A Rare Cause of Neonatal Seizures—A Case Report

A male term infant with an uncomplicated perinatal background presented on day of life 13 with a brief history of isolated jerking of the right lower limb at home. On review, a witnessed event in clinic showed non-suppressible tonic–clonic movement of the right lower limb with secondary generalisation. The baby was admitted to the neonatal intensive care unit (NICU), and amplitude integrated electroencephalography (aEEG) was commenced. A subsequent witnessed event, as described, showed correlating electrographic activity. A full septic work-up was performed with a cerebrospinal fluid (CSF) white cell count of 42 mm3 and red cell count of 54 mm3. The infant received a loading dose of Phenobarbitone 20 mg/kg and transitioned to maintenance therapy of 2.5 mg/kg thereafter. The infant was also commenced on Aciclovir, Amoxicillin, Cefotaxime, and Gentamicin. A cranial ultrasound was performed which showed tectal plate echogenicity and suggested an MRI brain. Peripheral blood white cell count was within normal limits and there was no evidence of coagulopathy. Transaminases and renal function were normal with an elevated C-reactive protein of 15 mg/L [0–5]. Interleukin-6 was mildly elevated at 11.3 [1.5–7]. CSF viral and bacterial polymerase chain reactions were negative. Rectal and throat swabs were negative for enterovirus. Urine and blood cultures showed no growth. The CSF microscopy showed a pleocytosis, which prompted anti-microbial therapy for meningitis; the culture transpired to be negative. Afterwards, this was felt to be partially due to a partially traumatic tap and inflammation secondary to the thrombosis. MRI Brain demonstrated loss of normal flow voids in the transverse sinuses, the straight sinus, and the superior sagittal sinus, all of which were distended on T2 sequence (Figure 1). Extensive T1 shortening was noted in the same distribution with an absence of flow in the aforementioned sinuses on MR-Venogram (Figure 2). Haemosiderin blood products were seen in the same distribution on the gradient echo Swan sequence, in keeping with the evolving appearance of thrombus. T1 prolongation compatible with thrombus extended into some of the draining cortical veins at the vertex. On the Swan sequence, susceptibility artefact outlined a distended internal cerebral vein extending superior to the left globus pallidus, into the anterior aspect of the left posterior limb of the internal capsule. Of note, there were no antenatal, neonatal, perinatal, or maternal risk factors for thrombosis. There was also no paternal history of thromboembolic disease. Paediatric Haematology was consulted and advised the commencement of subcutaneous Tinzaparin at 300 units/kg with dose titration according to daily factor Xa levels. After one week of Tinzaparin therapy, the infant was switched to Rivaroxaban. The infant was discharged home two days later. Serial follow-up outpatient appointments until the age of six months showed normal neurological examinations and neurodevelopment. A repeat MRI Brain at three months showed interval significant improvement in the appearances of the venous sinuses with some residual lack of flow-related enhancement in the right transverse and sigmoid sinus. The infant has ongoing neurological/neurodevelopmental follow-up and subsequent MRI Brain has shown persistence of decreased flow-related enhancement in the right transverse and sigmoid sinuses. They will go on to have a Bailey's developmental assessment with a Physiotherapist, Neonatologist, and Psychologist at the age of two years. Seizures are a common problem faced by clinicians in the field of neonatology, with an incidence of 2–3 per 1000 live births [1]. A differential diagnosis for seizure activity in the neonate is cerebral venous sinus thrombosis (CVST), defined as a focal or diffuse obstruction of flow secondary to occlusion of cerebral sinuses or veins [2]. Across the paediatric patient population, CVST has an incidence of 0.67 per 100 000 children per year, with neonates comprising the most commonly affected in this patient cohort [3]. To date, there have been no randomised controlled studies addressing optimal management of CVST in neonatal patient populations. CVST has a broad clinical spectrum, with a high index of clinical suspicion required for diagnosis in the newborn. Symptoms and signs are subtle and non-specific to the pathology in question, typically presenting as any of the following—seizures, irritability, hypotonia, hypertonia, or feed intolerance [4, 5]. CVST in neonates has a complex, multi-faceted risk factor profile, comprising maternal, fetal and neonatal variables. These have been described across the available literature and include dehydration, sepsis, perinatal asphyxia, prolonged central vascular catheterisation, pre-eclampsia, gestational diabetes, and meningitis [6]. A recent cohort study of 11 infants with venous thrombosis included two with CVST, both of whom had risk factors prompting thrombosis—sepsis and asphyxia respectively. One of these patients was treated with low molecular weight heparin; outcome data was not reported [7]. In paediatric and adult populations, thrombophilia screening plays an integral role in the investigation and subsequent management of CVST. The role of thrombophilia screening in neonatal venous thromboembolic disease is not well established. Literature to date suggests it is of limited utility, advising that neonatal VTE is multi-factorial and that clinical risk factors play a greater role than heritable thrombophilia in this population [8-11]. Routine thrombophilia screening in this patient population does not yet have an established evidence base and should be considered on a case-by-case basis. There also remains a lack of consensus around the management of CVST in the newborn, where there are ethical challenges around conducting randomised controlled trials, where the outcome may influence the neurodevelopmental outcome of the patient. A systematic review and meta-analysis by Rossor et al. highlighted the small number of studies pertaining to neonatal CVST and called for well-designed, randomised trials to assess the safety and efficacy of anti-coagulation in this cohort [12]. A secondary analysis of the Kids-DOTT study included eight neonatal patients with CVST and concluded that six weeks of anti-coagulation was safe in the broader paediatric patient population [13]. Presently, therapeutic approaches vary greatly and are extrapolated from best practice in adult populations due to limited cohort-specific data. As such, it is imperative each case is comprehensively investigated, with the decision for anti-coagulant therapy made based on the entire clinical picture, alongside correction of any modifiable risk factors (dehydration, sepsis etc.). In this case, following investigation for dehydration, sepsis, antenatal/perinatal risk factors and imaging, the decision was made to therapeutically anti-coagulate, as the benefit to the patient outweighed the risks of therapy. Cerebral venous sinus thrombosis is an under-recognised cause of neonatal seizures and should be considered as part of a differential diagnosis for the seizing infant. The importance of timely neuroimaging in the event of neonatal seizure has been highlighted by this case. As this was an individual case, where the patient's guardian provided consent, no hospital board ethical approval was required. The authors declare that the research presented in this manuscript adheres to the ethical principles outlined by the Rotunda Hospital Ethics Committee. All procedures involving human participants were conducted in accordance with the ethical standards of the Rotunda Hospital, Dublin, Ireland, and the Declaration of Helsinki (1964), as revised in 2013. Verbal consent was taken from the patient's guardian and documented in the medical file. No identifiable patient characteristics were reported. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.