Blood-brain barrier injury and neuroinflammation in pre-eclampsia and eclampsia
Valentina Bucher, Owen Herrock, Sonja Schell, J. de Visser, Henrik Imberg, Jonathan Burke, Henrik Zetterberg, Kaj Blennow, Susan Walker, Stephen Tong, C. Joakim Ek, Catherine Cluver, Lina Bergman
Abstract
BACKGROUND: Cerebral complications of pre-eclampsia are a leading cause of maternal mortality. Better understanding of the pathophysiology may enable the development of novel strategies to protect the maternal brain. We aimed to investigate blood-brain barrier injury and neuroinflammatory pathways in women with eclampsia and pre-eclampsia compared to normotensive pregnancies. METHODS: This observational cross-sectional study conducted between March 2021 and June 2023, included women with eclampsia, pre-eclampsia, and normotensive pregnancies admitted to Tygerberg Hospital, Cape Town, South Africa who underwent caesarean delivery. Cerebrospinal fluid and plasma samples were collected during caesarean delivery. Blood-brain barrier injury was assessed using immunonephelometry for albumin and ELISA assays for claudin-5 and matrix metalloproteinase-9 (MMP-9). Neuroinflammatory markers were analysed on the multiplex Bio-Plex Pro Human Cytokine-Screening assay. Data were analysed using parametric methods after log transformation and are presented as fold changes (geometric mean ratios) between groups. FINDINGS: The study included 129 women: Eleven had eclampsia, 17 had pre-eclampsia with end-organ complications, 88 had pre-eclampsia without end-organ complications, and 13 with normotensive pregnancies. Women with eclampsia had increased cerebrospinal fluid concentrations of claudin-5 (2.7-fold, 95% CI 1.4-5.1, p = 0.002 vs normotensive control) and MMP-9 (2.5-fold, 95% CI 1.1-5.3, p = 0.024 vs pre-eclampsia with end-organ complications). They also demonstrated increased cerebrospinal fluid cytokine levels compared to normotensive controls, reflecting inflammatory recruitment (Interleukin-8: 7.2-fold, 95% CI 2.7-18.5, p < 0.001), cytotoxicity (Interleukin-6: 20.7-fold, 95% CI 6.4-63.6, p < 0.001), and immune modulation (Interleukin-10: 2.0-fold, 95% CI 1.2-3.1, p = 0.004). Neuroprotective markers were reduced in eclampsia (stem cell factor: 0.5-fold, 95% CI 0.3-0.8, p = 0.005) compared to normotensive controls. There was no correlation between cytokine concentrations in the cerebrospinal fluid and plasma. Women with pre-eclampsia showed less pronounced changes indicative of blood-brain barrier injury and immune modulation. INTERPRETATION: Eclampsia is associated with blood-brain barrier injury and acute neuroinflammation originating from cerebral tissue, inducing cytotoxicity. This may be an underlying mechanism for seizures and cerebral injury in eclampsia and pre-eclampsia. FUNDING: This study was supported by the Swedish Research Council, Herbert och Karin Jacobsson Stiftelse, Wilhelm and Martina Lundgren Foundations, and Swedish Society Of Medicine.