Blood-brain barrier injury and neuroinflammation in pre-eclampsia and eclampsia

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.