Brain-derived circulating endothelial cells in peripheral blood of newborn infants with seizures: a potential biomarker for cerebrovascular injury

Abstract

Neonatal seizures have been associated with cerebrovascular endothelial injury and neurological disabilities. In a piglet model, the long-term loss of endothelial regulation of cerebral blood flow coincides with the surge of brain-derived circulating endothelial cells (BCECs) in blood. We hypothesized that BCECs could serve as a noninvasive biomarker of cerebrovascular injury in neonates with seizures. In a prospective pilot feasibility study, we enrolled newborn infants with confirmed diagnoses of perinatal asphyxia and intraventricular hemorrhage (IVH); both are commonly associated with seizures. Infants without clinical evidence of cerebrovascular injuries were representative of the control group. BCECs were detected in the CD45-negative fraction of peripheral blood mononuclear cells by coexpression of CD31 (common endothelial antigen) and GLUT1 (blood-brain barrier antigen) via automated flow cytometry method. In Infants with asphyxia (n = 12) and those with IVH grade III/IV (n = 5), the BCEC levels were 9.9 ± 0.9% and 19.0 ± 2.0%, respectively. These levels were significantly higher than the control group (n = 27), 0.9 ± 0.2%, P < 0.001. BCECs in infants with cerebrovascular insults with documented clinical seizures (n = 10; 16.8 ± 1.3%) were significantly higher than infants with cerebrovascular insults with subclinical or no seizures (n = 7; 9.5 ± 1.2%); P < 0.001. BCEC levels decreased with seizure control. BCECs levels were elevated in infants with seizures caused by severe IVH and perinatal asphyxia. We suggest that monitoring BCEC levels in peripheral blood can potentially offer a biological marker that reflects cerebrovascular insult and recovery. Further studies with a larger number of patients are required to support these findings.

Preventing harmful effects of epileptic seizures on cerebrovascular functions in newborn pigs: does sex matter?

“…In newborn pigs of both sexes, epileptic seizures lead to cerebral vascular injury, apoptosis, and long-term insufficiencies in cerebral vascular functions, including sustained loss of endothelium- and astrocyte-mediated regulation of CBF ( 5 – 8 ). Clinical studies in newborn babies with epileptic seizures caused by neonatal hypoxic-ischemic encephalopathy and severe intraventricular hemorrhage (IVH III–IV) revealed the occurrence of cerebral vascular damage diagnosed by the surge of circulating endothelial cells of brain origin (BCECs) in peripheral blood ( 9 ). Cerebral vascular insufficiencies have been also detected in epileptic patients ( 10 , 11 ).…”

Selective head cooling during neonatal seizures prevents postictal cerebral vascular dysfunction without reducing epileptiform activity

“…intraventricular hemorrhage (III/IV); these infants also had poor neurological outcome (39). Overall, our experimental and clinical findings suggest that BCEC levels in peripheral blood offer a proper biological indicator that reflects cerebrovascular insult and recovery.…”

“…The presence of BCECs serves as an early systemic indicator of the severity of the endothelial damage that predicts the later occurrence of cerebral vascular dysfunction (35). Importantly, our pilot clinical studies in newborn babies with seizures of different etiologies suggest that the number of BCECs in peripheral blood can serve as an early predictor of adverse neurological outcome (39).…”

Blood-brain barrier disruption in a model of neonatal hypoxic-ischaemic encephalopathy

“…Neurovascular unit disruption has been demonstrated in neonates with HIE and animal models of HI. Direct injury to neurovascular endothelial cells that can last between days to weeks has been demonstrated in human neonates with HIE (Pourcyrous et al 2015). Pourcyrous and colleagues demonstrated that newborns with HIE had significantly greater brain-derived endothelial cells in circulating blood which implies damage to the cerebral vasculature.…”

“…However, very little is known regarding the role BBB-disruption plays in the evolution of neonatal seizure. To the best of my knowledge, the only pieces of evidence that BBB-disruption following HIE are associated with seizures are from Pourcyrous et al, 2015and Schiering et al, 2005. Pourcyrous and colleagues (2015 found that neonates with seizures following HIE have been found to have increased levels of circulating brain-derived endothelial cells than control babies and HIE babies without seizure, which suggests that seizures are associated with damage to the NVU which is essential for BBB integrity.…”