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Year : 2020  |  Volume : 9  |  Issue : 4  |  Page : 300-304

Recurrent seizures in a neonate with intracranial hemorrhage and congenital factor VII deficiency: A missed diagnosis

1 Department of Hematology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Neonatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Date of Submission02-Jun-2020
Date of Decision10-Jul-2020
Date of Acceptance09-Aug-2020
Date of Web Publication01-Oct-2020

Correspondence Address:
Dr. Rajesh Kashyap
Department of Hematology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Rae Bareli Road, Lucknow - 226 014, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcn.JCN_67_20

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Intracranial hemorrhage (ICH) is an uncommon life-threatening event occurring in full-term neonates. Neonates with inherited coagulation disorders are at a greater risk of developing ICH. Factor VII deficiency is associated with spontaneous and often recurrent ICH in infants. Factor VII deficiency is often confused with Vitamin K deficiency bleeding (VKDB) as the clinical and laboratory findings in both these conditions are similar. We present the case of a neonate who had recurrent seizures secondary to ICH since the 11th day of life and was initially managed as VKDB disorder. Inherited Factor VII deficiency was diagnosed only on the 44th day of life. This delay in diagnosis and appropriate treatment was associated with severe morbidity in the infant. Prompt recognition of ICH and underlying coagulation defect is the key to successful management of these patients.

Keywords: Factor VII deficiency, intracranial hemorrhage, intraventricular hemorrhage, neonate

How to cite this article:
Alim M, Chandra D, Singh R, Kashyap R. Recurrent seizures in a neonate with intracranial hemorrhage and congenital factor VII deficiency: A missed diagnosis. J Clin Neonatol 2020;9:300-4

How to cite this URL:
Alim M, Chandra D, Singh R, Kashyap R. Recurrent seizures in a neonate with intracranial hemorrhage and congenital factor VII deficiency: A missed diagnosis. J Clin Neonatol [serial online] 2020 [cited 2021 Jan 28];9:300-4. Available from: https://www.jcnonweb.com/text.asp?2020/9/4/300/297007

  Introduction Top

Intracranial hemorrhage (ICH) is uncommon in normal healthy full-term infants when compared to preterm neonates. The true incidence of ICH in full-term neonates is not well established. The incidence of symptomatic ICH is reported to be approximately 3.8/10,000 live births. The majority of the neonates with ICH are asymptomatic and often go undiagnosed.[1] They are detected only on radiological imaging.[2],[3] Intraventricular hemorrhage (IVH) occurs primarily in preterm infants. In contrast, subdural hematoma (SDH) and subarachnoid hemorrhage (SAH) are the most common type of ICH in full-term neonates.[3],[4]

Birth trauma secondary to prolonged labor, forceps delivery, and vacuum extraction has been identified as risk factors for ICH in full-term newborns.[4],[5] Congenital factor deficiencies are a rare cause of ICH in neonates and hemophilia A and B are the most common defects causing ICH in this age group.[1] The incidence of ICH in patients with rare bleeding disorders (RBD) is higher and it has been observed that more than 20% of patients with F VII deficiency have ICH in their lifetime and the majority of these events occur in the first few weeks of life.[6],[7],[8],[9] ICH is associated with high morbidity and mortality in full-term newborns and therefore prompt recognition and treatment are essential.[4],[5]

We report a 1.5-month-old female who initially presented on the 6th day of life with umbilical stump bleed and was managed as a case of Vitamin K deficiency bleeding (VKDB). She later presented with recurrent episodes of seizures and was diagnosed to have ICH with Factor VII deficiency (on the 44th day of life). This delay in diagnosis and start of treatment with recombinant F VIIa (rFVIIa) was associated with severe morbidity in the infant.

  Case Report Top

A 1.5-month-old female infant was referred to us with a history of recurrent seizures with suspected ICH. She was born full-term (37 weeks of gestation) to nonconsanguineous parents after an uncomplicated pregnancy and normal spontaneous unassisted vaginal delivery. The birth weight was 3.4 kg and the APGAR score was 8/10 and 9/10 at 1 and 5 min, respectively. On the 6th day of life, the baby had profuse bleeding from umbilical cord stump and developed anemia and was seen at a local community hospital. She was empirically diagnosed to have VKDB and was treated with parenteral Vitamin K and packed red blood cells transfusion for anemia. There was the cessation of umbilical stump bleed and the patient was sent home after 48 h of observation. On day 11 of life, she had an episode of generalized tonic-clonic seizures and was treated with antiepileptic drugs and discharged after 4 days of treatment. On day 40 of life, the baby developed lethargy, abnormal cry, and refusal to feed and was readmitted in the same hospital and was treated for seizures and suspected septicemia. However, she showed no clinical improvement after 3 days of treatment and was referred to our center for further evaluation and management. There was no family history of any bleeding disorders.

At presentation, the baby was lethargic, had an abnormal cry, vomiting, and recurrent episodes of seizures. The seizures were tonic-clonic and focal in type. On physical examination, the infant was pale, the body temperature was 37.4°C, the pulse rate was irregular (70–100 beats/min), and the respiratory was irregular with apnoeic spells. The patient was put on mechanical ventilator support, midazolam infusion, and antiepileptic (levetiracetam) drug.

A computerized tomogram (CT) scan of the head region showed a large parenchymal bleed in the left frontotemporoparietal region with bilateral IVH. Bilateral subdural hematoma (SDH) in the frontotemporoparietal region was also present [Figure 1].
Figure 1: A computerized tomogram scan of the head region (axial plane) showed a large parenchyma bleed in the left frontotemporoparietal region (yellow arrow), subdural hematoma in the frontotemporoparietal region (white arrow), and intraventricular hemorrhages (red arrow)

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Laboratory investigations revealed hemoglobin level 8.2 g/dl, total leukocyte count 14.2 × 109/l, and platelet count 132 × 109/l. Coagulation studies revealed normal activated partial thromboplastin time (APTT) 40.4 s (control 35.0 s); thrombin time (TT) 20.6 s (control 19.5 s); and fibrinogen level 341 mg/dl. There was an isolated prolongation of prothrombin time (PT) 57.5 s (control 12.2 s) and international normalized ratio 6.73. The FVII: C level was 2% of the normal. A diagnosis of congenital FVII deficiency with ICH was made. There was no family history of bleeding episodes. The coagulation studies in both the parents were normal.

Activated recombinant FVII (rFVIIa, Novo Seven, Novo Nordisk) was administered at a dose of 30 mcg kg every 6 h. The patient underwent a right frontoparietal burr hole evacuation of the right SDH and a left frontotemporoparietal craniotomy with evacuation of the left frontotemporoparietal SDH. Postsurgery, the baby had features of raised ICT in the form of intermittent posturing, vomiting, seizures, and intermittent abnormal breathing. A repeat CT scan of the head on the 4th postoperative day showed the development of subdural hygroma with communicating hydrocephalus. A ventriculoperitoneal shunt was placed under rFVIIa coverage. The patient showed clinical improvement and was weaned off the ventilator by the 9th postoperative day. The rFVIIa therapy was continued at dosage schedule 30 mcg/kg, every 6 h for the next 14 days followed by once a day till the day 24. She was discharged from the hospital on postoperative day 24. At discharge, the baby was hemodynamically stable and was accepting oral feeds. No further bleeding or seizure activity was present. Prophylactic rFVIIa regimen consisting of weekly infusions at a dosage of 30 mcg/kg and oral antiepileptic drugs was started. A repeat CT scan was planned at a later date to assess the resolution of ICH and the family was advised regular follow-up.

  Discussion Top

ICH or central nervous system (CNS) bleed is a life-threatening event and is less frequent in full-term newborns compared to preterm infants.[1] The CNS bleed in full-term newborns is associated with high rates of mortality and long-term neurological disability.[1],[5],[10] The true incidence of ICH in term infants is not well established since a significant number of these cases are asymptomatic at birth and are not detected.[2],[3] Whitby et al. have reported an 8% prevalence of SDH among asymptomatic term neonates on magnetic resonance (MR) imaging.[2] In another study, Looney et al. found that 26% of asymptomatic newborns in their study had ICH on MR imaging.[3]

Prolonged labor, forceps-assisted vaginal delivery, and use of ventouse during delivery have been identified as an important obstetrical risk for ICH in full-term neonates.[2],[4] Thrombocytopenia has been observed in 22%–31% of neonates with ICH and is also the most frequent hematological risk factor for ICH in this age group.[4],[11] Coagulation disorders are a less frequent cause of CNS bleed in full-term infants.[1] VKDB is the most common coagulation defect associated with ICH in neonates. Vitamin K is required for carboxylation of the coagulation Factors II, VII, IX, and X, and its deficiency produces decreased levels of these factors resulting in bleeding episodes in the newborn. The VKDB is a major problem in newborns in developing countries and among breastfed infants. Late-onset VKDB is associated with ICH in 50%–75% of cases.[12],[13] CNS bleed is a major problem in infants with congenital factor deficiencies. Rare bleeding disorders like factors VII, X and XIII are more frequently associated with ICH.[14],[15],[16],[17],[18],[19] In infants with coagulation disorders, ICH usually occurs spontaneously, recurrent bleeds are common, and ICH is the predominantly intraparenchymal type.[14],[15],[16],[17],[18] Siboni et al. studied 36 episodes of ICH in 24 patients with RBD. They found that Factor XIII (62.5%) was the most common RBD, followed by Factor VII (16.7%) and Factor X and afibrinogenemia (8.3%). In 26% (7 cases), the CNS bleed occurred below the age of 2 years. The ICH event was spontaneous in 76% of cases and recurrent episodes were seen in 25% of cases. However, this study does not mention the incidence of ICH in neonates.[14]

The incidence of ICH in patients with Factor VII deficiency is reported to range between 4% and 21%.[6],[7],[8],[9],[19] The majority of the ICH events in Factor VII-deficient patients unlike in other RBD occur within the first 1 month of life and are associated with high morbidity and mortality.[9],[15],[16],[17],[18],[19] Ragni et al., in a study of 72 patients with Factor VII, found that 16% (12 cases) had ICH event, and in five (41.7%) of these 12 cases, the ICH event occurred within the 1st week of life and none of these neonates survived.[19] Kankirawatana et al. have reported 4 neonatal cases who developed ICH within the 1st week of life (mean age 3.3 days). All these four neonates had multiple episodes of ICH within their 1st year of life and two of them died.[9] Similarly, Traivaree et al. have reported 4 neonates with factor seven deficiency who developed CNS bleed with the first 2 weeks of life and one case had CNS bleed at birth.[20] The incidence of ICH is higher in patients with Factor VII level of < 2% of the normal, the high-risk group.[7] However, it has been observed that there is no correlation between the Factor VII levels and severity of bleeding episodes in patients with Factor VII deficiency.[6],[7] ICH has also been documented in neonates with Factor VII levels >2%.[9],[15],[16],[20] Recurrent episodes of ICH are common in these patients.[9],[21] It has been observed that a history of umbilical stump bleed in patients with F VII deficiency is a predictor for the development of ICH at a younger age.[22] Intraparenchymal hemorrhage is the most common type of ICH in patients with coagulation disorders.[1],[14],[15],[20] However, many neonates have bleeds at multiple sites in the same event of ICH.[16],[20] Lee and Park have reported a 28-day-old male neonate who had bilateral IVH in the lateral ventricles with hydrocephalus and intraparenchymal bleed in the parietotemporal lobe and corpus callosum. His Factor VII level was 2%.[16] Traivaree et al. have reported a 4-day-old female neonate with Factor VII level of 4%, who had bilateral IVH in the lateral and third ventricles, intracerebral bleed in the right temporal and occipital lobes, cerebellar vermis bleed, and SAH. She was born through normal spontaneous vaginal delivery and had no history of birth trauma.[20] This neonate died on the 6th day. Our case had bilateral SDH and IVH along with intraparenchymal bleed.

Factor VII deficiency has to be differentiated from VKDB as in both of these conditions, there is an isolated prolongation of PT with normal APTT, TT, and fibrinogen levels. The correction of prolonged PT with Vitamin K administration and a decrease in bleeding is diagnostic of VKDB. If the PT is not corrected, an underlying F VII deficiency should be suspected and factor VII levels should be estimated.

Before the availability of rFVIIa, fresh frozen plasma was the only source of factor VII for the treatment of bleeding episodes in these patients. Treatment of ICH was inadequate and the mortality rates were high.[9],[15],[19] The rFVIIa is highly effective in the management of bleeding episodes in patients with congenital F VII deficiency.[23],[24] The recommended dose of rFVIIa for severe bleeding is 15–30 μg/kg every 4–6 h and for prophylaxis, the dosage is 20–40 μg/kg three times a week.[23] Recombinant F VIIa has shown to be effective in treatment of ICH in neonates with Factor VII deficiency with a reduction in the mortality rates.[16],[25],[26] Prophylaxis with rFVIIa has prevented the recurrence of ICH in these patients.[16],[25],[26] In infants and young children, venous access can be a major problem, and administering the drug thrice a week is a challenging task. Placement of port-a-cath will be needed is such situations. However, prophylaxis with weekly administration of rFVIIa 30 μg/kg has shown to be equally effective and may overcome this problem.[25],[26]

Our patient presented with prolonged umbilical stump bleeding on the 6th day of life and was suspected to have VKDB and treated with parenteral Vitamin K. She later presented with recurrent episodes of seizures and was treated with antiepileptic drugs. The treating doctor did consider the possibility of ICH as the cause of recurrent seizures but no radiological imaging for detecting ICH or laboratory coagulation tests could be performed because of the limited facilities available at the primary health-care centers in a developing country like ours.

Our case highlights the importance of prompt evaluation of a neonate presenting with seizures for ICH. Coagulation tests should be done to detect an underlying inherited coagulation disorder in all patients with ICH. Second, the failure of PT to correct with Vitamin K administration should make the physician suspected inherited factor VII deficiency and the factor seven levels should be estimated. Prompt therapy with rFVIIa and prophylaxis improves the overall outcome of ICH in these patients. It also highlights the need for greater awareness among pediatricians and family practice physicians, especially in developing countries with limited resources about coagulation disorders and the importance of laboratory evaluation of term neonates and infants presenting with ICH.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

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Looney CB, Smith JK, Merck LH, Wolfe HM, Chescheir NC, Hamer RM, et al. Intracranial hemorrhage in asymptomatic neonates: Prevalence on MR images and relationship to obstetric and neonatal risk factors. Radiology 2007;242:535-41.  Back to cited text no. 3
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Salcioglu Z, Akcay A, Sen HS, Aydogan G, Akici F, Tugcu D, et al. Factor VII deficiency: A single-center experience. Clin Appl Thromb Hemost 2012;18:588-93.  Back to cited text no. 8
Kankirawatana S, Mahasandana C, Veerakul G, Seeloem J, Suwantol L, Tanphaichitr V, et al. Successful prophylaxis of intracranial hemorrhage in infants with severe congenital factor VII deficiency. Southeast Asian J Trop Med Public Health 2000;31:795-800.  Back to cited text no. 9
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Siboni SM, Zanon E, Sottilotta G, Consonni D, Castaman G, Mikovic D, et al. Central nervous system bleeding in patients with rare bleeding disorders. Haemophilia 2012;18:34-8.  Back to cited text no. 14
Ariffin H, Lin HP. Neonatal intracranial hemorrhage secondary to congenital factor VII deficiency: Two case reports. Am J Hematol 1997;54:263.  Back to cited text no. 15
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