Child’s Nerv Syst (1999) 15: 128 – 130 © Springer-Verlag 1999 O. Witt P. L. Pereira W. Tillmann Received: 12 May 1998 O. Witt (½) 1 · W. Tillmann Kinderklinik Minden, Portastrasse 7–9, D-32390 Minden, Germany P. L. Pereira Abteilung für Radiologische Diagnostik, Radiologische Klinik, Eberhard-Karls-Universität Tübingen, Hoppe-Seyler-Strasse, D-72076 Tübingen, Germany Present address: 1 Universitäts-Kinderklinik, Robert-Koch-Strasse 40, D-37075 Göttingen, Germany Tel.: +49-551-394 601 Fax: +49-551-396 252 CASE REPORT Severe cerebral venous sinus thrombosis and dural arteriovenous fistula in an infant with protein S deficiency Abstract A 12-month-old infant presented with cerebral seizures and neurological deficits. MRI scan of the brain and angiography showed massive cerebral venous sinus thrombosis complicated by a dural arteriovenous fistula. Subsequent clotting analysis revealed a protein S deficiency. Screening for inherited coagulation inhibitor deficiency is recommended in children with unexplained or atypical thrombotic events. Introduction Protein S is an important inhibitor of the clotting cascade. Its deficiency results in a hypercoagulable state most commonly presenting as deep vein thrombosis, but uncommon sites of thrombosis and arterial thrombembolic events in young patients have been published. In this paper we report the clinical course of an infant with protein S deficiency who suffered from a particularly severe venous sinus thrombosis complicated by a dural arteriovenous fistula. To our knowledge, this is the first report of the association of venous sinus thrombosis, AV malformation and an inherited coagulation inhibitor defect. Case report After a 1-week history of upper respiratory febrile infection, sudden onset of generalized tonic-clonic seizures developed in a 12-monthold male infant. On admission the boy was somnolent with generalized muscle hypotonia, and he had signs of an upper respiratory in- Key words Venous sinus thrombosis · Dural arteriovenous fistula · Protein S deficiency fection without fever. The remaining physical examination was normal. There was no history of previous seizures, and the medical and family history was noncontributory. Initial laboratory evaluation, including full blood count, C-reactive-protein, serum electrolytes, serum glucose, blood gases, liver function tests, kidney function tests, prothrombin time, partial thromboplastin time, and cerebrospinal fluid, yielded normal values. EEG and fundoscopy revealed no pathologic findings. The boy was treated for possible meningoencephalitis. The treatment was discontinued following negative spinal fluid cultures and an uncomplicated clinical course. Within the next few days after admission the boy developed progressive left-sided muscle weakness and gradually lost his ability to pull himself up into a standing position and to sit without support. Contrast-enhanced computed tomography (CT) of the brain showed a vascular malformation with an internal and external hydrocephalus. Magnetic resonance imaging (MRI; Fig. 1) with MR angiography (MRA) and cerebral angiography (Fig. 2) confirmed the diagnosis of a dural arteriovenous malformation localized in the torcular region, associated with stenosis of the right lateral sinus and of the left jugular bulb. The venous drainage was very poor, with the occipital sinus representing the only venous exit route owing to massive thrombosis of the entire venous system with subsequent hyperpressure and congestion. An embolization of the dural arteriovenous fistula was performed in an outside medical center (Prof. P. Lasjaunias, Unité de Neuroradiologie Vasculaire, Centre Hospitalier de Bicêtre, Le Kremlin Bicêtre, France) resulting in occlusion of three pedicles of the malformation. 129 Table 1 Review of nine pediatric cases with venous sinus thrombosis associated with a hereditary coagulation inhibitor deficiency (PS protein S, ATIII antithrombin III, PC protein C, URI upper respiratory infection) Fig. 1 MRI of the brain (sagittal view, T1 weighted) suggests a large occipital vascular malformation (arrow) with ectatic latero-mesencephalic veins and enlargement of the subarachnoidal spaces Age (years) Sex Deficiency state Risk Reference 7 2 14 4 1 16 17 2 weeks 18 M M F M M M M M F PS PS PS PS PS ATIII ATIII ATIII PC No Pneumonia Contraception Head trauma URI Surgery No No Delivery [15] [17] [11] [18] This case [9] [10] [3] [20] gen, antithrombin III, protein C levels and activated protein C resistance were within normal limits. Plasma amino acid chromatography showed no evidence of homocystinuria. The patient received intravenous heparin for anticoagulation, and oral anticoagulation treatment was then started. However, despite chronic anticoagulation therapy and intense physiotherapy the boy’s neurological condition gradually deteriorated. At the age of 2 years, his neuromotor developmental status was equal to that of a 6-month-old infant. The patient died at the age of 2 years following sudden cardiorespiratory arrest at home after a 2-day history of herpetic gingivostomatitis. Discussion Fig. 2 Right carotid angiogram view shows stenosis of the lateral sinuses and confirms a dural arteriovenous fistula in the torcular region fed by the middle meningeal artery and by the occipital artery. Venous drainage was mainly by way of the occipital sinus Shortly after this procedure the boy’s neurological condition improved and the patient started to regain his ability to sit without support. Extended clotting studies revealed a reproducible deficiency of unbound protein S (40% and 45%, respectively, normal 60–150%), whereas total protein S was normal in one sample and lowered in another sample (63% and 52% respectively, normal 60–150%). Fibrino- In addition to antithrombin III deficiency, protein C deficiency and activated protein C resistance, protein S deficiency is among the most common causes of hereditary blood protein defects associated with thrombosis [1, 6]. Onset of symptoms in early childhood is rare and usually presents with deep vein thrombosis, which is similar to the presentation in adults [2, 5]. However, reports of uncommon sites of thrombosis such as stroke [8], chronic pulmonary embolism [14], arterial leg thrombosis [7], purpura fulminans [4], and venous sinus thrombosis have been published (Table 1). Our review of the pediatric literature revealed nine cases of venous sinus thrombosis associated with a deficiency of a coagulation inhibitor: protein S deficiency in five cases, antithrombin III deficiency in three cases and protein C deficiency in one case (Table 1). Interestingly, seven of these nine cases were in male patients. Most of these patients had an additional risk factor for precipitation of a thrombotic event. Our patient presented with a particularly severe thrombosis involving almost the entire cerebral venous drainage, associated with a dural arteriovenous malformation as evidenced by MRI scan and cerebral angiography. This associated AV malformation had probably arisen from the venous hyperpressure owing to the severe occlusion of the cerebral venous drainage. On the other hand, arteriovenous malformations per se are known to cause cerebral venous thrombosis in infants, resulting in external and internal hy- 130 drocephalus and brain atrophy [19]. Treatment of cerebral arteriovenous malformations by an endovascular approach has been recommended in children, before irreversible brain damage has occurred [13, 19]. Oral anticoagulation therapy in patients with protein S deficiency appears to prevent recurrent venous thrombosis in adults [5, 12], but no data are available on long-term oral anticoagulation therapy in children with protein S deficiency. The unfortunate outcome of this case was probably due to the severe brain atrophy already manifest on admission, which suggested that a subclinical sinus thrombosis had evolved over a relatively long period prior to the first apparent clinical event. We conclude that the presentation of an unexplained cerebral thrombosis and AV malformation in a child must alert the physician to screen for a possible inherited coagulation inhibitor deficiency. References 1. Bick RL (1994) Hypercoagulability and thrombosis. Med Clin North Am 78: 635–665 2. 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