Seizures in a Term Newborn.

Abstract

A 31-year-old gravida 7, para 4 woman delivers a male infant via vaginal delivery without the use of forceps or vacuum extraction after induction of labor at 39 weeks and 2 days of gestation. The pregnancy was complicated by tobacco use throughout gestation. The mother received routine prenatal care and her laboratory findings were negative for infections, including group B Streptococcus. Membranes ruptured 2 hours before delivery, and the amniotic fluid was meconium stained. Resuscitation is routine, and the neonate’s Apgar scores are 8 and 9 at 1 and 5 minutes, respectively. The infant’s birthweight of 3,465 g places him in the 50th to 75th percentile for age and his length and head circumference are greater than the 90th percentile for age. He undergoes triage in the well-baby nursery where his admission physical examination findings are normal. He remains with his mother until approximately 22 hours after birth when he develops apnea and respiratory distress.Radiographs of the chest and abdomen are normal. The infant is transferred to the NICU. On admission, he is noted to have left face and eyelid twitching and left upper extremity stiffening associated with apnea and hypoxemia concerning for seizures. These episodes last 20 to 40 seconds and resolve spontaneously. The patient is given an intravenous phenobarbital load. An arterial blood gas measurement and complete blood cell count are within normal limits. A complete metabolic panel shows normal serum electrolytes, glucose, creatinine, and liver enzymes. A urine toxicology screen is negative. Bacterial blood culture and blood herpes simplex virus (HSV) polymerase chain reaction (PCR) are performed, and a lumbar puncture is attempted but unsuccessful. Umbilical artery and venous catheters are inserted, and intravenous ampicillin, gentamicin, and acyclovir are started. The infant is transferred to a level IV NICU for subspecialty care.The differential diagnosis of seizures in the newborn includes the following: Hypoxic ischemic encephalopathyNeonatal-onset epilepsy.Central nervous system infection.Electrolyte disturbances.Intracranial or extracranial hemorrhage.Stroke.Metabolic disorders.Intracranial hemorrhage due to hemophilia A.Upon admission to the level IV NICU, the patient undergoes intubation and receives mechanical ventilation for severe apnea. Computed tomography of the head without contrast shows extensive intracranial hemorrhage (ICH) in the pineal region and posterior fossa including the cerebellum with regional mass effect and compression of the fourth ventricle with obstructive hydrocephalus. Magnetic resonance angiography and venography are subsequently performed, which reveal patent intracranial arteries without arteriovenous or vein of Galen malformations. Due to significant mass effect on the brainstem, the infant undergoes a suboccipital craniectomy and cerebellar hemorrhage evacuation and expansile duraplasty on day 2 after birth, without major complications. The neonate receives 10 mL/kg of fresh frozen plasma (FFP) before the procedure.Although there was no family history of bleeding disorders, given the severity of the bleed, a bleeding diathesis evaluation is initiated. The patient is found to have a slightly prolonged prothrombin time of 16.9 seconds (normal 10.1–15.9 seconds [1]) and a significantly prolonged activated partial thomboplastin time of 78 seconds (normal 31.3–54.5 seconds [1]). International normalized ratio and fibrinogen are normal. Plasma clotting factor VIII (FVIII), factor IX, and factor XIII activity assays are obtained approximately 6 hours after the patient received FFP. Factors IX and XIII activity are normal for age; however, FVIII activity is low, at 12% (normal 50%–178% [1]).On postoperative day 1, FVIII replacement therapy is started. The patient receives therapy for a total of 12 days and FVIII activity remains more than 100% while receiving inpatient replacement therapy. Serial postoperative head imaging studies show residual blood in the central nervous system and a decrease in the size of the ventricles without additional hemorrhage.The patient has no additional seizures and phenobarbital is discontinued. He undergoes extubation on postoperative day 2 and is quickly weaned to room air. The blood culture is without growth and the HSV PCR from the blood is negative. Antibiotics and acyclovir are discontinued on day 3 after birth.The patient is discharged from the hospital on day 15 after birth without major neurologic deficits. FVIII activity is less than 1% at 1 and 2 months of age consistent with severe hemophilia A. The patient has 1 bleeding episode since discharge lasting several hours after cutting his finger which resolves without medical intervention. He continues to be followed in the hematology and neurosurgery clinics.Hemophilia A is an inherited bleeding disorder caused by a functional deficiency of FVIII, a plasma protein necessary for the generation of thrombin and fibrin. (2) Two-thirds of patients with hemophilia have a family history of the disorder, whereas the other one-third of patients represent sporadic cases. (2) Hemophilia A is inherited in an X-linked fashion and is caused by variants in F8, located at the distal portion of the X chromosome. (2) The prevalence of hemophilia A is estimated to be 1 in 4,000 male births in developed countries, with severe hemophilia A accounting for approximately one-third of cases. (3)The diagnosis of hemophilia A is often made in the setting of a positive family history or after a significant bleeding event in sporadic cases. Coagulation studies often reveal a prolonged partial thromboplastin time (PTT), and the diagnosis is confirmed with plasma factor activity (also called concentration or level). Hemophilia A is classified as mild, moderate, or severe based on the plasma activity of FVIII. (4) If plasma FVIII activity is less than 1% of normal, the hemophilia is designated as severe; if FVIII activity is 1% to 5% of normal, the hemophilia is designated as moderate; and if FVIII activity is greater than 5% but less than 40% of normal, the hemophilia is designated as mild. (4) The severity of clinical manifestations is often proportional to the concentration of factor present. (3) Diagnosing hemophilia in the newborn period presents unique challenges, as neonates have prolonged PTT due to a physiologic reduction in factor IX and other vitamin K–dependent factors. (2) Furthermore, the stress of birth may transiently increase FVIII concentration, further confusing the clinical picture. (2)Although ICH during the newborn period is infrequent in the general population, it remains a potentially life-threatening complication in patients with hemophilia. (5) The first estimate of the incidence of ICH in patients with hemophilia in the newborn period was made by Baehner and Strauss in 1966. (6) In a cohort of 192 patients with hemophilia, only 1 patient experienced ICH in the newborn period. More recent attempts to quantify the incidence of ICH in the newborn period in patients with hemophilia have placed the number much higher. In a review of several case studies, Ljung estimated the true incidence of ICH in the newborn period in patients with hemophilia in developed countries to be 3.5% to 4%. (7) This is much higher than the ICH incidence in the general population, which occurs in 1 in 1,900 (0.05%) spontaneous vaginal deliveries, 1 in 907 (0.11%) cesarean sections during labor, and 1 in 860 (0.12%) deliveries after vacuum extraction. (8) Like newborns without hemophilia, the risk of ICH and extracranial hemorrhage (subgaleal hemorrhage or cephalohematoma) increases after prolonged delivery or with use of forceps or vacuum extraction. (7)(9) While minimizing trauma in the perinatal period decreases the likelihood of ICH in patients with hemophilia, it does not wholly eliminate the risk, as evidenced by reports of newborns with hemophilia experiencing ICH after elective cesarean section without labor. (10) Although the optimal mode of delivery in infants suspected of having hemophilia remains a topic of debate, it is generally agreed that prolonged labor, difficult deliveries, and use of instrumentation should be avoided if possible. (11)(12)The neurologic prognosis of newborns with hemophilia who have ICH varies widely among case series. For example, Yoffe and Buchanan reported that 62% of patients in their cohort of newborns with hemophilia and early ICH went on to develop chronic neurologic sequelae. (5) In contrast, Ljung et al had a similar cohort with no patients who developed persistent neurologic sequelae. (13) Most case series report that at least some newborns with early ICH in the setting of hemophilia suffer long-term neurologic consequences, such as seizures, paralysis, and focal neurologic deficits. (5)(7)(9)