Download PDF
Semin Thromb Hemost 2011; 37(7): 786-793
DOI: 10.1055/s-0031-1297169
© Thieme Medical Publishers

Childhood Arterial Ischemic Stroke: A Review of Etiologies, Antithrombotic Treatments, Prognostic Factors, and Priorities for Future Research

Courtney A. Lyle1 , 2 , Timothy J. Bernard3 , 4 , 5 , Neil A. Goldenberg3 , 5 , 6
  • 1Division of Hematology/Oncology, Department of Pediatrics, University of California
  • 2Rady Children's Hospital, San Diego, California, University of Colorado, Aurora, Colorado
  • 3Department of Pediatrics, University of Colorado, Aurora, Colorado
  • 4Sections of Child Neurology, University of Colorado, Aurora, Colorado
  • 5Department of Hematology/Oncology/Bone Marrow Transplantation and the Mountain States Regional Hemophilia and Thrombosis Center, University of Colorado, Aurora, Colorado
  • 6Department of Medicine, University of Colorado, Aurora, Colorado, University of Colorado, Aurora, Colorado
Further Information

Publication History

Publication Date:
20 December 2011 (online)

    Permissions and Reprints

ABSTRACT

Childhood arterial ischemic stroke (AIS) is a rare, but serious, medical condition, which is fatal in approximately 3% and associated with both acute and long-term neurologic impairment in over 70% of cases. Common etiologies include sickle cell disease, congenital heart disease, arterial dissection, prothrombotic conditions, and preceding viral infections; however, one in four cases is considered idiopathic. To date, no randomized controlled clinical trials (RCTs) have been conducted to establish evidence for current therapeutic strategies outside of sickle cell disease, thus, treatment strategies are largely shaped by consensus-based guidelines, in which, beyond the acute period, aspirin is the mainstay of therapy and anticoagulation is reserved for select circumstances. In recent years, evidence on prognostic factors has accumulated, helping to inform the future design of prognostically stratified RCTs. In this narrative review, we discuss the current understanding of etiologies, consensus-based treatment recommendations, contemporary treatment data, and prognostic factors in childhood AIS. We also identify priorities for future research.

KEYWORDS

Childhood arterial ischemic stroke - pediatric stroke

REFERENCES

  • 1 Fullerton H J, Wu Y W, Zhao S, Johnston S C. Risk of stroke in children: ethnic and gender disparities.  Neurology. 2003;  61 (2) 189-194
    Google Scholar
  • 2 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. 2009;  40 (11) 3415-3421
    Google Scholar
  • 3 Giroud M, Lemesle M, Gouyon J B, Nivelon J L, Milan C, Dumas R. 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. 1995;  48 (11) 1343-1348
    Google Scholar
  • 4 Bernard T J, Goldenberg N A. Pediatric arterial ischemic stroke.  Hematol Oncol Clin North Am. 2010;  24 (1) 167-180
    Google Scholar
  • 5 Bernard T J, Goldenberg N A, Armstrong-Wells J, Amlie-Lefond C, Fullerton H J. Treatment of childhood arterial ischemic stroke.  Ann Neurol. 2008;  63 (6) 679-696
    Google Scholar
  • 6 Goldenberg N A, Bernard T J, Fullerton H J, Gordon A, deVeber G. International Pediatric Stroke Study Group . Antithrombotic treatments, outcomes, and prognostic factors in acute childhood-onset arterial ischaemic stroke: a multicentre, observational, cohort study.  Lancet Neurol. 2009;  8 (12) 1120-1127
    Google Scholar
  • 7 Sträter R, Becker S, von Eckardstein A et al.. Prospective assessment of risk factors for recurrent stroke during childhood—a 5-year follow-up study.  Lancet. 2002;  360 (9345) 1540-1545
    Google Scholar
  • 8 Ganesan V, Prengler M, Wade A, Kirkham F J. Clinical and radiological recurrence after childhood arterial ischemic stroke.  Circulation. 2006;  114 (20) 2170-2177
    Google Scholar
  • 9 Lanthier S, Carmant L, David M, Larbrisseau A, de Veber G. Stroke in children: the coexistence of multiple risk factors predicts poor outcome.  Neurology. 2000;  54 (2) 371-378
    Google Scholar
  • 10 Fullerton H J, Wu Y W, Sidney S, Johnston S C. Risk of recurrent childhood arterial ischemic stroke in a population-based cohort: the importance of cerebrovascular imaging.  Pediatrics. 2007;  119 (3) 495-501
    Google Scholar
  • 11 Chabrier S, Husson B, Lasjaunias P, Landrieu P, Tardieu M. Stroke in childhood: outcome and recurrence risk by mechanism in 59 patients.  J Child Neurol. 2000;  15 (5) 290-294
    Google Scholar
  • 12 deVeber G A, MacGregor D, Curtis R, Mayank S. Neurologic outcome in survivors of childhood arterial ischemic stroke and sinovenous thrombosis.  J Child Neurol. 2000;  15 (5) 316-324
    Google Scholar
  • 13 Ganesan V, Hogan A, Shack N, Gordon A, Isaacs E, Kirkham F J. Outcome after ischaemic stroke in childhood.  Dev Med Child Neurol. 2000;  42 (7) 455-461
    Google Scholar
  • 14 Steinlin M, Roellin K, Schroth G. Long-term follow-up after stroke in childhood.  Eur J Pediatr. 2004;  163 (4-5) 245-250
    Google Scholar
  • 15 Lee J C, Lin K L, Wang H S et al.. Seizures in childhood ischemic stroke in Taiwan.  Brain Dev. 2009;  31 (4) 294-299
    Google Scholar
  • 16 Monagle P, Chalmers E, Chan A American College of Chest Physicians et al. Antithrombotic therapy in neonates and children: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).  Chest. 2008;  133 (6, Suppl) 887S-968S
    Google Scholar
  • 17 Pediatric Stroke Working Group .Stroke in childhood: Clinical guidelines for diagnosis, management, and rehabilitation. Royal College of Physicians; 2004. Available at: http://bookshop.rcplondon.ac.uk/contents/f98c6540-a541-4bed-837d-ef293ac458bf.pdf Accessed November 15, 2010
    Google Scholar
  • 18 Roach E S, Golomb M R, Adams R American Heart Association Stroke Council et al. Management of stroke in infants and children: a scientific statement from a Special Writing Group of the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young.  Stroke. 2008;  39 (9) 2644-2691
    Google Scholar
  • 19 Biller J. Stroke in Children and Young Adults. 2nd ed. Philadelphia, PA: Saunders/Elsevier; 2009
    Google Scholar
  • 20 Lo W, Stephens J, Fernandez S. Pediatric stroke in the United States and the impact of risk factors.  J Child Neurol. 2009;  24 (2) 194-203
    Google Scholar
  • 21 Ricci S. Embolism from the heart in the young patient: a short review.  Neurol Sci. 2003;  24 (Suppl 1) S13-S14
    Google Scholar
  • 22 deVeber G. Arterial ischemic strokes in infants and children: an overview of current approaches.  Semin Thromb Hemost. 2003;  29 (6) 567-573
    Google Scholar
  • 23 DeVeber G. Risk factors for childhood stroke: little folks have different strokes!.  Ann Neurol. 2003;  53 (2) 149-150
    Google Scholar
  • 24 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. 2003;  53 (2) 167-173
    Google Scholar
  • 25 Benedik M P, Zaletel M, Meglic N P, Podnar T. Patent foramen ovale and unexplained ischemic cerebrovascular events in children.  Catheter Cardiovasc Interv. 2007;  70 (7) 999-1007
    Google Scholar
  • 26 Wu L A, Malouf J F, Dearani J A et al.. Patent foramen ovale in cryptogenic stroke: current understanding and management options.  Arch Intern Med. 2004;  164 (9) 950-956
    Google Scholar
  • 27 Earley C J, Kittner S J, Feeser B R et al.. Stroke in children and sickle-cell disease: Baltimore-Washington Cooperative Young Stroke Study.  Neurology. 1998;  51 (1) 169-176
    Google Scholar
  • 28 Rothman S M, Fulling K H, Nelson J S. Sickle cell anemia and central nervous system infarction: a neuropathological study.  Ann Neurol. 1986;  20 (6) 684-690
    Google Scholar
  • 29 Tuohy A M, McKie V, Manci E A, Adams R J. Internal carotid artery occlusion in a child with sickle cell disease: case report and immunohistochemical study.  J Pediatr Hematol Oncol. 1997;  19 (5) 455-458
    Google Scholar
  • 30 Merkel K H, Ginsberg P L, Parker Jr J C, Post M J. Cerebrovascular disease in sickle cell anemia: a clinical, pathological and radiological correlation.  Stroke. 1978;  9 (1) 45-52
    Google Scholar
  • 31 Dowling M M, Lee N, Quinn C T et al.. Prevalence of intracardiac shunting in children with sickle cell disease and stroke.  J Pediatr. 2010;  156 (4) 645-650
    Google Scholar
  • 32 Danchaivijitr N, Cox T C, Saunders D E, Ganesan V. Evolution of cerebral arteriopathies in childhood arterial ischemic stroke.  Ann Neurol. 2006;  59 (4) 620-626
    Google Scholar
  • 33 Amlie-Lefond C, Bernard T J, Sébire G International Pediatric Stroke Study Group et al. Predictors of cerebral arteriopathy in children with arterial ischemic stroke: results of the International Pediatric Stroke Study.  Circulation. 2009;  119 (10) 1417-1423
    Google Scholar
  • 34 Chabrier S, Lasjaunias P, Husson B, Landrieu P, Tardieu M. Ischaemic stroke from dissection of the craniocervical arteries in childhood: report of 12 patients.  Eur J Paediatr Neurol. 2003;  7 (1) 39-42
    Google Scholar
  • 35 Sepelyak K, Gailloud P, Jordan L C. Athletics, minor trauma, and pediatric arterial ischemic stroke.  Eur J Pediatr. 2010;  169 (5) 557-562
    Google Scholar
  • 36 Shaffer L, Rich P M, Pohl K R, Ganesan V. Can mild head injury cause ischaemic stroke?.  Arch Dis Child. 2003;  88 (3) 267-269
    Google Scholar
  • 37 Kieslich M, Fiedler A, Heller C, Kreuz W, Jacobi G. Minor head injury as cause and co-factor in the aetiology of stroke in childhood: a report of eight cases.  J Neurol Neurosurg Psychiatry. 2002;  73 (1) 13-16
    Google Scholar
  • 38 Fullerton H J, Johnston S C, Smith W S. Arterial dissection and stroke in children.  Neurology. 2001;  57 (7) 1155-1160
    Google Scholar
  • 39 Rafay M F, Armstrong D, Deveber G, Domi T, Chan A, MacGregor D L. Craniocervical arterial dissection in children: clinical and radiographic presentation and outcome.  J Child Neurol. 2006;  21 (1) 8-16
    Google Scholar
  • 40 Patel H, Smith R R, Garg B P. Spontaneous extracranial carotid artery dissection in children.  Pediatr Neurol. 1995;  13 (1) 55-60
    Google Scholar
  • 41 Brandt T, Grond-Ginsbach C. Spontaneous cervical artery dissection: from risk factors toward pathogenesis.  Stroke. 2002;  33 (3) 657-658
    Google Scholar
  • 42 Sébire G, Fullerton H, Riou E, deVeber G. Toward the definition of cerebral arteriopathies of childhood.  Curr Opin Pediatr. 2004;  16 (6) 617-622
    Google Scholar
  • 43 Manceau E, Giroud M, Dumas R. Moyamoya disease in children. A review of the clinical and radiological features and current treatment.  Childs Nerv Syst. 1997;  13 (11-12) 595-600
    Google Scholar
  • 44 Rosser T L, Vezina G, Packer R J. Cerebrovascular abnormalities in a population of children with neurofibromatosis type 1.  Neurology. 2005;  64 (3) 553-555
    Google Scholar
  • 45 Kirkham F J, DeBaun M R. Stroke in children with sickle cell disease.  Curr Treat Options Neurol. 2004;  6 (5) 357-375
    Google Scholar
  • 46 Jea A, Smith E R, Robertson R, Scott R M. Moyamoya syndrome associated with Down syndrome: outcome after surgical revascularization.  Pediatrics. 2005;  116 (5) e694-e701
    Google Scholar
  • 47 Morris B, Partap S, Yeom K, Gibbs I C, Fisher P G, King A A. Cerebrovascular disease in childhood cancer survivors: A Children's Oncology Group Report.  Neurology. 2009;  73 (22) 1906-1913
    Google Scholar
  • 48 Roder C, Nayak N R, Khan N, Tatagiba M, Inoue I, Krischek B. Genetics of Moyamoya disease.  J Hum Genet. 2010;  55 (11) 711-716
    Google Scholar
  • 49 Bernard T J, Fenton L Z, Apkon S D et al.. Biomarkers of hypercoagulability and inflammation in childhood-onset arterial ischemic stroke.  J Pediatr. 2010;  156 (4) 651-656
    Google Scholar
  • 50 Askalan R, Laughlin S, Mayank S et al.. Chickenpox and stroke in childhood: a study of frequency and causation.  Stroke. 2001;  32 (6) 1257-1262
    Google Scholar
  • 51 Kutlesa M, Tesović G, Knezović I, Mise B, Visković K, Barisić N. Ischemic stroke associated with adenoviral infection in a 4-year-old boy.  Wien Klin Wochenschr. 2009;  121 (23-24) 776-779
    Google Scholar
  • 52 Lanthier S, Armstrong D, Domi T, deVeber G. Post-varicella arteriopathy of childhood: natural history of vascular stenosis.  Neurology. 2005;  64 (4) 660-663
    Google Scholar
  • 53 Dlamini N, Mackay M, Fullerton H, Freeman J, deVeber G. Intracranial Dissection Mimicking Transient Cerebral Arteriopathy in Childhood Arterial Ischemic Stroke. International Stroke Conference Abstract 2010
    Google Scholar
  • 54 Braun K P, Bulder M M, Chabrier S et al.. The course and outcome of unilateral intracranial arteriopathy in 79 children with ischaemic stroke.  Brain. 2009;  132 (Pt 2) 544-557
    Google Scholar
  • 55 Kenet G, Sadetzki S, Murad H et al.. Factor V Leiden and antiphospholipid antibodies are significant risk factors for ischemic stroke in children.  Stroke. 2000;  31 (6) 1283-1288
    Google Scholar
  • 56 deVeber G, Monagle P, Chan A et al.. Prothrombotic disorders in infants and children with cerebral thromboembolism.  Arch Neurol. 1998;  55 (12) 1539-1543
    Google Scholar
  • 57 Sträter R, Vielhaber H, Kassenböhmer R, von Kries R, Göbel U, Nowak-Göttl U. Genetic risk factors of thrombophilia in ischaemic childhood stroke of cardiac origin. A prospective ESPED survey.  Eur J Pediatr. 1999;  158 (Suppl 3) S122-S125
    Google Scholar
  • 58 Kenet G, Lütkhoff L K, Albisetti M 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. 2010;  121 (16) 1838-1847
    Google Scholar
  • 59 Haywood S, Liesner R, Pindora S, Ganesan V. Thrombophilia and first arterial ischaemic stroke: a systematic review.  Arch Dis Child. 2005;  90 (4) 402-405
    Google Scholar
  • 60 Nowak-Göttl U, Sträter R, Heinecke A et al.. Lipoprotein (a) and genetic polymorphisms of clotting factor V, prothrombin, and methylenetetrahydrofolate reductase are risk factors of spontaneous ischemic stroke in childhood.  Blood. 1999;  94 (11) 3678-3682
    Google Scholar
  • 61 Maguire J L, deVeber G, Parkin P C. Association between iron-deficiency anemia and stroke in young children.  Pediatrics. 2007;  120 (5) 1053-1057
    Google Scholar
  • 62 Alvarez-Larrán A, Cervantes F, Bellosillo B et al.. Essential thrombocythemia in young individuals: frequency and risk factors for vascular events and evolution to myelofibrosis in 126 patients.  Leukemia. 2007;  21 (6) 1218-1223
    Google Scholar
  • 63 Rolfs A, Böttcher T, Zschiesche M et al.. Prevalence of Fabry disease in patients with cryptogenic stroke: a prospective study.  Lancet. 2005;  366 (9499) 1794-1796
    Google Scholar
  • 64 Granild-Jensen J, Jensen U B, Schwartz M, Hansen U S. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy resulting in stroke in an 11-year-old male.  Dev Med Child Neurol. 2009;  51 (9) 754-757
    Google Scholar
  • 65 Hsich G E, Robertson R L, Irons M, Soul J S, du Plessis A J. Cerebral infarction in Menkes' disease.  Pediatr Neurol. 2000;  23 (5) 425-428
    Google Scholar
  • 66 Alehan F, Saygi S, Gedik S, Kayahan Ulu E M. Stroke in early childhood due to homocystinuria.  Pediatr Neurol. 2010;  43 (4) 294-296
    Google Scholar
  • 67 Kaku D A, Lowenstein D H. Emergence of recreational drug abuse as a major risk factor for stroke in young adults.  Ann Intern Med. 1990;  113 (11) 821-827
    Google Scholar
  • 68 Westover A N, McBride S, Haley R W. Stroke in young adults who abuse amphetamines or cocaine: a population-based study of hospitalized patients.  Arch Gen Psychiatry. 2007;  64 (4) 495-502
    Google Scholar
  • 69 Sträter R, Kurnik K, Heller C, Schobess R, Luigs P, Nowak-Göttl U. Aspirin versus low-dose low-molecular-weight heparin: antithrombotic therapy in pediatric ischemic stroke patients: a prospective follow-up study.  Stroke. 2001;  32 (11) 2554-2558
    Google Scholar
  • 70 Burak C R, Bowen M D, Barron T F. The use of enoxaparin in children with acute, nonhemorrhagic ischemic stroke.  Pediatr Neurol. 2003;  29 (4) 295-298
    Google Scholar
  • 71 Bernard T J, Goldenberg N A, Tripputi M, Manco-Johnson M J, Niederstadt T, Nowak-Göttl U. Anticoagulation in childhood-onset arterial ischemic stroke with non-moyamoya arteriopathy: findings from the Colorado and German (COAG) collaboration.  Stroke. 2009;  40 (8) 2869-2871
    Google Scholar
  • 72 Georgiadis D, Arnold M, von Buedingen H C et al.. Aspirin vs anticoagulation in carotid artery dissection: a study of 298 patients.  Neurology. 2009;  72 (21) 1810-1815
    Google Scholar
  • 73 Amlie-Lefond C, deVeber G, Chan A K International Pediatric Stroke Study et al. Use of alteplase in childhood arterial ischaemic stroke: a multicentre, observational, cohort study.  Lancet Neurol. 2009;  8 (6) 530-536
    Google Scholar
  • 74 Arnold M, Steinlin M, Baumann A et al.. Thrombolysis in childhood stroke: report of 2 cases and review of the literature.  Stroke. 2009;  40 (3) 801-807
    Google Scholar
  • 75 Carlson M D, Leber S, Deveikis J, Silverstein F S. Successful use of rt-PA in pediatric stroke.  Neurology. 2001;  57 (1) 157-158
    Google Scholar
  • 76 Gruber A, Nasel C, Lang W, Kitzmüller E, Bavinzski G, Czech T. Intra-arterial thrombolysis for the treatment of perioperative childhood cardioembolic stroke.  Neurology. 2000;  54 (8) 1684-1686
    Google Scholar
  • 77 Noser E A, Felberg R A, Alexandrov A V. Thrombolytic therapy in an adolescent ischemic stroke.  J Child Neurol. 2001;  16 (4) 286-288
    Google Scholar
  • 78 Thirumalai S S, Shubin R A. Successful treatment for stroke in a child using recombinant tissue plasminogen activator.  J Child Neurol. 2000;  15 (8) 558
    Google Scholar
  • 79 Amlie-Lefond C, Chan A K, Kirton A Thrombolysis in Pediatric Stroke (TIPS) Investigators et al. Thrombolysis in acute childhood stroke: design and challenges of the thrombolysis in pediatric stroke clinical trial.  Neuroepidemiology. 2009;  32 (4) 279-286
    Google Scholar
  • 80 Rafay M F, Pontigon A M, Chiang J et al.. Delay to diagnosis in acute pediatric arterial ischemic stroke.  Stroke. 2009;  40 (1) 58-64
    Google Scholar
  • 81 Srinivasan J, Miller S P, Phan T G, Mackay M T. Delayed recognition of initial stroke in children: need for increased awareness.  Pediatrics. 2009;  124 (2) e227-e234
    Google Scholar
  • 82 Gabis L V, Yangala R, Lenn N J. Time lag to diagnosis of stroke in children.  Pediatrics. 2002;  110 (5) 924-928
    Google Scholar
  • 83 Domi T, deVeber G, Shroff M, Kouzmitcheva E, MacGregor D L, Kirton A. Corticospinal tract pre-wallerian degeneration: a novel outcome predictor for pediatric stroke on acute MRI.  Stroke. 2009;  40 (3) 780-787
    Google Scholar
  • 84 Ganesan V, Ng V, Chong W K, Kirkham F J, Connelly A. Lesion volume, lesion location, and outcome after middle cerebral artery territory stroke.  Arch Dis Child. 1999;  81 (4) 295-300
    Google Scholar
  • 85 Cnossen M H, Aarsen F K, Akker SLj et al.. Paediatric arterial ischaemic stroke: functional outcome and risk factors.  Dev Med Child Neurol. 2010;  52 (4) 394-399
    Google Scholar

Courtney A. LyleM.D. 

Rady Children's Hospital, 3020 Children's Way MC 5035

San Diego, CA 92123

Email: calyle@rchsd.org

      >