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NeoReviews Vol.9 No.1 2008 e39
© 2008 American Academy of Pediatrics

Index of suspicion in the nursery

	Case Presentation

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A 2,496-g male infant was born at term to a 20-year-old primiparous African American woman whose pregnancy was complicated by a primary herpes simplex virus (HSV) outbreak 9 days prior to delivery. Prenatal laboratory findings were unremarkable, including negative results for human immunodeficiency virus, syphilis, hepatitis B, and group B Streptococcus screening tests and a normal glucose tolerance test result. The mother presented to the labor and delivery unit of a community hospital with concerns about decreased fetal movement. Fetal heart rate monitoring revealed late decelerations and lack of heart rate variability, so an emergent cesarean section was performed. At delivery, thick meconium was present, and the infant had abnormally increased tone, decorticate posturing, and minimal respiratory effort. Meconium was suctioned from below the vocal cords, after which the infant began crying spontaneously. Apgar scores at 1 and 5 minutes were 5 and 8, respectively. The infant was transferred to the nursery, where pulse oximetry revealed fluctuating oxygen saturations of 80% to 90%. He was placed under an oxygen hood with an FiO₂ of 0.50 to maintain oxygen saturations greater than 90%. On physical examination, he exhibited increased work of breathing with retractions and abnormally increased tone.

At 30 minutes after birth, the infant developed overt seizure activity manifested by lip smacking, eye deviation, and tonic-clonic movements of the extremities. A dextrose stick revealed a blood glucose concentration of less than 20 mg/dL (1.1 mmol/L), so a bolus of 10% dextrose solution was administered. Hypoglycemia persisted, requiring additional boluses of 10% dextrose and administration of dextrose-containing maintenance intravenous fluids. The infant ultimately required a glucose infusion rate of 8 mg/kg per minute to maintain euglycemia. Despite blood glucose concentrations of greater than 40 mg/dL (2.2 mmol/L), seizure activity continued for more than 20 minutes, finally ceasing after administration of two doses of lorazepam and a loading dose of phenobarbital. A sepsis evaluation, including blood culture, cerebrospinal (CSF) culture, and polymerase chain reaction testing of CSF for HSV, was completed, and ampicillin, gentamicin, and acyclovir therapy was initiated. The infant was transported emergently to a level III neonatal intensive care unit (NICU) for further management. Admission laboratory tests revealed significant thrombocytopenia. Findings on a computed tomography (CT) scan of the head led to the diagnosis.

	Case Discussion

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     Differential Diagnosis and Case Progression
The differential diagnosis for seizures in this neonate included metabolic derangements (hypoglycemia), infection (bacterial or HSV), hypoxic-ischemic injury, stroke, central nervous system structural abnormalities, and intracranial hemorrhage. The infant’s seizures were attributed initially to hypoglycemia, but the seizure activity persisted after blood glucose concentrations normalized, prompting a head CT scan. The head CT scan revealed extensive dural venous sinus thromboses with significant dural venous congestion. Subsequent magnetic resonance imaging (including angiography and venography) confirmed the presence of thromboses in the superior sagittal sinus, straight sinus, proximal aspects of the transverse sinuses, and multiple cortical veins, but showed the development of collateral venous drainage with no evidence of ischemia or infarction of the brain parenchyma. The infant and his mother were evaluated for prothrombotic conditions. Hematology studies revealed low protein C activity, low-normal protein S activity, and normal antithrombin 3 activity in the infant. The mother’s study results were unremarkable. The father was unavailable for laboratory evaluation, but reportedly had multiple people in his family who had deep venous thromboses or cerebrovascular accidents at young ages, raising suspicion for an inherited hypercoagulability disorder in the father’s family. Because of the massive extent of cerebral vein involvement and the laboratory values suggesting protein C deficiency, the infant was started on anticoagulation therapy, initially with intravenous heparin, then switched to low-molecular weight heparin.

The infant’s NICU course was complicated by thrombocytopenia requiring multiple platelet transfusions and prolonged hypoglycemia requiring glucose infusion rates up to 13 mg/kg per minute to maintain euglycemia. Findings of an extensive endocrine evaluation for pathologic causes of hypoglycemia were unremarkable. By postnatal day 7, the infant was able to maintain normoglycemia on oral feedings of human milk and term formula without additional intravenous supplementation. He had normal electroencephalography results and exhibited no further seizure activity during his hospitalization. He was discharged from the hospital NICU on postnatal day 16 with normal findings on physical examination and continued anticoagulation therapy with low-molecular weight heparin.

     Pathophysiology
Neonatal seizures are caused most commonly by perinatal hypoxic-ischemic events, but the differential diagnosis of neonatal seizures is broad and includes dural venous sinus thrombosis. (1)(2) Dural, or cerebral, venous sinus thrombosis occurs in approximately 0.67 per 100,000 children per year, with neonates comprising the largest represented age range. (3) Dural venous sinus thromboses occur most commonly in the superior sagittal sinus, lateral sinuses, and straight sinus; the vein of Galen, internal cerebral vein, jugular vein, and cortical veins occasionally are affected. (3)(4) The most common presenting sign of dural venous sinus thrombosis in neonates is seizure. (3)

Cerebral venous sinus thrombosis can be diagnosed by CT scan or Doppler ultrasonography, but magnetic resonance imaging with venography is the optimal technique for establishing the diagnosis. Risk factors for venous sinus thrombosis in neonates include hypoxia, premature rupture of membranes, maternal infection, placental abruption, gestational diabetes, dehydration, and acquired and congenital prothrombotic disorders. (2) Prothrombotic disorders associated with venous sinus thrombosis include deficiencies of proteins C and S, fibrinogen, and antithrombin, as well as the presence of lupus anticoagulant, anticardiolipin antibody, factor V Leiden, and the prothrombin G20210A gene mutation. (3)(5) In the Canadian Pediatric Ischemic Stroke Registry, 32% of the children who underwent testing for prothrombotic disorders had at least one abnormality, but the presence of a prothrombotic state was more common among older children than neonates. (3) Interestingly, only 3% of dural venous sinus thromboses were idiopathic in the Canadian Pediatric Ischemic Stroke Registry. (3) Although inherited prothrombotic disorders are less common than acquired hypercoagulable states in children, inherited disorders most often are identified in cases of otherwise idiopathic venous sinus thrombosis.

     Treatment and Long-term Outcome
The use of anticoagulation in children who have cerebral venous sinus thrombosis is controversial. (2)(3) In neonates, options for anticoagulation include heparin and low-molecular weight heparin. Because of the extent of thrombosis in this patient and the possibility of protein C deficiency, anticoagulation therapy was initiated with intravenous heparin. Prior to discharge, the infant was transitioned to subcutaneous low-molecular weight heparin (enoxaparin). The infant will need further laboratory evaluation, including repeat measurements of protein C and S at 4 to 6 months of age, to confirm the diagnosis because the low protein C activity on initial evaluation may have resulted from protein C consumption after the initial thrombotic event.

The long-term outcome of neonates who have dural sinus venous thrombosis is unclear. The best available estimate is that after a mean follow-up period of 2.1 years, 77% of neonates are neurologically normal. (6) In the Canadian Pediatric Ischemic Stroke Registry, the presence of infarcts in conjunction with dural sinus venous thrombosis predicted adverse neurologic outcomes in neonates. Long-term follow-up of affected neonates is important because the onset of signs of neurologic injury can be delayed.

     Lessons for the Clinician
Cerebral venous sinus thrombosis is a rare but serious condition that can cause seizures in neonates. Inherited prothrombotic disorders often are identified in cases of dural venous sinus thrombosis that appear to be idiopathic. A hypercoagulability evaluation is indicated at some point in infants presenting with dural venous sinus thrombosis, although interpretation of the results may be difficult during the acute thrombotic event. The use of anticoagulation in affected neonates remains controversial. (Benjamin Blevins, MD, Department of Pediatrics, Uniformed Services University of Health Sciences, Bethesda, Md.; Amy K. Evans, MD, Department of Pediatrics, National Naval Medical Center, Bethesda, Md.; Ryan T. Moore, MD, Department of Pediatrics, Uniformed Services University of Health Sciences, Bethesda, Md., and Department of Pediatrics, Walter Reed Army Medical Center, Washington, DC; Nicole R. Dobson, MD, Department of Pediatrics, Uniformed Services University of Health Sciences, Bethesda, Md., and Department of Pediatrics, Walter Reed Army Medical Center, Washington, DC)

The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Army, the Department of the Navy, the Department of Defense, or the US Government.

Benjamin Blevins, MD
Amy K. Evans, MD
Ryan T. Moore, MD
Nicole R. Dobson, MD

Department of Pediatrics, Uniformed Services University of Health Sciences, Bethesda, Md
Department of Pediatrics, National Naval Medical Center, Bethesda, Md
Department of Pediatrics, Walter Reed Army Medical Center, Washington, DC

	Footnotes

 
Author Disclosure

Drs Blevins, Evans, Moore, and Dobson did not disclose any financial relationships relevant to this case.

	References

Top Case Presentation Case Discussion References

 
1. Zupanc M. Neonatal seizures. Pediatr Clin North Am. 2004;51 :961 –978[CrossRef][Medline]

2. Thornburg C, Pipe S. Neonatal thromboembolic emergencies. Semin Fetal Neonat Med. 2006;11 :198 –206[CrossRef]

3. deVeber G, Andrew M, Adams C, et al. Cerebral sinovenous thrombosis in children. N Engl J Med. 2001;345 :417 –423[Abstract/Free Full Text]

4. Sebire G, Tabarki B, Saunders D, et al. Cerebral venous sinus thrombosis in children: risk factors, presentation, diagnosis and outcome. Brain. 2005;128 :477 –489[Abstract/Free Full Text]

5. Nowak-Gottl U, Kosch A, Schlegel N. Neonatal thromboembolism. Semin Thromb Hemost. 2003;29 :227 –234[CrossRef][Medline]

6. deVeber G, MacGregor D, Curtis R, Mayank S. Neurologic outcome in survivors of childhood arterial ischemic stroke and sinovenous thrombosis. J Child Neurol. 2000;15 :316 –324[Abstract/Free Full Text]

This Article Extract Full Text (PDF) E-Letters: Submit a response Alert me when this article is cited Alert me when E-Letters are posted Alert me if a correction is posted Services E-mail this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Request Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Blevins, B. Articles by Dobson, N. R. Search for Related Content PubMed Articles by Blevins, B. Articles by Dobson, N. R.