The effect of impaired blood brain barrier in the response to anti-seizure medication in acute symptomatic seizures in severe falciparum malaria

Background Blood brain barrier disruption is documented in severe falciparum malaria, but the role of the cerebrospinal fluid (CSF) proteins on pathogenesis and control of acute symptomatic seizures is not studied. We hypothesized that elevated CSF proteins (markers of blood brain breakdown) in malaria may affect risk of acute symptomatic seizures in malaria and response to anti-seizure medications (ASM). Methods We measured CSF levels of proteins such as albumin, ferritin and s100, in 45 children with carefully phenotyped seizures in the context of severe falciparum malaria and documented the response of these seizures to ASM. We compared the distribution of these protein in those with and without seizures, and in those requiring second line ASM versus those controlled on first line ASM. We further documented the occurrence of acute symptomatic seizures in those with evidence of blood brain barrier disruption. Results In the 45 children with severe falciparum malaria who had CSF protein levels measured, 36 (80.0%) had acute symptomatic seizures, of which 32 (88.9%) were complex seizures (focal, repetitive and/or prolonged). CSF Protein s100 was associated with acute symptomatic seizures ((adjusted risk ratio (aRR) = 1.06 (95%CI:1.01–1.11); P = 0.012)). Acute symptomatic seizures stopping spontaneously or without requiring second-line ASM was associated with CSF ferritin (aRR = 1.12 (95%CI:1.03–1.23); P = 0.008), CSF s100 (aRR = 1.33 (95%CI:1.00-1.78); P = 0.051) and CSF total proteins (aRR = 1.01 (95%CI:1.00-1.01); P = 0.023). Seizures responding to first line ASM or stopping spontaneously were more frequent in those with blood brain barrier disruption (as measured by elevated total proteins and albumin) compared to those without disruption (aRR = 2.72 (95%CI:1.08–6.83); P = 0.032). Evidence of blood brain barrier disruption was associated with simple seizures. Conclusion Elevated CSF proteins may promote anti-seizure activity and appear not to affect bioavailability of ASM in Kenyan children with acute symptomatic seizures in severe falciparum malaria. Protein s100 may be involved in the pathogenesis of acute symptomatic seizures in malaria, with a proinflammatory response underlying simple seizures possibly a cause of the blood brain barrier damage. Future well-powered longitudinal studies are required to confirm these findings.