Correspondence

Cerebral Sinovenous Thrombosis

N Engl J Med 2001; 345:1777-1778December 13, 2001

Article

To the Editor:

The study by deVeber and colleagues (Aug. 9 issue),1 which reported 12 deaths among 160 children with cerebral sinovenous thrombosis, raises important issues about the future treatment of such patients, since only 1 of the children received any type of fibrinolytic therapy (urokinase was used in a nonneonate). It is unclear whether this single patient benefited from treatment. Limited data show that local urokinase infusion can be a lifesaving treatment in children.2

I have successfully treated four young adults with cerebral-vein thrombosis by retrograde venous infusion of urokinase directly into the clot, with good outcomes in all. Two of these four patients presented with seizures, subcortical hemorrhagic changes, and rapid neurologic deterioration due to extensive thrombosis of the superior sagittal sinus. The condition of a third patient developed more slowly, with thrombosis of only the anterior half of the sinus; in a fourth patient, the deep cerebral veins were involved. In all four patients, remarkable sustained clinical and radiologic improvement was found with slow local urokinase infusions given for as long as 30 hours. An initial finding of associated secondary hemorrhagic changes, as identified in these 4 patients, as well as in 45 of the 66 patients with venous infarcts studied by deVeber et al., should not dissuade physicians from considering retrograde venous infusion of fibrinolytic agents directly into the clot, since this may have a lifesaving effect by relieving the obstruction and the secondary venous hypertension that caused the bleeding.

Michael Andrew Meyer, M.D.
Dent Neurologic Institute, Williamsville, NY 14221

2 References

1
deVeber G, Andrew M, Adams C, et al. Cerebral sinovenous thrombosis in children. N Engl J Med 2001;345:417-423
Full Text | Web of Science | Medline

2
Griesemer DA, Theodorou AA, Berg RA, Spera TD. Local fibrinolysis in cerebral venous thrombosis. Pediatr Neurol 1994;10:78-80
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Author/Editor Response

The authors reply:

To the Editor: We thank Dr. Meyer for raising the important issue of catheter-directed thrombolytic therapy for cerebral sinovenous thrombosis by describing his successful treatment of four adults. He suggests that this therapy should be considered on the basis of the deaths of 12 children in our study.

As stated in our report, 6 of the 12 deaths in our cohort of 160 children were attributable to sinovenous thrombosis, a disease-specific mortality of 4 percent. Among the six patients who died was the one patient who received catheter-directed urokinase. Of the other five, one was treated with anticoagulants alone, and four were treated without anticoagulants. Among 85 children treated with anticoagulants (unfractionated or low-molecular-weight heparin), only 1 child died from sinovenous thrombosis, and no child experienced major hemorrhagic complications.

In several case reports of catheter-directed thrombolytic therapy for sinovenous thrombosis in neonates and children, the treatment was successful, but one major hemorrhagic complication was reported.1 A cohort study of seven consecutive children with systemic thrombosis reported successful lysis in only one, with major complications in three.2 A large population-based study of children with deep-vein thrombosis reported a failure of thrombolytic therapy in one third of children to whom it was administered.3 The hemostatic system in children differs significantly from that in adults. Neonates have reduced plasminogen levels, and in children levels of plasminogen-activator inhibitor type 1, the primary inhibitor of tissue plasminogen activator, and α₂-macroglobulin, a plasmin inhibitor, are increased.4 These differences may result in a relative resistance to fibrinolytic therapy in childhood.

The first-line therapy recommended for adults with cerebral sinus thrombosis is anticoagulation, on the basis of evidence from randomized, controlled trials.5 Catheter-directed thrombolysis for adult cerebral venous thrombosis has been reported in a number of small series. Reperfusion has been observed in the majority of cases. However, there is a risk of selection and publication bias. The risk of hemorrhage and the functional outcome have not been compared with those associated with heparin therapy. Although some authors advocate thrombolytic therapy for sinovenous thrombosis as an early intervention, most authors suggest limiting its use to life-threatening events or extension of thrombosis despite appropriate anticoagulant therapy.

We believe that there may be a role for catheter-directed thrombolysis in selected children or adults with sinus thrombosis. However, on the basis of the current evidence, we would recommend against this method of treatment as first-line therapy outside of carefully designed cohort studies or randomized, controlled trials.

Gabrielle deVeber, M.D.
Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
deveber@sickkids.on.ca

Michele David, M.D.
University of Montreal, Montreal QC, Canada

Lesley Mitchell, A.R.T., M.Sc.
Hospital for Sick Children, Toronto, ON M5G 1X8, Canada

5 References

1
Horowitz M, Purdy P, Unwin H, et al. Treatment of dural sinus thrombosis using selective catheterization and urokinase. Ann Neurol 1995;38:58-67
CrossRef | Web of Science | Medline

2
Monagle P, Phelan E, Downie P, Andrew M. Local thrombolytic therapy in children. Thromb Haemost 1997;77:Suppl:504-504 abstract.
Web of Science | Medline

3
Andrew M, David M, Adams M, et al. Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE. Blood 1994;83:1251-1257
Web of Science | Medline

4
Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L. Maturation of the hemostatic system during childhood. Blood 1992;80:1998-2005
Web of Science | Medline

5
Albers GW, Amarenco P, Easton JD, Sacco RL, Teal P. Antithrombotic and thrombolytic therapy for ischemic stroke. Chest 2001;119:Suppl 1:300S-320S
CrossRef | Web of Science | Medline

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