et al. Influence of patient age on angioarchitecture of brain arteriovenous malformations. AJNR Am. J. Neuroradiol. 35, 1376–1380 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Garzelli, L. et al. Risk factors for early brain AVM rupture: cohort study of pediatric and adult patients. AJNR Am. J. Neuroradiol. 41, 2358–2363 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Klimo, P., Rao, G. & Brockmeyer, D. Pediatric arteriovenous malformations: a 15-year experience with an emphasis on residual and recurrent lesions. Childs Nerv. Syst. 23, 31–37 (2007).

    Article  PubMed  Google Scholar 

  121. Jhaveri, A. et al. Predictive value of MRI in diagnosing brain AVM recurrence after angiographically documented exclusion in children. AJNR Am. J. Neuroradiol. 40, 1227–1235 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Copelan, A. et al. Brain arteriovenous malformation recurrence after apparent microsurgical cure: increased risk in children who present with arteriovenous malformation rupture. Stroke 51, 2990–2996 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Sorenson, T. J., Brinjikji, W., Bortolotti, C., Kaufmann, G. & Lanzino, G. Recurrent brain arteriovenous malformations (AVMs): a systematic review. World Neurosurg. 116, e856–e866 (2018).

    Article  PubMed  Google Scholar 

  124. Sonstein, W. J. et al. Expression of vascular endothelial growth factor in pediatric and adult cerebral arteriovenous malformations: an immunocytochemical study. J. Neurosurg. 85, 838–845 (1996).

    Article  CAS  PubMed  Google Scholar 

  125. Nikolaev, S. I. et al. Somatic activating KRAS mutations in arteriovenous malformations of the brain. N. Engl. J. Med. 378, 250–261 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Hong, T. et al. High prevalence of KRAS/BRAF somatic mutations in brain and spinal cord arteriovenous malformations. Brain 142, 23–34 (2019).

    Article  PubMed  Google Scholar 

  127. Couto, J. A. et al. Somatic MAP2K1 mutations are associated with extracranial arteriovenous malformation. Am. J. Hum. Genet. 100, 546–554 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Al-Olabi, L. et al. Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy. J. Clin. Invest. 128, 1496–1508 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Braicu, C. et al. A comprehensive review on MAPK: a promising therapeutic target in cancer. Cancers 11, 1618 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  130. Bameri, O., Salarzaei, M. & Parooie, F. KRAS/BRAF mutations in brain arteriovenous malformations: a systematic review and meta-analysis. Interv. Neuroradiol. 27, 539–546 (2021).

    Article  PubMed  Google Scholar 

  131. Fish, J. E. et al. Somatic gain of KRAS function in the endothelium is sufficient to cause vascular malformations that require MEK but not PI3K signaling. Circ. Res. 127, 727–743 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Park, E. S. et al. Selective endothelial hyperactivation of oncogenic KRAS induces brain arteriovenous malformations in mice. Ann. Neurol. 89, 926–941 (2021).

    Article  CAS  PubMed  Google Scholar 

  133. Pan, P. et al. Review of treatment and therapeutic targets in brain arteriovenous malformation. J. Cereb. Blood Flow. Metab. 41, 3141–3156 (2021).

    Article  CAS  PubMed  Google Scholar 

  134. Kim, H., Su, H., Weinsheimer, S., Pawlikowska, L. & Young, W. L. Brain arteriovenous malformation pathogenesis: a response-to-injury paradigm. Acta Neurochir.Suppl. 111, 83–92 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Mouchtouris, N. et al. Biology of cerebral arteriovenous malformations with a focus on inflammation. J. Cereb. Blood Flow. Metab. 35, 167–175 (2015).

    Article  CAS  PubMed  Google Scholar 

  136. Zhang, R. et al. Persistent infiltration and pro-inflammatory differentiation of monocytes cause unresolved inflammation in brain arteriovenous malformation. Angiogenesis 19, 451–461 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Mcdonald, J. et al. Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis. Clin. Genet. 79, 335–344 (2011).

    Article  CAS  PubMed  Google Scholar 

  138. Pawlikowska, L. et al. The ACVRL1 c.314-35A>G polymorphism is associated with organ vascular malformations in hereditary hemorrhagic telangiectasia patients with ENG mutations, but not in patients with ACVRL1 mutations. Am. J. Med. Genet. A 167, 1262–1267 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Pawlikowska, L. et al. Polymorphisms in transforming growth factor-β-related genes ALK1 and ENG are associated with sporadic brain arteriovenous malformations. Stroke 36, 2278–2280 (2005).

    Article  CAS  PubMed  Google Scholar 

  140. Boshuisen, K. et al. Polymorphisms in ACVRL1 and endoglin genes are not associated with sporadic and HHT-related brain AVMs in Dutch patients. Transl. Stroke Res. 4, 375–378 (2013).

    Article  CAS  PubMed  Google Scholar 

  141. Kilian, A. et al. Genotype–phenotype correlations in children with HHT. J. Clin. Med. 9, 2714 (2020).

    Article  PubMed Central  Google Scholar 

  142. Kim, H. et al. Hemorrhage rates from brain arteriovenous malformation in patients with hereditary hemorrhagic telangiectasia. Stroke 46, 1362–1364 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Eerola, I. et al. Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am. J. Hum. Genet. 73, 1240–1249 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Revencu, N. et al. RASA1 mutations and associated phenotypes in 68 families with capillary malformation-arteriovenous malformation. Hum. Mutat. 34, 1632–1641 (2013).

    Article  CAS  PubMed  Google Scholar 

  145. Amyere, M. et al. Germline loss-of-function mutations in EPHB4 cause a second form of capillary malformation-arteriovenous malformation (CM-AVM2) deregulating RAS-MAPK signaling. Circulation 136, 1037–1048 (2017).

    Article  CAS  PubMed  Google Scholar 

  146. Wooderchak-Donahue, W. L. et al. Phenotype of CM-AVM2 caused by variants in EPHB4: how much overlap with hereditary hemorrhagic telangiectasia (HHT)? Genet. Med. 21, 2007–2014 (2019).

    Article  PubMed  Google Scholar 

  147. Vivanti, A. et al. Loss of function mutations in EPHB4 are responsible for vein of Galen aneurysmal malformation. Brain 141, 979–988 (2018).

    Article  PubMed  Google Scholar 

  148. Weinsheimer, S. et al. EPHB4 gene polymorphisms and risk of intracranial hemorrhage in patients with brain arteriovenous malformations. Circ. Cardiovasc. Genet. 2, 476–482 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Fehnel, K. P. et al. Dysregulation of the EphrinB2−EphB4 ratio in pediatric cerebral arteriovenous malformations is associated with endothelial cell dysfunction in vitro and functions as a novel noninvasive biomarker in patients. Exp. Mol. Med. 52, 658–671 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Whitehead, K. J. et al. The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases. Nat. Med. 15, 177–184 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Stockton, R. A., Shenkar, R., Awad, I. A. & Ginsberg, M. H. Cerebral cavernous malformations proteins inhibit Rho kinase to stabilize vascular integrity. J. Exp. Med. 207, 881–896 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Borikova, A. L. et al. Rho kinase inhibition rescues the endothelial cell cerebral cavernous malformation phenotype. J. Biol. Chem. 285, 11760–11764 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Ren, A. A. et al. PIK3CA and CCM mutations fuel cavernomas through a cancer-like mechanism. Nature 594, 271–276 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Shenkar, R., Shi, C., Check, I. J., Lipton, H. L. & Awad, I. A. Concepts and hypotheses: inflammatory hypothesis in the pathogenesis of cerebral cavernous malformations. Neurosurgery 61, 693–702 (2007).

    Article  PubMed  Google Scholar 

  155. Shi, C. et al. Immune response in human cerebral cavernous malformations. Stroke 40, 1659–1665 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Tan, H. et al. Quantitative susceptibility mapping in cerebral cavernous malformations: clinical correlations. AJNR Am. J. Neuroradiol. 37, 1209–1215 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Tang, A. T. et al. Endothelial TLR4 and the microbiome drive cerebral cavernous malformations. Nature 545, 305–310 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Tang, A. T. et al. Distinct cellular roles for PDCD10 define a gut-brain axis in cerebral cavernous malformation. Sci. Transl. Med. 11, eaaw3521 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Polster, S. P. et al. Permissive microbiome characterizes human subjects with a neurovascular disease cavernous angioma. Nat. Commun. 11, 2659 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Choquet, H. et al. Polymorphisms in inflammatory and immune response genes associated with cerebral cavernous malformation type 1 severity. Cerebrovasc. Dis. 38, 433–440 (2014).

    Article  CAS  PubMed  Google Scholar 

  161. Girard, R. et al. Plasma biomarkers of inflammation reflect seizures and hemorrhagic activity of cerebral cavernous malformations. Transl. Stroke Res. 9, 34–43 (2018).

    Article  CAS  PubMed  Google Scholar 

  162. Petersen, T. A., Morrison, L. A., Schrader, R. M. & Hart, B. L. Familial versus sporadic cavernous malformations: differences in developmental venous anomaly association and lesion phenotype. AJNR Am. J. Neuroradiol. 31, 377–382 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Gross, B. A., Du, R., Orbach, D. B., Scott, R. M. & Smith, E. R. The natural history of cerebral cavernous malformations in children. J. Neurosurg. Pediatr. 17, 123–128 (2016).

    Article  PubMed  Google Scholar 

  164. Gastelum, E. et al. Rates and characteristics of radiographically detected intracerebral cavernous malformations after cranial radiation therapy in pediatric cancer patients. J. Child. Neurol. 30, 842–849 (2015).

    Article  PubMed  Google Scholar 

  165. Shenkar, R. et al. Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations. Genet. Med. 17, 188–196 (2015).

    Article  CAS  PubMed  Google Scholar 

  166. Riant, F. et al. CCM3 mutations are associated with early-onset cerebral hemorrhage and multiple meningiomas. Mol. Syndromol. 4, 165–172 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Lee, K. S. Cerebral cavernous malformations: incidence and familial occurrence. Surg. Gynecol. Obstet. 170, 59 (1990).

    Google Scholar 

  168. Laurans, M. S. H. et al. Mutational analysis of 206 families with cavernous malformations. J. Neurosurg. 99, 38–43 (2003).

    Article  CAS  PubMed  Google Scholar 

  169. Akers, A. et al. Synopsis of guidelines for the clinical management of cerebral cavernous malformations: consensus recommendations based on systematic literature review by the Angioma Alliance Scientific Advisory Board clinical experts panel. Clin. Neurosurg. 80, 665–680 (2017).

    Article  Google Scholar 

  170. Salman, R. A. S. et al. Untreated clinical course of cerebral cavernous malformations: a prospective, population-based cohort study. Lancet Neurol. 11, 217–224 (2012).

    Article  Google Scholar 

  171. Horne, M. A. et al. Clinical course of untreated cerebral cavernous malformations: a meta-analysis of individual patient data. Lancet Neurol. 15, 166–173 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  172. Al-Holou, W. N. et al. Natural history and imaging prevalence of cavernous malformations in children and young adults. Clinical article. J. Neurosurg. Pediatr. 9, 198–205 (2012).

    Article  PubMed  Google Scholar 

  173. Jordan, L. C., Johnston, S. C., Wu, Y. W., Sidney, S. & Fullerton, H. J. The importance of cerebral aneurysms in childhood hemorrhagic stroke: a population-based study. Stroke 40, 400–405 (2009).

    Article  PubMed  Google Scholar 

  174. Chalouhi, N., Hoh, B. L. & Hasan, D. Review of cerebral aneurysm formation, growth, and rupture. Stroke 44, 3613–3622 (2013).

    Article  PubMed  Google Scholar 

  175. Krings, T., Geibprasert, S. & TerBrugge, K. G. Pathomechanisms and treatment of pediatric aneurysms. Child’s Nerv. Syst. 26, 1309–1318 (2010).

    Article  Google Scholar 

  176. Zhou, S., Dion, P. A. & Rouleau, G. A. Genetics of intracranial aneurysms. Stroke 49, 780–787 (2018).

    Article  PubMed  Google Scholar 

  177. Bakker, M. K. et al. Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors. Nat. Genet. 52, 1303–1313 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Bendjilali, N. et al. Common variants on 9p21.3 are associated with brain arteriovenous malformations with accompanying arterial aneurysms. J. Neurol. Neurosurg. Psychiatry 85, 1280–1283 (2014).

    Article  PubMed  Google Scholar 

  179. Hetts, S. W. et al. Intracranial aneurysms in childhood: 27-year single-institution experience. AJNR Am. J. Neuroradiol. 30, 1315–1324 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Huang, J., McGirt, M. J., Gailloud, P. & Tamargo, R. J. Intracranial aneurysms in the pediatric population: case series and literature review. Surg. Neurol. 63, 424–432 (2005).

    Article  PubMed  Google Scholar 

  181. Garg, N., Khunger, M., Gupta, A. & Kumar, N. Optimal management of hereditary hemorrhagic telangiectasia. J. Blood Med. 5, 191–206 (2014).

    PubMed  PubMed Central  Google Scholar 

  182. Lasjaunias, P., Wuppalapati, S., Alvarez, H., Rodesch, G. & Ozanne, A. Intracranial aneurysms in children aged under 15 years: review of 59 consecutive children with 75 aneurysms. Childs Nerv. Syst. 21, 437–450 (2005).

    Article  PubMed  Google Scholar 

  183. De Rooij, N. K., Linn, F. H. H., Van Der Plas, J. A., Algra, A. & Rinkel, G. J. E. Incidence of subarachnoid haemorrhage: a systematic review with emphasis on region, age, gender and time trends. J. Neurol. Neurosurg. Psychiatry 78, 1365–1372 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  184. Vlak, M. H. M., Algra, A., Brandenburg, R. & Rinkel, G. J. E. Prevalence of unruptured intracranial aneurysms, with emphasis on sex, age, comorbidity, country, and time period: a systematic review and meta-analysis. Lancet Neurol. 10, 626–636 (2011).

    Article  PubMed  Google Scholar 

  185. Hetts, S. W. et al. Pediatric intracranial aneurysms: new and enlarging aneurysms after index aneurysm treatment or observation. AJNR Am. J. Neuroradiol. 32, 2017–2022 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Yock-Corrales, A., MacKay, M. T., Mosley, I., Maixner, W. & Babl, F. E. Acute childhood arterial ischemic and hemorrhagic stroke in the emergency department. Ann. Emerg. Med. 58, 156–163 (2011).

    Article  PubMed  Google Scholar 

  187. Mackay, M. T. et al. Differentiating childhood stroke from mimics in the emergency department. Stroke 47, 2476–2481 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  188. Chadehumbe, M. A. et al. Seizures are common in the acute setting of childhood stroke: a population-based study. J. Child. Neurol. 24, 9–12 (2009).

    Article  PubMed  Google Scholar 

  189. Abend, N. S. et al. Seizures as a presenting symptom of acute arterial ischemic stroke in childhood. J. Pediatr. 159, 479–483 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  190. Singh, R. K. et al. Seizures in acute childhood stroke. J. Pediatr. 160, 291–296 (2012).

    Article  PubMed  Google Scholar 

  191. Beslow, L. A. et al. Predictors of outcome in childhood intracerebral hemorrhage: a prospective consecutive cohort study. Stroke 41, 313–318 (2010).

    Article  PubMed  Google Scholar 

  192. Braun, K. P. J., Rafay, M. F., Uiterwaal, C. S. P. M., Pontigon, A. M. & DeVeber, G. Mode of onset predicts etiological diagnosis of arterial ischemic stroke in children. Stroke 38, 298–302 (2007).

    Article  PubMed  Google Scholar 

  193. Ichord, R. N. et al. Interrater reliability of the Pediatric National Institutes of Health Stroke Scale (PedNIHSS) in a multicenter study. Stroke 42, 613–617 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  194. Indave, B. I. et al. Risk of stroke in prescription and other amphetamine-type stimulants use: a systematic review. Drug Alcohol. Rev. 37, 56–69 (2018).

    Article  PubMed  Google Scholar 

  195. Li, F. et al. Oral contraceptive use and increased risk of stroke: a dose–response meta-analysis of observational studies. Front. Neurol. 10, 993 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Reith, W. et al. Multislice diffusion mapping for 3-d evolution of cerebral ischemia in a rat stroke model. Neurology 45, 172–177 (1995).

    Article  CAS  PubMed  Google Scholar 

  197. Thomalla, G. et al. MRI-guided thrombolysis for stroke with unknown time of onset. N. Engl. J. Med. 379, 611–622 (2018).

    Article  PubMed  Google Scholar 

  198. Thomalla, G. et al. DWI-FLAIR mismatch for the identification of patients with acute ischaemic stroke within 4·5 h of symptom onset (PRE-FLAIR): a multicentre observational study. Lancet Neurol. 10, 978–986 (2011).

    Article  PubMed  Google Scholar 

  199. Ladner, T. R. et al. Pediatric acute stroke protocol activation in a children’s hospital emergency department. Stroke. 46, 2328–2331 (2015).

    Article  PubMed  Google Scholar 

  200. Albers, G. W. et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N. Engl. J. Med. 378, 708–718 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  201. Nogueira, R. G. et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N. Engl. J. Med. 378, 11–21 (2018).

    Article  PubMed  Google Scholar 

  202. Lee, S. et al. Neuroimaging selection for thrombectomy in pediatric stroke: a single-center experience. J. Neurointerv. Surg. 11, 940–946 (2019).

    Article  PubMed  Google Scholar 

  203. Dlamini, N. et al. Arterial wall imaging in pediatric stroke. Stroke 49, 891–898 (2018).

    Article  PubMed  Google Scholar 

  204. Edjlali, M. et al. Circumferential thick enhancement at vessel wall MRI has high specificity for intracranial aneurysm instability. Radiology 289, 181–187 (2018).

    Article  PubMed  Google Scholar 

  205. Wang, X., Zhu, C., Leng, Y., Degnan, A. J. & Lu, J. Intracranial aneurysm wall enhancement associated with aneurysm rupture: a systematic review and meta-analysis. Acad. Radiol. 26, 664–673 (2019).

    Article  PubMed  Google Scholar 

  206. Matouk, C. C. et al. Vessel wall magnetic resonance imaging identifies the site of rupture in patients with multiple intracranial aneurysms: proof of principle. Neurosurgery 72, 492–496 (2013).

    Article  PubMed  Google Scholar 

  207. Bhogal, P. et al. Vessel wall enhancement of a ruptured intra-nidal aneurysm in a brain arteriovenous malformation. Interv. Neuroradiol. 25, 310–314 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  208. Ganesan, V., Savvy, L., Chong, W. K. & Kirkham, F. J. Conventional cerebral angiography in children with ischemic stroke. Pediatr. Neurol. 20, 38–42 (1999).

    Article  CAS  PubMed  Google Scholar 

  209. Husson, B. & Lasjaunias, P. Radiological approach to disorders of arterial brain vessels associated with childhood arterial stroke – a comparison between MRA and contrast angiography. Pediatr. Radiol. 34, 10–15 (2004).

    Article  PubMed  Google Scholar 

  210. Kirton, A. et al. Fibromuscular dysplasia and childhood stroke. Brain 136, 1846–1856 (2013).

    Article  PubMed  Google Scholar 

  211. Aviv, R. I. et al. MR imaging and angiography of primary CNS vasculitis of childhood. AJNR Am. J. Neuroradiol. 27, 192–199 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. Scott, R. M. & Smith, E. R. Moyamoya disease and moyamoya syndrome. N. Engl. J. Med. 360, 1226–1237 (2009).

    Article  CAS  PubMed  Google Scholar 

  213. Sporns, P. B. et al. Neuroimaging of pediatric intracerebral hemorrhage. J. Clin. Med. 9, 1518 (2020).

    Article  PubMed Central  Google Scholar 

  214. Jimenez, J. E. et al. Role of follow-up imaging after resection of brain arteriovenous malformations in pediatric patients: a systematic review of the literature. J. Neurosurg. Pediatr. 19, 149–156 (2017).

    Article  PubMed  Google Scholar 

  215. Messé, S. R. et al. Practice advisory update summary: patent foramen ovale and secondary stroke prevention: report of the Guideline Subcommittee of the American Academy of Neurology. Neurology 94, 876–885 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  216. Shih, E. K. et al. Prevalence of patent foramen ovale in a cohort of children with cryptogenic ischemic stroke. Neurology 97, e2096–e2102 (2021).

    Article  CAS  PubMed  Google Scholar 

  217. Meier, N. M., Foster, M. L. & Battaile, J. T. Hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations: clinical aspects. Cardiovasc. Diagn. Ther. 8, 316–324 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  218. Haywood, S., Liesner, R., Pindora, S. & Ganesan, V. Thrombophilia and first arterial ischaemic stroke: a systematic review. Arch. Dis. Child. 90, 402–405 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Sträter, R. et al. Prospective assessment of risk factors for recurrent stroke during childhood– a 5-year follow-up study. Lancet 360, 1540–1545 (2002).

    Article  PubMed  Google Scholar 

  220. Mackay, M. T. et al. Stroke and nonstroke brain attacks in children. Neurology 82, 1434–1440 (2014).

    Article  PubMed  Google Scholar 

  221. Shellhaas, R. A., Smith, S. E., O’Tool, E., Licht, D. J. & Ichord, R. N. Mimics of childhood stroke: characteristics of a prospective cohort. Pediatrics 118, 704–709 (2006).

    Article  PubMed  Google Scholar 

  222. DeLaroche, A. M., Sivaswamy, L., Farooqi, A. & Kannikeswaran, N. Pediatric stroke clinical pathway improves the time to diagnosis in an emergency department. Pediatr. Neurol. 65, 39–44 (2016).

    Article  PubMed  Google Scholar 

  223. Mackay, M. T. et al. Differentiating arterial ischaemic stroke from migraine in the paediatric emergency department. Dev. Med. Child. Neurol. 60, 1117–1122 (2018).

    Article  PubMed  Google Scholar 

  224. McGlennan, C. & Ganesan, V. Delays in investigation and management of acute arterial ischaemic stroke in children. Dev. Med. Child. Neurol. 50, 537–540 (2008).

    Article  PubMed  Google Scholar 

  225. Rafay, M. F. et al. Delay to diagnosis in acute pediatric arterial ischemic stroke. Stroke 40, 58–64 (2009).

    Article  PubMed  Google Scholar 

  226. Srinivasan, J., Miller, S. P., Phan, T. G. & Mackay, M. T. Delayed recognition of initial stroke in children: need for increased awareness. Pediatrics 124, e227–e234 (2009).

    Article  PubMed  Google Scholar 

  227. Mallick, A. A. et al. Diagnostic delays in paediatric stroke. J. Neurol. Neurosurg. Psychiatry 86, 917–921 (2015).

    Article  PubMed  Google Scholar 

  228. Yock-Corrales, A. & Barnett, P. The role of imaging studies for evaluation of stroke in children. Pediatr. Emerg. Care 27, 966–967 (2011).

    Article  PubMed  Google Scholar 

  229. Stojanovski, B. et al. Prehospital emergency care in childhood arterial ischemic stroke. Stroke 48, 1095–1097 (2017).

    Article  PubMed  Google Scholar 

  230. Adams, R. & Brambilla, D. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. N. Engl. J. Med. 353, 2769–2778 (2005).

    Article  CAS  PubMed  Google Scholar 

  231. Ware, R. E. et al. Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia–TCD with Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial. Lancet 387, 661–670 (2016).

    Article  CAS  PubMed  Google Scholar 

  232. Giglia, T. M. et al. Prevention and treatment of thrombosis in pediatric and congenital heart disease: a scientific statement from the American Heart Association. Circulation 128, 2622–2703 (2013).

    Article  PubMed  Google Scholar 

  233. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group.Tissue plasminogen activator for acute ischemic stroke. N. Engl. J. Med. 333, 1581–1587 (1995).

    Article  Google Scholar 

  234. Amlie-Lefond, C. et al. Use of alteplase in childhood arterial ischaemic stroke: a multicentre, observational, cohort study. Lancet Neurol. 8, 530–536 (2009).

    Article  PubMed  Google Scholar 

  235. Rivkin, M. J. et al. Thrombolysis in Pediatric Stroke Study. Stroke 46, 880–885 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  236. Amlie-Lefond, C. et al. Risk of intracranial hemorrhage following intravenous tPA (tissue-type plasminogen activator) for acute stroke is low in children. Stroke 51, 542–548 (2020). Retrospective cohort study evaluating the largest cohort of children treated with intravenous alteplase suggesting that the incidence of symptomatic intracranial haemorrhage is low.

    Article  PubMed  Google Scholar 

  237. Monagle, P. et al. Developmental haemostasis. Impact for clinical haemostasis laboratories. Thromb. Haemost. 95, 362–372 (2006).

    Article  CAS  PubMed  Google Scholar 

  238. Aguiar de Sousa, D. et al. Access to and delivery of acute ischaemic stroke treatments: a survey of national scientific societies and stroke experts in 44 European countries. Eur. Stroke J. 4, 13–28 (2019).

    Article  PubMed  Google Scholar 

  239. Schwamm, L. H. et al. Temporal trends in patient characteristics and treatment with intravenous thrombolysis among acute ischemic stroke patients at Get With the Guidelines–Stroke Hospitals. Circ. Cardiovasc. Qual. Outcomes 6, 543–549 (2013).

    Article  PubMed  Google Scholar 

  240. Ghandehari, K. Barriers of thrombolysis therapy in developing countries. Stroke Res. Treat. 2011, 686797 (2011).

    PubMed  PubMed Central  Google Scholar 

  241. Goyal, M. et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet 387, 1723–1731 (2016).

    Article  PubMed  Google Scholar 

  242. Sporns, P. B. et al. Thrombectomy in childhood stroke. J. Am. Heart Assoc. 8, e011335 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  243. Bigi, S. et al. Feasibility, safety and outcome of recanalisation treatment in childhood stroke. Ann. Neurol. 83, 1125–1132 (2018).

    Article  PubMed  Google Scholar 

  244. Sporns, P. B. et al. Feasibility, safety, and outcome of endovascular recanalization in childhood stroke: the Save ChildS Study. JAMA Neurol. 77, 25–34 (2020). A large multicentre study demonstrating the safety of mechanical thrombectomy in children.

    Article  PubMed  Google Scholar 

  245. Sporns, P. B. et al. Clinical diffusion mismatch to select pediatric patients for embolectomy 6 to 24 hours after stroke: an analysis of the Save ChildS Study. Neurology 96, e343–e351 (2021). A secondary analysis of the Save ChildS Study providing evidence that extending thrombectomy to >6 h after onset is possible using CT perfusion or MRI diffusion/perfusion imaging.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Chabrier, S. et al. Hyperacute recanalization strategies and childhood stroke in the evidence age. Stroke 52, 381–384 (2021).

    Article  PubMed  Google Scholar 

  247. Sun, L. R. et al. Mechanical thrombectomy for acute ischemic stroke: considerations in children. Stroke 51, 3174–3181 (2020).

    Article  PubMed  Google Scholar 

  248. Sun, L. R. et al. Endovascular therapy for acute stroke in children: age and size technical limitations. J. Neurointerv. Surg. 13, 794–798 (2021).

    Article  PubMed  Google Scholar 

  249. Sporns, P. B. & Psychogios, M. Thrombectomy in childhood stroke: important considerations in borderline indications. Stroke 51, 2890–2891 (2020).

    Article  PubMed  Google Scholar 

  250. Sporns, P. B. et al. Expanding indications for endovascular thrombectomy–how to leave no patient behind. Ther. Adv. Neurol. Disord. 14, 1756286421998905 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  251. Sporns, P. B. et al. Does device selection impact recanalization rate and neurological outcome? An analysis of the Save ChildS Study. Stroke 51, 1182–1189 (2020).

    Article  PubMed  Google Scholar 

  252. Sporns, P. B. et al. A prospective multicenter registry on feasibility, safety, and outcome of endovascular recanalization in childhood stroke (Save ChildS Pro). Front. Neurol. 12, 736092 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  253. Martins, S. O. et al. Thrombectomy for stroke in the public health care system of Brazil. N. Engl. J. Med. 382, 2316–2326 (2020).

    Article  PubMed  Google Scholar 

  254. Bhatti, A. et al. Mechanical thrombectomy using retrievable stents in pediatric acute ischemic stroke. Indian. Pediatr. 56, 571–575 (2019).

    Article  PubMed  Google Scholar 

  255. Pan, Y. et al. Cost-effectiveness of mechanical thrombectomy within 6 h of acute ischaemic stroke in China. BMJ Open 8, e018951 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  256. Laage Gaupp, F. M. et al. Tanzania IR initiative: training the first generation of interventional radiologists. J. Vasc. Interv. Radiol. 30, 2036–2040 (2019).

    Article  PubMed  Google Scholar 

  257. Capes, S. E., Hunt, D., Malmberg, K., Pathak, P. & Gerstein, H. C. Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke 32, 2426–2432 (2001).

    Article  CAS  PubMed  Google Scholar 

  258. Grelli, K. N., Gindville, M. C., Walker, C. H. & Jordan, L. C. Association of blood pressure, blood glucose, and temperature with neurological outcome after childhood stroke. JAMA Neurol. 73, 829–835 (2016).

    Article  PubMed  Google Scholar 

  259. Azzimondi, G. et al. Fever in acute stroke worsens prognosis: a prospective study. Stroke 26, 2040–2043 (1995).

    Article  CAS  PubMed  Google Scholar 

  260. Reith, J. et al. Body temperature in acute stroke: relation to stroke severity, infarct size, mortality, and outcome. Lancet 347, 422–425 (1996).

    Article  CAS  PubMed  Google Scholar 

  261. Li, J. & Jiang, J. Y. Chinese head trauma data bank: effect of hyperthermia on the outcome of acute head trauma patients. J. Neurotrauma 29, 96–100 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  262. Adil, M. M., Beslow, L. A., Qureshi, A. I., Malik, A. A. & Jordan, L. C. Hypertension is associated with increased mortality in children hospitalized with arterial ischemic stroke. Pediatr. Neurol. 56, 25–29 (2016).

    Article  PubMed  Google Scholar 

  263. Mackey, J. et al. Prophylactic anticonvulsants in intracerebral hemorrhage. Neurocrit. Care 27, 220–228 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  264. Zandieh, A., Messé, S. R., Cucchiara, B., Mullen, M. T. & Kasner, S. E. Prophylactic use of antiepileptic drugs in patients with spontaneous intracerebral hemorrhage. J. Stroke Cerebrovasc. Dis. 25, 2159–2166 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  265. Chesnut, R. M. et al. A trial of intracranial-pressure monitoring in traumatic brain injury. N. Engl. J. Med. 367, 2471–2481 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Kochanek, P. M. et al. Guidelines for the management of pediatric severe traumatic brain injury, third edition: update of the Brain Trauma Foundation guidelines, executive summary. Clin. Neurosurg. 84, 1169–1178 (2019).

    Article  Google Scholar 

  267. Poungvarin, N. et al. Effects of dexamethasone in primary supratentorial intracerebral hemorrhage. N. Engl. J. Med. 316, 1229–1233 (1987).

    Article  CAS  PubMed  Google Scholar 

  268. Das, S., Mitchell, P., Ross, N. & Whitfield, P. C. Decompressive hemicraniectomy in the treatment of malignant middle cerebral artery infarction: a meta-analysis. World Neurosurg. 123, 8–16 (2019).

    Article  PubMed  Google Scholar 

  269. Smith, S. E. et al. Outcome following decompressive craniectomy for malignant middle cerebral artery infarction in children. Dev. Med. Child. Neurol. 53, 29–33 (2011).

    Article  PubMed  Google Scholar 

  270. Rahme, R. et al. Malignant MCA territory infarction in the pediatric population: subgroup analysis of the Greater Cincinnati/Northern Kentucky Stroke Study. Childs Nerv. Syst. 29, 99–103 (2013).

    Article  PubMed  Google Scholar 

  271. Shah, S., Murthy, S. B., Whitehead, W. E., Jea, A. & Nassif, L. M. Decompressive hemicraniectomy in pediatric patients with malignant middle cerebral artery infarction: case series and review of the literature. World Neurosurg. 80, 126–133 (2013).

    Article  PubMed  Google Scholar 

  272. Mathew, P., Teasdale, G., Bannan, A. & Oluoch-Olunya, D. Neurosurgical management of cerebellar haematoma and infarct. J. Neurol. Neurosurg. Psychiatry 59, 287–292 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  273. Lambertsen, K. L., Finsen, B. & Clausen, B. H. Post-stroke inflammation–target or tool for therapy? Acta Neuropathol. 137, 693–714 (2019).

    Article  PubMed  Google Scholar 

  274. Steinlin, M., O’callaghan, F. & Mackay, M. T. Planning interventional trials in childhood arterial ischaemic stroke using a Delphi consensus process. Dev. Med. Child. Neurol. 59, 713–718 (2017).

    Article  PubMed  Google Scholar 

  275. Park, Y., Fullerton, H. J. & Elm, J. J. A pragmatic, adaptive clinical trial design for a rare disease: the FOcal Cerebral Arteriopathy Steroid (FOCAS) trial. Contemp. Clin. Trials 86, 105852 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  276. Goldenberg, N. A. et al. Antithrombotic treatments, outcomes, and prognostic factors in acute childhood-onset arterial ischaemic stroke: a multicentre, observational, cohort study. Lancet Neurol. 8, 1120–1127 (2009).

    Article  CAS  PubMed  Google Scholar 

  277. Stacey, A., Toolis, C. & Ganesan, V. Rates and risk factors for arterial ischemic stroke recurrence in children. Stroke 49, 842–847 (2018).

    Article  PubMed  Google Scholar 

  278. Bernard, T. J. et al. Anticoagulation in childhood-onset arterial ischemic stroke with non-moyamoya arteriopathy: findings from the Colorado and German (COAG) collaboration. Stroke 40, 2869–2871 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  279. Medley, T. L. et al. Australian Clinical Consensus Guideline: the diagnosis and acute management of childhood stroke. Int. J. Stroke 14, 94–106 (2019).

    Article  PubMed  Google Scholar 

  280. Darteyre, S. et al. Lack of progressive arteriopathy and stroke recurrence among children with cryptogenic stroke. Neurology 79, 2342–2348 (2012).

    Article  PubMed  Google Scholar 

  281. Estcourt, L. J., Kohli, R., Hopewell, S., Trivella, M. & Wang, W. C. Blood transfusion for preventing primary and secondary stroke in people with sickle cell disease. Cochrane Database Syst. Rev. 7, CD003146 (2020).

    PubMed  Google Scholar 

  282. Appireddy, R. et al. Surgery for moyamoya disease in children. J. Child. Neurol. 34, 517–529 (2019).

    Article  PubMed  Google Scholar 

  283. Newman, S., Boulter, J. H., Malcolm, J. G., Pradilla, I. & Pradilla, G. Outcomes in patients with moyamoya syndrome and sickle cell disease: a systematic review. World Neurosurg. 135, 165–170 (2020).

    Article  PubMed  Google Scholar 

  284. Giustini, A. J., Stone, S. A. & Ramamoorthy, C. Moyamoya disease in children and its anesthetic implications: a review. Paediatric Anaesth. 30, 1191–1198 (2020).

    Article  Google Scholar 

  285. Mohr, J. P. et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet 383, 614–621 (2014).

    Article  CAS  PubMed  Google Scholar 

  286. Mohr, J. P. et al. Functional impairments for outcomes in a randomized trial of unruptured brain AVMs. Neurology 89, 1499–1506 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  287. Mohr, J. P. et al. Medical management with interventional therapy versus medical management alone for unruptured brain arteriovenous malformations (ARUBA): final follow-up of a multicentre, non-blinded, randomised controlled trial. Lancet Neurol. 19, 573–581 (2020).

    Article  PubMed  Google Scholar 

  288. Molyneux, A. J. et al. Risk of recurrent subarachnoid haemorrhage, death, or dependence and standardised mortality ratios after clipping or coiling of an intracranial aneurysm in the International Subarachnoid Aneurysm Trial (ISAT): long-term follow-up. Lancet Neurol. 8, 427–433 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  289. Molyneux, A. J. et al. International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm occlusion. Lancet 366, 809–817 (2005).

    Article  PubMed  Google Scholar 

  290. Sanchez-Mejia, R. O. et al. Superior outcomes in children compared with adults after microsurgical resection of brain arteriovenous malformations. J. Neurosurg. 105, 82–87 (2006).

    PubMed  Google Scholar 

  291. Derdeyn, C. P. et al. Management of brain arteriovenous malformations: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 48, e200–e224 (2017).

    Article  PubMed  Google Scholar 

  292. Spetzler, R. F. & Martin, N. A. A proposed grading system for arteriovenous malformations. J. Neurosurg. 65, 476–483 (1986).

    Article  CAS  PubMed  Google Scholar 

  293. Stricker, S. et al. Acute surgical management of children with ruptured brain arteriovenous malformation. J. Neurosurg. Pediatr. 27, 437–445 (2021).

    Article  PubMed  Google Scholar 

  294. Ravindra, V. M. et al. A study of pediatric cerebral arteriovenous malformations: clinical presentation, radiological features, and long-term functional and educational outcomes with predictors of sustained neurological deficits. J. Neurosurg. Pediatr. 24, 1–8 (2019).

    Article  PubMed  Google Scholar 

  295. Deng, Z. et al. Long-term outcomes and prognostic predictors of 111 pediatric hemorrhagic cerebral arteriovenous malformations after microsurgical resection: a single-center experience. Neurosurg. Rev. 44, 915–923 (2021).

    Article  PubMed  Google Scholar 

  296. Yang, W. et al. Long-term hemorrhagic risk in pediatric patients with arteriovenous malformations. J. Neurosurg. Pediatr. 18, 329–338 (2016).

    Article  PubMed  Google Scholar 

  297. Gross, B. A., Storey, A., Orbach, D. B., Scott, R. M. & Smith, E. R. Microsurgical treatment of arteriovenous malformations in pediatric patients: the Boston Children’s Hospital experience. J. Neurosurg. Pediatr. 15, 71–77 (2015).

    Article  PubMed  Google Scholar 

  298. Terada, A., Komiyama, M., Ishiguro, T., Niimi, Y. & Oishi, H. Nationwide survey of pediatric intracranial arteriovenous shunts in Japan: Japanese Pediatric Arteriovenous Shunts Study (JPAS). J. Neurosurg. Pediatr. 22, 550–558 (2018).

    Article  PubMed  Google Scholar 

  299. Börcek, A. Ö., Çeltikçi, E., Aksogˇan, Y. & Rousseau, M. J. Clinical outcomes of stereotactic radiosurgery for cerebral arteriovenous malformations in pediatric patients: systematic review and meta-analysis. Clin. Neurosurg. 85, E629–E640 (2019).

    Article  Google Scholar 

  300. Chen, C. J. et al. Stereotactic radiosurgery for unruptured versus ruptured pediatric brain arteriovenous malformations. Stroke 50, 2745–2751 (2019).

    Article  CAS  PubMed  Google Scholar 

  301. Walcott, B. P. et al. Proton beam stereotactic radiosurgery for pediatric cerebral arteriovenous malformations. Neurosurgery 74, 367–373 (2014).

    Article  PubMed  Google Scholar 

  302. Rajshekhar, V. et al. Results of a conservative dose plan linear accelerator-based stereotactic radiosurgery for pediatric intracranial arteriovenous malformations. World Neurosurg. 95, 425–433 (2016).

    Article  PubMed  Google Scholar 

  303. Alexander, M. D. et al. Targeted embolization of aneurysms associated with brain arteriovenous malformations at high risk for surgical resection: a case-control study. Clin. Neurosurg. 82, 343–349 (2018).

    Article  Google Scholar 

  304. Lin, N., Smith, E. R., Scott, R. M. & Orbach, D. B. Safety of neuroangiography and embolization in children: complication analysis of 697 consecutive procedures in 394 patients. J. Neurosurg. Pediatr. 16, 432–438 (2015).

    Article  PubMed  Google Scholar 

  305. Faughnan, M. E. et al. Second international guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia. Ann. Intern. Med. 173, 989–1001 (2020).

    Article  PubMed  Google Scholar 

  306. Meybodi, A. T. et al. Surgical treatment vs nonsurgical treatment for brain arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia: a retrospective multicenter consortium study. Neurosurgery 82, 35–47 (2018).

    Article  PubMed  Google Scholar 

  307. Krings, T. et al. Hereditary hemorrhagic telangiectasia in children: endovascular treatment of neurovascular malformations. Neuroradiology 47, 946–954 (2005).

    Article  CAS  PubMed  Google Scholar 

  308. Weon, Y. C. et al. Supratentorial cerebral arteriovenous fistulas (AVFs) in children: review of 41 cases with 63 non choroidal single-hole AVFs. Acta Neurochir. 147, 17–31 (2005).

    Article  CAS  PubMed  Google Scholar 

  309. Hetts, S. W. et al. Pediatric intracranial dural arteriovenous fistulas: age-related differences in clinical features, angioarchitecture, and treatment outcomes. J. Neurosurg. Pediatr. 18, 602–610 (2016).

    Article  PubMed  Google Scholar 

  310. Yasin, J. T. et al. Treatment of pediatric intracranial aneurysms: case series and meta-analysis. J. Neurointerv. Surg. 11, 257–264 (2019).

    Article  PubMed  Google Scholar 

  311. Cherian, J. et al. Flow diversion for treatment of intracranial aneurysms in pediatric patients: multicenter case series. Neurosurgery 87, 53–62 (2020).

    Article  PubMed  Google Scholar 

  312. Kalani, M. Y. S. et al. Revascularization and pediatric aneurysm surgery: clinical article. J. Neurosurg. Pediatr. 13, 641–646 (2014).

    Article  PubMed  Google Scholar 

  313. Alawieh, A., Chaudry, M. I., Turner, R. D., Turk, A. S. & Spiotta, A. M. Infectious intracranial aneurysms: a systematic review of epidemiology, management, and outcomes. J. Neurointerv. Surg. 10, 713–721 (2018).

    Article  Google Scholar 

  314. Gross, B. A., Batjer, H. H., Awad, I. A., Bendok, B. R. & Du, R. Brainstem cavernous malformations: 1390 surgical cases from the literature. World Neurosurg. 80, 89–93 (2013).

    Article  PubMed  Google Scholar 

  315. Lee, C. C. et al. Gamma Knife radiosurgery for cerebral cavernous malformation. Sci. Rep. 9, 19743 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  316. Kida, Y. et al. Radiosurgery for symptomatic cavernous malformations: a multi-institutional retrospective study in Japan. Surg. Neurol. Int. 6, S249–S257 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  317. Nagy, G. et al. Contemporary radiosurgery of cerebral cavernous malformations: Part 1. Treatment outcome for critically located hemorrhagic lesions. J. Neurosurg. 1306, 1817–1825 (2019).

    Article  Google Scholar 

  318. Nagy, G. et al. Contemporary radiosurgery of cerebral cavernous malformations: Part 2. Treatment outcome for hemispheric lesions. J. Neurosurg. 1306, 1826–1834 (2019).

    Article  Google Scholar 

  319. Mirkowski, M. et al. Nonpharmacological rehabilitation interventions for motor and cognitive outcomes following pediatric stroke: a systematic review. Eur. J. Pediatr. 178, 433–454 (2019).

    Article  CAS  PubMed  Google Scholar 

  320. Hebert, D. et al. Canadian stroke best practice recommendations: stroke rehabilitation practice guidelines, update 2015. Int. J. Stroke 11, 459–484 (2016).

    Article  PubMed  Google Scholar 

  321. Lohse, K. R., Lang, C. E. & Boyd, L. A. Is more better? Using metadata to explore dose-response relationships in stroke rehabilitation. Stroke 45, 2053–2058 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  322. Sakzewski, L., Provan, K., Ziviani, J. & Boyd, R. N. Comparison of dosage of intensive upper limb therapy for children with unilateral cerebral palsy: how big should the therapy pill be? Res. Dev. Disabil. 37, 9–16 (2015).

    Article  PubMed  Google Scholar 

  323. Jackman, M. et al. What is the threshold dose of upper limb training for children with cerebral palsy to improve function? A systematic review. Aust. Occup. Ther. J. 67, 269–280 (2020).

    Article  PubMed  Google Scholar 

  324. Ramey, S. L. et al. Constraint-induced movement therapy for cerebral palsy: a randomized trial. Pediatrics 148, e2020033878 (2021).

    Article  PubMed  Google Scholar 

  325. Ballantyne, A. O., Spilkin, A. M., Hesselink, J. & Trauner, D. A. Plasticity in the developing brain: Intellectual, language and academic functions in children with ischaemic perinatal stroke. Brain 131, 2975–2985 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  326. Neuner, B. et al. Health-related quality of life in children and adolescents with stroke, self-reports, and parent/proxies reports: cross-sectional investigation. Ann. Neurol. 70, 70–78 (2011).

    Article  PubMed  Google Scholar 

  327. Cnossen, M. H. et al. Paediatric arterial ischaemic stroke: functional outcome and risk factors. Dev. Med. Child. Neurol. 52, 394–399 (2010).

    Article  PubMed  Google Scholar 

  328. Kornfeld, S. et al. Quality of life after paediatric ischaemic stroke. Dev. Med. Child. Neurol. 59, 45–51 (2017).

    Article  PubMed  Google Scholar 

  329. Ghotra, S. K. et al. Age at stroke onset influences the clinical outcome and health-related quality of life in pediatric ischemic stroke survivors. Dev. Med. Child. Neurol. 57, 1027–1034 (2015).

    Article  PubMed  Google Scholar 

  330. O’Keeffe, F. et al. Psychosocial outcome and quality of life following childhood stroke – a systematic review. Dev. Neurorehabil. 20, 428–442 (2017).

    Article  PubMed  Google Scholar 

  331. Gordon, A. L. et al. Self-reported needs after pediatric stroke. Eur. J. Paediatr. Neurol. 22, 791–796 (2018).

    Article  PubMed  Google Scholar 

  332. Lehman, L. L. et al. Prevalence of symptoms of anxiety, depression, and post-traumatic stress disorder in parents and children following pediatric stroke. J. Child. Neurol. 35, 472–479 (2020).

    Article  PubMed  Google Scholar 

  333. Bemister, T. B., Brooks, B. L., Dyck, R. H. & Kirton, A. Predictors of caregiver depression and family functioning after perinatal stroke. BMC Pediatr. 15, 75 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  334. Kurowski, B. G. et al. Caregiver ratings of long-term executive dysfunction and attention problems after early childhood traumatic brain injury: family functioning is important. PM R. 3, 836–845 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  335. Ryan, N. P. et al. Longitudinal outcome and recovery of social problems after pediatric traumatic brain injury (TBI): contribution of brain insult and family environment. Int. J. Dev. Neurosci. 49, 23–30 (2016).

    Article  PubMed  Google Scholar 

  336. Greenham, M. et al. Environmental contributions to social and mental health outcomes following pediatric stroke. Dev. Neuropsychol. 40, 348–362 (2015).

    Article  PubMed  Google Scholar 

  337. Ledochowski, J., Desrocher, M., Williams, T., Dlamini, N. & Westmacott, R. Mental health outcomes in children with acquired dystonia after basal ganglia stroke and associations with cognitive and motor outcomes. Child. Neuropsychol. 26, 691–710 (2020).

    Article  PubMed  Google Scholar 

  338. Felling, R. J. et al. Predicting recovery and outcome after pediatric stroke: results from the International Pediatric Stroke Study. Ann. Neurol. 87, 840–852 (2020).

    Article  PubMed  Google Scholar 

  339. Mineyko, A. et al. Seizures and outcome one year after neonatal and childhood cerebral sinovenous thrombosis. Pediatr. Neurol. 105, 21–26 (2020).

    Article  PubMed  Google Scholar 

  340. Lo, W. D., Hajek, C., Pappa, C., Wang, W. & Zumberge, N. Outcomes in children with hemorrhagic stroke. JAMA Neurol. 70, 66–71 (2013).

    Article  PubMed  Google Scholar 

  341. deVeber, G. A. et al. Epidemiology and outcomes of arterial ischemic stroke in children: the Canadian Pediatric Ischemic Stroke Registry. Pediatr. Neurol. 69, 58–70 (2017).

    Article  PubMed  Google Scholar 

  342. Mallick, A. A. et al. Outcome and recurrence 1 year after pediatric arterial ischemic stroke in a population-based cohort. Ann. Neurol. 79, 784–793 (2016).

    Article  PubMed  Google Scholar 

  343. Malone, L. A. & Felling, R. J. Pediatric stroke: unique implications of the immature brain on injury and recovery. Pediatric Neurol. 102, 3–9 (2020).

    Article  Google Scholar 

  344. Anderson, V., Spencer-Smith, M. & Wood, A. Do children really recover better? Neurobehavioural plasticity after early brain insult. Brain 134, 2197–2221 (2011).

    Article  PubMed  Google Scholar 

  345. Yee, A. X., Hsu, Y.-T. & Chen, L. A metaplasticity view of the interaction between homeostatic and Hebbian plasticity. Philos. Trans. R. Soc. B Biol. Sci. 372, 20160155 (2017).

    Article  Google Scholar 

  346. Ismail, F. Y., Fatemi, A. & Johnston, M. V. Cerebral plasticity: windows of opportunity in the developing brain. Eur. J. Paediatric Neurol. 21, 23–48 (2017). This is a thoughtful review that poses many questions regarding chronological periods of plasticity in the developing brain.

    Article  Google Scholar 

  347. Liu, Z., Xin, H. & Chopp, M. Axonal remodeling of the corticospinal tract during neurological recovery after stroke. Neural Regen. Res. 16, 939–943 (2021).

    Article  PubMed  Google Scholar 

  348. Wittenberg, G. F. Neural plasticity and treatment across the lifespan for motor deficits in cerebral palsy. Dev. Med. Child. Neurol. 51, 130–133 (2009).

    Article  PubMed  Google Scholar 

  349. Eyre, J. A. et al. Is hemiplegic cerebral palsy equivalent to amblyopia of the corticospinal system? Ann. Neurol. 62, 493–503 (2007).

    Article  PubMed  Google Scholar 

  350. Zewdie, E., Damji, O., Ciechanski, P., Seeger, T. & Kirton, A. Contralesional corticomotor neurophysiology in hemiparetic children with perinatal stroke: developmental plasticity and clinical function. Neurorehabil. Neural Repair. 31, 261–271 (2017).

    Article  PubMed  Google Scholar 

  351. Berweck, S. et al. Abnormal motor cortex excitability in congenital stroke. Pediatr. Res. 63, 84–88 (2008).

    Article  PubMed  Google Scholar 

  352. Crofts, A., Kelly, M. E. & Gibson, C. L. Imaging functional recovery following ischemic stroke: clinical and preclinical fMRI studies. J. Neuroimaging 30, 5–14 (2020).

    Article  PubMed  Google Scholar 

  353. Wilke, M. et al. Somatosensory system in two types of motor reorganization in congenital hemiparesis: topography and function. Hum. Brain Mapp. 30, 776–788 (2009).

    Article  PubMed  Google Scholar 

  354. Baker, K., Carlson, H. L., Zewdie, E. & Kirton, A. Developmental remodelling of the motor cortex in hemiparetic children with perinatal stroke. Pediatr. Neurol. 112, 34–43 (2020).

    Article  PubMed  Google Scholar 

  355. Walther, M. et al. Motor cortex plasticity in ischemic perinatal stroke: a transcranial magnetic stimulation and functional MRI study. Pediatr. Neurol. 41, 171–178 (2009).

    Article  PubMed  Google Scholar 

  356. Guzzetta, A. et al. Language organisation in left perinatal stroke. Neuropediatrics 39, 157–163 (2008).

    Article  CAS  PubMed  Google Scholar 

  357. Tillema, J. M. et al. Cortical reorganization of language functioning following perinatal left MCA stroke. Brain Lang. 105, 99–111 (2008).

    Article  PubMed  Google Scholar 

  358. Bartha-Doering, L. et al. Atypical language representation is unfavorable for language abilities following childhood stroke. Eur. J. Paediatr. Neurol. 23, 102–116 (2019).

    Article  PubMed  Google Scholar 

  359. François, C. et al. Right structural and functional reorganization in four-year-old children with perinatal arterial ischemic stroke predict language production. eNeuro 6, 447–465 (2019).

    Article  Google Scholar 

  360. Ilves, P. et al. Different plasticity patterns of language function in children with perinatal and childhood stroke. J. Child. Neurol. 29, 756–764 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  361. Carlson, H. L., Sugden, C., Brooks, B. L. & Kirton, A. Functional connectivity of language networks after perinatal stroke. Neuroimage Clin. 23, 101861 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  362. Lidzba, K., Küpper, H., Kluger, G. & Staudt, M. The time window for successful right-hemispheric language reorganization in children. Eur. J. Paediatr. Neurol. 21, 715–721 (2017).

    Article  PubMed  Google Scholar 

  363. Tibussek, D., Mayatepek, E., Klee, D. & Koy, A. Post stroke hemi-dystonia in children: a neglected area of research. Mol. Cell. Pediatr. 2, 14 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  364. Tabone, L. et al. Regional pediatric acute stroke protocol: initial experience during 3 years and 13 recanalization treatments in children. Stroke 48, 2278–2281 (2017).

    Article  PubMed  Google Scholar 

  365. Bernard, T. J. et al. Preparing for a ‘pediatric stroke alert’. Pediatric Neurol. 56, 18–24 (2016).

    Article  Google Scholar 

  366. Harrar, D. B. et al. A stroke alert protocol decreases the time to diagnosis of brain attack symptoms in a pediatric emergency department. J. Pediatr. 216, 136–141.e6 (2020).

    Article  PubMed  Google Scholar 

  367. Bernard, T. J. et al. Emergence of the primary pediatric stroke center: impact of the Thrombolysis in Pediatric Stroke trial. Stroke 45, 2018–2023 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  368. Wharton, J. D. et al. Pediatric acute stroke protocol implementation and utilization over 7 years. J. Pediatr. 220, 214–220.e1 (2020).

    Article  PubMed  Google Scholar 

  369. Kazmierczak, P. M. et al. Ultrafast brain magnetic resonance imaging in acute neurological emergencies: diagnostic accuracy and impact on patient management. Invest. Radiol. 55, 181–189 (2020).

    Article  PubMed  Google Scholar 

  370. Sarracanie, M. & Salameh, N. Low-field MRI: how low can we go? A fresh view on an old debate. Front. Phys. 8, 172 (2020).

    Article  Google Scholar 

  371. Al Harrach, M. et al. Is the blood oxygenation level-dependent fMRI response to motor tasks altered in children after neonatal stroke? Front. Hum. Neurosci. 14, 154 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  372. Guggisberg, A. G., Koch, P. J., Hummel, F. C. & Buetefisch, C. M. Brain networks and their relevance for stroke rehabilitation. Clin. Neurophysiol. 130, 1098–1124 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  373. Cassidy, J. M. & Cramer, S. C. Spontaneous and therapeutic-induced mechanisms of functional recovery after stroke. Transl. Stroke Res. 8, 33–46 (2017).

    Article  CAS  PubMed  Google Scholar 

  374. Hankey, G. J. et al. Twelve-month outcomes of the affinity trial of fluoxetine for functional recovery after acute stroke: Affinity Trial steering committee on behalf of the AFFINITY Trial Collaboration. Stroke 52, 2502–2509 (2021).

    Article  CAS  PubMed  Google Scholar 

  375. Mehrholz, J., Pohl, M., Platz, T., Kugler, J. & Elsner, B. Electromechanical and robot-assisted arm training for improving activities of daily living, arm function, and arm muscle strength after stroke. Cochrane Database Syst. Rev. 9, CD006876 (2018).

    PubMed  Google Scholar 

  376. Rodgers, H. et al. Robot assisted training for the upper limb after stroke (RATULS): a multicentre randomised controlled trial. Lancet 394, 51–62 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  377. El-Shamy, S. M. Efficacy of Armeo® robotic therapy versus conventional therapy on upper limb function in children with hemiplegic cerebral palsy. Am. J. Phys. Med. Rehabil. 97, 164–169 (2018).

    Article  PubMed  Google Scholar 

  378. Kirton, A. et al. Brain stimulation and constraint for perinatal stroke hemiparesis. Neurology 86, 1659–1667 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  379. Gillick, B. T. et al. Primed low-frequency repetitive transcranial magnetic stimulation and constraint-induced movement therapy in pediatric hemiparesis: a randomized controlled trial. Dev. Med. Child. Neurol. 56, 44–52 (2014).

    Article  PubMed  Google Scholar 

  380. Kirton, A. et al. Transcranial direct current stimulation for children with perinatal stroke and hemiparesis. Neurology 88, 259–267 (2017).

    Article  PubMed  Google Scholar 

  381. Gillick, B. et al. Transcranial direct current stimulation and constraint-induced therapy in cerebral palsy: a randomized, blinded, sham-controlled clinical trial. Eur. J. Paediatr. Neurol. 22, 358–368 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  382. Satani, N. et al. Aspirin in stroke patients modifies the immunomodulatory interactions of marrow stromal cells and monocytes. Brain Res. 1720, 146298 (2019).

    Article  CAS  PubMed  Google Scholar 

  383. Hawkins, K. E. et al. Embryonic stem cell-derived mesenchymal stem cells (MSCs) have a superior neuroprotective capacity over fetal MSCs in the hypoxic-ischemic mouse brain. Stem Cell Transl. Med. 7, 439–449 (2018).

    Article  CAS  Google Scholar 

  384. Wagenaar, N. et al. Promoting neuroregeneration after perinatal arterial ischemic stroke: neurotrophic factors and mesenchymal stem cells. Pediatric Res. 83, 372–384 (2018). Contemporary, systematic review of the neurotrophic growth factors and stem cell approaches that may be useful in treating perinatal arterial ischaemic stroke.

    Article  CAS  Google Scholar 

  385. Liu, Y., Wang, J., Gao, Y. & Ma, C. Stem cell transplantation for ischemic stroke. J. Clin. Rehabilitative Tissue Eng. Res. 12, 2339–2342 (2008).

    CAS  Google Scholar 

  386. Serrenho, I. et al. Stem cell therapy for neonatal hypoxic-ischemic encephalopathy: a systematic review of preclinical studies. Int. J. Mol. Sci. 22, 3142 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  387. van Velthoven, C. T. et al. Mesenchymal stem cells attenuate MRI-identifiable injury, protect white matter, and improve long-term functional outcomes after neonatal focal stroke in rats. J. Neurosci. Res. 95, 1225–1236 (2017).

    Article  PubMed  Google Scholar 

  388. Van Velthoven, C. T. J. et al. Mesenchymal stem cell transplantation attenuates brain injury after neonatal stroke. Stroke 44, 1426–1432 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  389. Larpthaveesarp, A. et al. Enhanced mesenchymal stromal cells or erythropoietin provide long-term functional benefit after neonatal stroke. Stroke 52, 284–293 (2021).

    Article  CAS  PubMed  Google Scholar 

  390. Fernández-López, D., Natarajan, N., Ashwal, S. & Vexler, Z. S. Mechanisms of perinatal arterial ischemic stroke. J. Cereb. Blood Flow. Metab. 34, 921–932 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  391. Srivastava, R. & Kirton, A. Perinatal stroke: a practical approach to diagnosis and management. NeoReviews 22, e163–e176 (2021).

    Article  PubMed  Google Scholar 

  392. Dunbar, M. & Kirton, A. Perinatal stroke: mechanisms, management, and outcomes of early cerebrovascular brain injury. Lancet Child Adolesc. Health 2, 666–676 (2018).

    Article  PubMed  Google Scholar 

  393. Kirton, A. & deVeber, G. Life after perinatal stroke. Stroke 44, 3265–3271 (2013).

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

Introduction (M.W. and P.B.S.); Epidemiology (H.J.F. and H.K.); Mechanisms/pathophysiology (H.J.F., S.L., H.K., W.D.L. and M.T.M.); Diagnosis, screening and prevention (M.W., P.B.S., H.J.F., S.L., H.K., W.D.L. and M.T.M.); Management (M.W., P.B.S., H.J.F., S.L., H.K. and M.T.M.); Quality of life (H.J.F. and W.D.L.); Outlook (M.W., P.B.S., H.J.F., S.L., H.K., W.D.L. and M.T.M.); Overview of Primer (M.W.).

Corresponding author

Correspondence to Moritz Wildgruber.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Disease Primers thanks A. Mallick, who co-reviewed with R. Spaull; L. Beslow; N. Dlamini; R. Westmacott; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Glossary

Tetralogy of Fallot

Congenital disorder characterized by a ventricular septal defect, pulmonary stenosis, overriding aorta and right ventricular hypertrophy.

Transposition of the great vessels

A disorder in which the aorta arises from the right ventricle and the pulmonary trunk arises from the left ventricle.

Hypoplastic left heart syndrome

A disorder in which the left ventricle, and mitral and aortic valves are underdeveloped and unable to support the systemic circulation.

Sub-intimal haematoma

Vessel wall haematoma accompanied by separation of the layers of the arterial wall.

Rotational vertebral arteriopathy

Injury of the vertebral artery due to repeated mechanical impingement from adjacent bony or soft tissue structures in the neck.

Coarctation of the aorta

Narrowing of the aorta, most frequently located along the aortic arch.

String sign

A string of contrast material distal to a stenotic segment visible on angiography.

Double lumen

A sign on angiography representing the true and false lumen.

Intimal flap

A flap of the intima protruding into the perfused vessel lumen.

Arterial banding

Narrowing of the vessel following external compression.

Posterior fossa decompression

Removal of a portion of bone in the back of the skull to allow expansion of cerebellar swelling.