Arterial Ischemic Stroke in Neonates, Infants, and Children: An Overview of Underlying Conditions, Imaging Methods, and Treatment Modalities

Ulrike Nowak-Göttl; Gudrun Günther; Karin Kurnik; Ronald Sträter; Fenella Kirkham

doi:10.1055/s-2003-42590

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2003; 29(4): 405-414
DOI: 10.1055/s-2003-42590

Arterial Ischemic Stroke in Neonates, Infants, and Children: An Overview of Underlying Conditions, Imaging Methods, and Treatment Modalities

Ulrike Nowak-Göttl^1,2,3 , Gudrun Günther³ , Karin Kurnik⁴ , Ronald Sträter² , Fenella Kirkham⁵

¹Professor, University of Münster Münster
²Department of Paediatric Haematology/Oncology University of Münster Münster
³Department of Paediatrics University Children's Hospital Magdeburg
⁴Department of Paediatrics University Children's Hospital Munich, Germany
⁵Neurosciences Unit, Institute of Child Health, University College, London and Southampton General Hospital NHS Trust, United Kingdom

Abstract

ABSTRACT

Conditions associated with arterial ischemic stroke (AIS) in children include congenital heart malformations, sickle cell disease, and meningitis, although around half of all cases are cryptogenic. Up to 80% of children with ischemic stroke have cerebrovascular disease, and case control studies demonstrate an association of arterial ischemic stroke in children with hereditary prothrombotic risk factors and infections such as VARICELLA. Conventional risk factors, such as hypertension and dyslipidemia, may also play a role and most children have several potential triggers rather than a single cause. Treatment recommendations are based on small case series or have been adapted from adult stroke studies; there are no evidence-based data on efficacy in children. Low-dose aspirin appears to be relatively safe. Anticoagulation with heparins, for example, low-molecular-weight heparin or warfarin, may be indicated in children with cardioembolic stroke, arterial dissection, or persistent hypercoagulable states, and blood transfusion has a role in patients with sickle cell disease. Tissue plasminogen activator has been used in a few patients within 3 hours of the onset of symptoms. At present, the benefit of treatment has to be weighed against the risk for each patient, but randomized controlled trials for primary prevention, acute treatment, and secondary prevention of pediatric ischemic stroke are urgently needed.

KEYWORDS

Arterial ischemic stroke - children - etiology - magnetic resonance - prothrombotic risk factors - therapy

Full Text

References

REFERENCES

1 Williams A N. Childhood stroke-beyond re-inventing the wheel. Eur J Paediatr Neurol . 2000; 4 103-107
2 Schoenberg B, Mellinger J, Schoenberg D. Cerebrovascular disease in infants and children: a study of incidence, clinical features, and survival. Neurology . 1978; 28 763-768
3 Earley C J, Kittner S J, Feeser B R. et al . Stroke in children and sickle-cell disease. Neurology . 1998; 51 169-176
4 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 1343-1348
5 Nicolaides P, Appelton R E. Stroke in children. Dev Med Child Neurol . 1996; 38 172-180
6 Roach E S. Etiology of stroke in children. Semin Pediatr Neurol . 2000; 7 244-260
7 deVeber G, Roach E S, Riela A R, Wiznitzer M. Stroke in children: recognition, treatment, and future directions. Semin Pediatr Neurol . 2000; 7 309-317
8 Abram H S, Knepper L E, Warty V S, Painter M J. Natural history, prognosis, and lipid abnormalities of idiopathic ischemic childhood stroke. J Child Neurol . 1996; 11 2762-2782
9 Lynch J K, Hirtz D G, deVeber G, Nelson K B. Report on the National Institute of Neurological Disorders and Stroke Workshop on Perinatal and Childhood Stroke. Pediatrics . 2002; 109 116-123
10 Kirkham F J. Stroke in childhood. Arch Dis Child . 1999; 81 85-89
11 Kirkham F J, Prengler M, Hewes K M, Ganesan V. Risk factors for arterial ischemic stroke in children. J Child Neurol . 2000; 15 299-307
12 Prengler M, Pavlakis S G, Prohovnik I, Adams R J. Sickle cell disease: the neurological complications. Ann Neurol . 2002; 51 543-552
13 Sebire G, Meyer L, Chabrier S. Varicella as a risk factor for cerebral infarction in childhood: a case-control study. Ann Neurol . 1999; 45 679-680
14 Roach E S, deVeber G, Kirkham F. Knowledge of consensus: understanding stroke in children. J Child Neurol . 2000; 15 277-278
15 Williams L S, Garg B P, Cohen M, Fleck J D, Biller J. Subtypes of ischaemic stroke in children and young adults. Neurology . 1997; 49 1541-1545
16 Fullerton H J, Johnston S C, Smith W S. Arterial dissection and stroke in children. Neurology . 2001; 57 1155-1160
17 Shields W D, Ziter F A, Oeborn A G, Allen J. Fibromuscular dysplasia as a cause of stroke in infancy and childhood. Pediatrics . 1977; 59 899-901
18 Chabrier S, Rodesch G, Lasjaunias P. et al . Transient cerebral arteriopathy: a disorder recognized by serial angiograms in children with stroke. J Child Neurol . 1998; 13 27-32
19 Ganesan V, Savvy L, Chong W K, Kirkham F J. Conventional cerebral angiography in the investigation of children with ischaemic stroke. Pediatr Neurol . 1999; 20 38-42
20 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; 53 167-173
21 Shirane R, Sato S, Yoshimoto T. Angiographic findings of ischaemic stroke in children. Childs Nerv Syst . 1992; 8 432-436
22 Velkey I, Lombay B, Panczel G. Obstruction of the cerebral arteries in childhood stroke. Pediatr Radiol . 1992; 22 386-387
23 Kirkham F J, Prengler M. Genetics of paediatric stroke (in press). In: Markus HGenetics of Stroke. Oxford, England: Oxford University Press 2002
24 Akar N, Akar E, Özel D, Deda G, Sipahi T. Common mutations at the homocysteine metabolism pathway and pediatric stroke. Thromb Res . 2001; 102 115-120
25 Becker S, Heller C, Gropp F, Scharrer I, Kreuz W. Thrombophilic disorders in children with cerebral infarction. Lancet . 1998; 352 1756-1758
26 Bonduel M, Sciuccati G, Hepner M, Tores A F, Pieroni G, Frontroth J. Prethrombotic disorder in children with arterial ischemic stroke and sinovenous thrombosis. Arch Neurol . 1999; 56 967-971
27 Bonduel M, Hepner M, Sciuccati G, Torres A F, Tenembaum S. Prothrombotic disorders in children with moyamoya syndrome. Stroke . 2001; 32 1786-1792
28 Cardo E, Monros E, Colome C. et al . Children with stroke: polymorphism of the MTHFR gene, mild hyperhomocysteinemia, and vitamin status. J Child Neurol . 2000; 15 295-298
29 Debus O, Koch H G, Kurlemann G. et al . Factor V Leiden and genetic defects of thrombophilia in childhood porencephaly. Arch Dis Child Fetal Neonatal Ed . 1998; 78 F121-F124
30 Devilat M, Toso M, Morales M. Childhood stroke associated with protein C or S deficiency and primary antiphospholipid syndrome. Pediatr Neurol . 1993; 9 67-70
31 Ganesan V, Kelsey H, Cookson J, Osborn A, Kirkham F J. Activated protein C resistance in childhood stroke. Lancet . 1996; 347 260
32 Ganesan V, McShane M A, Liesner R, Cookson J, Hann I, Kirkham F J. Inherited prothrombotic states and ischaemic stroke in childhood. J Neurol Neurosurg Psychiatry . 1998; 65 508-511
33 Kenet G, Sadetzki S, Murad H. et al . Factor V Leiden and antiphospholipid antibodies are significant risk factors for ischaemic stroke in children. Stroke . 2000; 31 1283-1288
34 Günther G, Junker R, Sträter R. et al . Symptomatic ischaemic stroke in full-term neonates: role of acquired and genetic prothrombotic risk factors. Stroke . 2000; 31 2437-2441
35 Heller C, Becker S, Scharrer I, Kreuz W. Prothrombotic risk factors in childhood stroke and venous thrombosis. Eur J Pediatr . 1999; 158(Suppl) S117-S121
36 Lanthier S, Carmant L, David M, Larbrisseau A, deVeber G. Stroke in children. The coexistence of multiple risk factors predicts poor outcome. Neurology . 2000; 54 371-378
37 Manco-Johnson M J, Nuss R, Key N. et al . Lupus anticoagulant and protein S deficiency in children with postvaricella purpura fulminans or thrombosis. J Pediatr . 1996; 128 319-323
38 McColl M D, Chalmers E A, Thomas A. et al . Factor V Leiden, prothrombin 20210GA and the MTHFR C677T mutations in childhood stroke. Thromb Haemost . 1999; 81 690-694
39 Zenz W, Bodo Z, Plotho J. et al . Factor V Leiden and prothrombin gene G20210A variant in children with stroke. Thromb Haemost . 1998; 80 763-766
40 Miller V. Neonatal cerebral infarction. Semin Pediatr Neurol . 2000; 7 278-288
41 Nguyen P, Reynaud J, Pouzol P, Munzer M, Richard O, Francois P. Varicella and thrombotic complications associated with transient protein C and protein S deficiencies in children. Eur J Pediatr . 1994; 153 646-649
42 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 ischaemic stroke in childhood. Blood . 1999; 94 3678-3682
43 Prengler M, Sturt N, Krywawych S, Surtees R, Liesner R, Kirkham F. Homozygous thermolabile variant of the methylenetetrahydrofolate reductase gene: a potential risk factor for hyperhomocysteinaemia, CVD, and stroke in childhood. Dev Med Child Neurol . 2001; 43 220-225
44 Dusser A, Goutieres F, Aicardi J. Ischemic strokes in children. J Child Neurol . 1986; 1 131-136
45 Lanska M J, Lanska D J, Horwitz S J, Aram D M. Presentation, clinical course, and outcome of childhood stroke. Pediatr Neurol . 1991; 7 3337-3341
46 Delsing B JP, Catsman-Berrevoets C E, Appel I M. Early prognostic indicators of outcome in ischaemic childhood stroke. Pediatric Neurol . 2001; 24 283-289
47 Ganesan V, Hogan A, Jones A, Shack N, Kirkham F J. Parent-reported outcome in ischaemic stroke. Dev Med Child Neurol . 2000; 42 455-461
48 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 13-16
49 Shaffer L, Rich P M, Pohl K R, Ganesan V. Can mild head injury cause ischaemic stroke?. Arch Dis Child . 2003; 88 267-269
50 Hoggard N, Wilkinson I D, Griffiths P D. The imaging of ischaemic stroke. Clin Radiol . 2001; 56 171-183
51 Ganesan V, Kirkham F J. Recurrence after ischaemic stroke in childhood. Dev Med Child Neurol . 1998; 40(Suppl 79) 7
52 Husson B, Rodesch G, Lasjaunias P, Tardieu M, Sebire G. Magnetic resonance angiography in childhood arterial brain infarcts: a comparative study with contrast angiography. Stroke . 2002; 33 1280-1285
53 Askalan R, Laughlin S, Mayank S. et al . Chickenpox and stroke in childhood. A study of frequency and causation. Stroke . 2001; 32 1257-1262
54 Bydder G M, Rutherford M A. Diffusion-weighted imaging of the brain in neonates and infants. Magn Reson Imaging Clin N Am . 2001; 9 83-98
55 Kirkham F J, Hewes D KM, Prengler M, Wade A, Lane R, Evans J PM. Nocturnal hypoxaemia and central-nervous-system events in sickle-cell disease. Lancet . 2001; 357 1656-1659
56 Hargrave D R, Wade A, Evans J P, Hewes D K, Kirkham F J. Nocturnal oxygen saturation and painful sickle cell crises in children. Blood . 2003; 101 846-848
57 Van Beynum M I, Smeitink J A, den Heijer M, te Poele Pothoff T M, Blom H J. Hyperhomocysteinemia: a risk for ischemic stroke in children. Circulation . 1999; 99 2070-2072
58 Sträter R, Becker S, von Eckardstein A. et al . Prospective evaluation of risk factors for recurrent stroke during childhood-results of a 5-year-follow-up. Lancet . 2002; 360 1540-1545
59 deVeber G, Monagle P, Chan A. et al . Prothrombotic disorders in infants and children with cerebral thromboembolism. Arch Neurol . 1998; 55 1539-1543
60 Lanthier S, Lindsay S, Mitchell L. et al . Anticardiolipin antibodies are associated with cardioembolic stroke but does not predict recurrent cerebral ischemia in children. Neurology . 2001; 56(Suppl 3) A11
61 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; 15 290-294
62 Sreenan C, Bhargava R, Robertson C MT. Cerebral infarction in the term newborn: clinical presentation and long-term outcome. J Pediatr . 2000; 137 351-355
63 Ganesan V, Chong W K, Cox T C, Chawda S J, Prengler M, Kirkham F J. Posterior circulation stroke in childhood: risk factors and recurrence. Neurology . 2002; 26(59) 1552-1556
64 Gordon A L, Ganesan V, Towell A, Kirkham F J. Functional outcome following stroke in children. J Child Neurol . 2002; 17 429-434
65 Mancini J, Girard N, Chabrol B. et al . Ischemic cerebrovascular disease in children: retrospective study of 35 patients. J Child Neurol . 1997; 12 193-199
66 Adams R J. Lessons from the stroke prevention trial in sickle cell anemia (STOP) study. J Child Neurol . 2000; 15 344-349
67 Russel M O, Goldberg H I, Hodson A. et al . Effect of transfusion therapy on arteriographic abnormalities and on recurrence of stroke in sickle cell disease. Blood . 1984; 63 162-169
68 Ware R E, Zimmerman S A, Schultz W H. Hydroxyurea as an alternative to blood transfusions for the prevention of recurrent stroke in children with sickle cell disease. Blood . 1999; 94 3022-3026
69 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; 13 595-600
70 Albers G W, Easton J D, Sacco R L, Teal P. Antithrombotic and thrombolytic therapy for ischemic stroke. Chest . 1998; 114 S683-S698
71 Catto A, Zarter A, Irland H. et al . Factor V Leiden gene mutation and thrombin generation in relation to the development of acute stroke. Arterioscler Thromb Vasc Biol . 1995; 15 783-785
72 Press R D, Liu X Y, Beamer N, Coull M. Ischemic stroke in the elderly. Stroke . 1996; 27 44-48
73 Martinelli I, Franchi F, Akwan S, Bettini P, Merati G, Mannucci P M. The transition G to A at position 20210 in the 3'-untranslated region of the prothrombin gene is not associated with cerebral ischemia. Blood . 1997; 90 3806
74 Longstreth W T, Rosendaal F R, Siscovick D S. et al . Risk of stroke in young women and two prothrombotic mutations: factor V Leiden and prothrombin gene variant (G20210A). Stroke . 1998; 29 577-580
75 The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med . 1995; 333 1581-1587
76 Kaste M, Thomassen L, Grond M. et al . Thrombolysis for acute ischaemic stroke. A consensus statement of the 3rd Karolinska Stroke Update, October 30-31, 2000. Stroke . 2001; 32 2717-2718
77 Wardlaw J M, Warlow C P, Counsell C. Systematic review of evidence on thrombolytic therapy for acute ischaemic stroke. Lancet . 1997; 350 607-614
78 Kitzmüller E, Gruber A, Marx M. Supraselective intra-arterial thrombolysis for acute cardioembolic stroke in a child with idiopathic dilated cardiomyopathy. Intervent Radiol . 1999; 5 187-194
79 Gruber A, Nasel C, Lang W, Kitzmüller E, Bavinzki G, Czech T. Intra-arterial thrombolysis for the treatment of perioperative childhood cardioembolic stroke. Neurology . 2000; 54 1684-1686
80 Thirumalai S S, Shubin R A. Successful treatment for stroke in a child using recombinant tissue plasminogen activator. J Child Neurol . 2000; 15 558
81 Noser A, Felberg R A, Alexandrov A V. Thrombolytic therapy in an adolescent ischaemic stroke. J Child Neurol . 2001; 16 286-288
82 The International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. Lancet . 1997; 349 1569-1581
83 CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. Lancet . 1997; 349 1641-1649
84 Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Br Med J . 2002; 324 71-84
85 Hankey G J, Sudlow C LM, Dunbabin D W. Thienopyridines or aspirin to prevent stroke and other serious vascular events in patients at high risk of vascular disease?. <~>A systemic review of the evidence from randomized trials. Stroke . 2000; 31 1779-1784
86 Diener H C, Cunha L, Forbes C. et al . European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci . 1996; 143 1-13
87 Wallace R C, Furlan A J, Molterno D J. et al . Basilar artery rethrombosis: successful treatment with platelet glycoprotein IIb/IIIa receptor inhibitor. Am J Neuroradiol . 1997; 18 1257-1260
88 Hathaway W E. Use of antiplatelet agents in pediatric hypercoagulable states. Am J Dis Child . 1984; 138 301-304
89 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 stroke patients. A prospective follow-up study. Stroke . 2001; 32 2554-2558
90 LeBlanc J, Sett S, Vince D. Antiplatelet therapy in children with left-sided mechanical prostheses. Eur J Cardiothorac Surg . 1993; 7 211-215
91 Carcao M D, Blanchette V S, Dean J A. et al . The platelet function analyser (PFA-100): a novel in-vitro system for evaluation of primary haemostasis in children. Br J Haematol . 1998; 101 70-73
92 Israels S, Cheang T, McMillan-Ward E M, Cheang M. Evaluation of primary hemostasis in neonates with a new in vitro platelet function analyzer. J Pediatr . 2001; 138 116-119
93 Sandercock P AG, van den Belt G M A, Lindley R I, Slattery J. Antithrombotic therapy in acute ischaemic stroke: an overview of the completed randomised trials. J Neurol Neurosurg Psychiatry . 1993; 56 17-25
94 Andrew M, Marzinotto V, Blanchette V. et al . Heparin therapy in pediatric patients: a prospective cohort study. Pediatr Res . 1994; 35 78-83
95 Schmugge M, Risch L, Huber A R, Benn A, Fischer J E. Heparin-induced thrombocytopenia-associated thrombosis in pediatric intensive care patients. Pediatrics . 2002; 109 U69-U72
96 Zöhrer B, Zenz W, Rettenbacher A. et al . Danaparoid sodium (Orgaran;rM) in four children with heparin-induced thrombocytopenia type II. Acta Paediatr . 2001; 90 765-771
97 Hirsh J, Levine M. Low-molecular-weight heparin. Blood . 1992; 79 1-17
98 Kay R, Wong K S, Yu Y L. et al . Low-molecular-weight heparin for the treatment of acute ischaemic stroke. N Engl J Med . 1995; 333 1588-1593
99 Samama M M, Desnoyers P C, Conard J, Busser M G. Acute ischaemic stroke and heparin treatments. Thromb Haemost . 1997; 78 173-179
100 Kalafut M A, Gandhi R, Kidwell C S, Saver J L. Safety and cost of low-molecular-weight heparin as bridging anticoagulant therapy in subacute cerebral ischaemia. Stroke . 2000; 31 2563-2568
101 Bath P MW, Iddenden R, Bath F J. Low-molecular-weight heparins and heparinoids in acute ischaemic stroke-a meta-analysis of randomized controlled trials. Stroke . 2000; 31 1770-1778
102 Dix D, Andrew M, Marzinotto V. et al . The use of low-molecular-weight heparin in pediatric patients: a prospective cohort study. J Pediatr . 2000; 136 439-445
103 Mary V, Wahl F, Uzan A, Stutzmann J M. Enoxaparin in experimental stroke. Neuroprotection and therapeutic window of opportunity. Stroke . 2001; 32 993-999
104 Massicotte P, Adams M, Marzinotto V. et al . Low-molecular-weight heparin in pediatric patients with thrombotic disease: a dose finding study. J Pediatr . 1996; 128 313-318
105 Hofmann S, Knoefler R, Lorenz N. et al . Clinical experience with low-molecular-weight heparins in pediatric patients. Thromb Res . 2001; 103 345-353
106 Mohr J P, Thompson J LP, Lazar R M. et al . A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med . 2001; 345 1444-1451
107 Andrew M, Marzinotto V, Brooker L. et al . Oral anticoagulant therapy in pediatric patients. A prospective study. Thromb Haemost . 1994; 71 265-269
108 Streif W, Andrew M, Marzinotto V. et al . Analysis of warfarin therapy in pediatric patients: a prospective cohort study of 319 patients. Blood . 1999; 94 3007-3014
109 Massicotte P, Marzinotto V, Vegh P, Adams M, Andrew M. Home monitoring of warfarin therapy in children with a whole blood prothrombin time monitor. J Pediatr . 1995; 127 389-394