Stroke in a Neonate Heterozygous for Factor V Leiden Panayiotis N. Varelas, MD*, Barbara J. Sleight, MD†, Henry M. Rinder, MD‡, Gordon Sze, MD§, and Laura R. Ment, MD*† Activated protein C resistance is the most common hereditary coagulation abnormality and is caused by the factor V Leiden mutation. A newborn who developed seizures within hours after delivery and was found to have a bihemispheric stroke is described. This patient, determined to be heterozygous for factor V Leiden, is the first reported case of neonatal stroke associated with this common mutation. © 1998 by Elsevier Science Inc. All rights reserved. Varelas PN, Sleight BJ, Rinder HM, Sze G, Ment LR. Stroke in a neonate heterozygous for factor V Leiden. Pediatr Neurol 1998;18:262-264. Introduction In neonates, cerebral infarction is a relatively uncommon entity as compared with adults, with a 5.4% incidence among 592 infants examined at postmortem examination [1]. Stroke usually follows seemingly normal deliveries and more often involves the left anterior circulation than it does the right. Infarction may be secondary to either thrombotic or embolic causes, and major roles may be played by placental thrombi, congenital heart disease, sepsis, traumatic vascular damage, consumptive coagulopathy, or metabolic disorders [1-3]. Dural sinus thrombosis has also been described as a cause of stroke [4,5]. Activated protein C resistance (APC-R) is now recognized as the most prevalent hereditary risk factor of venous thrombosis, occurring in 20-60% of cases. Together with protein C, protein S, and antithrombin III From the Departments of *Neurology; †Pediatrics; ‡Laboratory Medicine; and §Diagnostic Radiology; Yale University School of Medicine; New Haven, Connecticut. 262 PEDIATRIC NEUROLOGY Vol. 18 No. 3 deficiencies, the APC-R phenotype may account for 6070% of cases of familial thrombophilia [6]. In 1994, Bertina et al. [7] reported an association of the APC-R phenotype with the presence of a guanidine-to-adenine substitution at nucleotide 1691 of the gene for coagulation factor V. The resultant factor V protein, having a glutamine substitution for arginine at amino acid 506 (FV R506Q), is termed factor V Leiden. In its activated form, this mutant protein is resistant to APC cleavage action, leading to a hypercoagulable state [7]. The Leiden mutation is found in more than 90% of cases with APC-R [8]. We report a neonate with APC-R and heterozygosity for factor V Leiden who presented in the newborn period with cerebral infarction. Case Report A 3,340-gm term male infant was born by vaginal delivery to a 32year-old mother, gravida 1, para 0 whose pregnancy was complicated by class A diabetes. Two days before delivery, decreased fetal movements were experienced, and on the day of delivery a nonstress test was abnormal. Delivery was induced by pitocin. The infant appeared healthy, with Apgar scores of 8 at 1 min and 9 at 5 min. The placenta appeared normal to visual inspection but was not subjected to pathologic analysis. At 3 hours of age, the patient developed tachypnea and jittery movements; 9 hours later he had an apneic episode followed by tonic posturing and deviation of the eyes to the right. Between ictal events, cranial nerves were normal, and he displayed decreased activity and increased passive tone and his deep tendon reflexes were 31. Serum electrolytes, blood/urea/nitrogen/creatinine, liver function tests, ammonia, lactate, pyruvate, pyruvate kinase, Venereal Diseases Research Laboratories and urine toxicology screen were normal, as were urine analysis of amino and organic acids. The electroencephalogram revealed rhythmic sharp activity emanating from the left temporal region that improved after treatment with intravenous phenobarbital. A cranial sonogram showed bilateral white matter edema, left . right, without signs of superior sagittal sinus thrombosis. An echocardiogram revealed a patent foramen ovale and ductus arteriosus with left to right shunt. On postnatal day 2, a computed tomography (CT) scan of the head revealed bilateral parieto-temporal hemorrhagic infarcts, again left . right (Fig 1). No sagittal or other sinus hyperdensity was observed. When the CT was repeated on day 7, no change was noted. His head circumference remained stable, and he progressively developed very brisk tendon reflexes with poor Moro’s reflex and improving sucking. He was started on oral feedings and on day 13 was discharged. Five months later, a magnetic resonance imaging (MRI) scan of the brain was obtained. It revealed posterior left hemisphere volume loss, ex-vacuo dilatation of the occipital horn of the left lateral ventricle, and hemosiderin deposition, suggesting prior hemorrhagic infarct. There was no family history in close relatives of strokes or deep venous thrombosis. Coagulation studies revealed no IgM or IgG anticardiolipin antibodies; prothrombin and activated thromboplastin times were normal; activities of protein C (0.26), total (0.47) and free (0.58) Communications should be addressed to: Dr. Ment; Departments of Pediatrics and Neurology; Yale University School of Medicine; 333 Cedar Street; New Haven, CT 06510. Received April 21, 1997; accepted July 22, 1997. © 1998 by Elsevier Science Inc. All rights reserved. PII S0887-8994(97)00166-5 ● 0887-8994/98/$19.00 Figure 1. Computed tomography of the head, done on day 2 of life, showing the left parieto-temporal hemorrhagic infarct. A smaller hemorrhagic infarct is present in the contralateral hemisphere. protein S, and antithrombin III (0.42) were also normal. The APC-R ratio (Coatest, Chromogenix, Mölndal, Sweden) was 1.4 (normal . 2.30). To determine the presence of factor V Leiden (FV R506Q), genomic DNA extracted from blood was amplified by PCR as previously described [7]. The 276-bp amplified product was then digested with Mnl I (New England Biolabs, Beverly, MA) and electrophoresed through a 3% agarose gel. The sample was run simultaneously with positive controls (blood samples from homozygous and heterozygous factor V Leiden patients) and negative controls (blood samples from individuals with normal factor V), as well as with DNA controls to confirm complete endonuclease digestion. The patient was found to be heterozygous for factor V Leiden mutation, and this result was confirmed on duplicate testing of a separate patient sample. Discussion Heterozygosity for FV R506Q confers an estimated 5- to 10-fold increased risk of venous thrombosis; homozygotes may have a 50- to 100-fold increased risk [6]. Although myocardial infarction or stroke have been reported in patients with APC-R [9] or APC-R and FV R506Q [10], larger studies have not found an association [11]. Six of 63 (9.5%) adult stroke patients in a recent study demonstrated APC-R as compared with none of 31 Hispanic control subjects [12]. None of these six exhibited FV R506Q, suggesting that some methods for determining functional APC-R have a high falsepositive rate for diagnosis of factor V Leiden. In fact, recent functional APC-R assays, using dilutions of patient plasma with factor V-deficient plasma, appear to be nearly 100% concordant with the presence of factor V Leiden [13]. In some thrombophilic families, cosegregation of FV R506Q and other factor deficiencies including protein C [14], factor V [15], and antithrombin III or protein S deficiency [16] have been reported. The presence of other triggering factors in patients with FV R506Q, such as oral contraceptives, trauma, surgery, or pregnancy, has also been reported to increase thrombotic risk [17]. There have been a few reports of stroke in very young patients who were heterozygous for FV R506Q. One patient reported by Simioni et al. experienced a spontaneous stroke in both hemispheres at 8 months of age [17]. In two families with combined factor V Leiden and antithrombin III deficiency, a 10-day-old infant experienced a sagittal sinus thrombosis, while a 14-month-old child manifested venous thrombosis and stroke [16]. The first clinical indications of a central nervous system insult in our patient, i.e., apnea and seizures, presented a few hours after birth; these are common in neonates with stroke [1]. The decreased fetal movement 2 days before delivery and the abnormal nonstress test on the day of delivery could represent a prepartum insult. The head ultrasound revealed the white matter lesions in both hemispheres, but it was the head CT that first clearly revealed bilateral hemispheric hemorrhagic infarctions. The pathophysiology of our patient’s stroke may be attributed to the thrombophilic state, as well as to local factors that might have contributed to clot formation (i.e., decreased blood flow) or to embolism from a distal site through a patent foramen ovale. A dural sinus thrombosis was not visualized in either the sonogram or in either of the two CT scans, but MRI is currently considered to be the most sensitive diagnostic test [3]. Although it was not done at the time, a follow-up MRI was performed 5 months later. On this examination the sinuses appeared normal. In particular, even after recanalization of previous superior sagittal sinus thrombosis, residual amounts of organized thrombus often are visible in the course of the sinus itself, as are persistent collaterals. In this case, none of these findings were present. This fact, in combination with the fact that the original CT scans failed to demonstrate any evidence of thrombus, suggests that sagittal sinus thrombosis probably was not the cause of this infant’s intracerebral hemorrhages. As it does in older patients with stroke, a clot may have been lysed, with subsequent reperfusion bleeding. Inferior vena cava thrombosis (a potential embolic source for stroke) has been described in one neonate found to be heterozygous for FV R506Q [18]. In our patient, echocardiogram did not reveal a cardiac embolic source; a placental source could not be excluded because a pathologic examination was not performed. The risk for another stroke in heterozygous neonates for FV R506Q is unknown. In an adult carrier population the cumulative incidence of recurrent venous thromboembolism reached 40% after 8 years. Of these heterozygous patients, 9.8% (4/41) had a recurrent thromboembolic episode, as compared with 2.9% (6/210) of controls, while on anticoagulation treatment [19]. Given the lack of data in children, we do not presently recommend such treatment for neonates. Our patient is the first reported case of neonatal stroke associated with APC-R and heterozygosity for factor V Varelas et al: Factor V Leiden in Neonatal Stroke 263 Leiden. This finding suggests that, for neonates with unexplained stroke, further evaluation of clotting status and MRI of the head is indicated. References [1] Barmada MA, Moossy J, Shuman RM. Cerebral infarcts with arterial occlusion in neonates. Ann Neurol 1979;6:495-502. [2] Ment LR, Duncan CC, Ehrenkranz RA. Perinatal cerebral infarction. Ann Neurol 1984;16:559-68. [3] Grossman R, Novak G, Patel M, Maytal J, Ferreira J, Eviatar L. MRI in neonatal dural sinus thrombosis. Pediatr Neurol 1993;9: 235-8. [4] Medlock M, Olivero W, Hanigan W, Wright R, Winek S. 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