Disruption of the blood–brain barrier after generalized tonic-clonic seizures correlates with cerebrospinal fluid MMP-9 levels

Ya-Jun Li,Chang-Jiang Guo,Xing Zuo,Tao Lin,Xiao Zhe,Bei Zhang,Zheng-Hai Wang,Shao-Ting Shi,Shi-Jun Zhang,Ming-Jue Wang,Xiang-Li Kong,Jing Bai,Hang Zhao

doi:10.1186/1742-2094-10-80

Ya-Jun Li, Chang-Jiang Guo + Show 11 more

Open Access

https://doi.org/10.1186/1742-2094-10-80

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Abstract

BackgroundIncreasing evidence suggests seizures cause blood–brain barrier (BBB) dysfunction including decreased seizure threshold and higher onset potential of future seizures. However, the mechanisms underlying BBB damage in seizures remains poorly understood. Evidence in human and animal models shows BBB disruption is associated with activation of matrix metalloproteinase-9 (MMP-9) after cerebral ischemia and inflammation. The objective of this study was to determine whether MMP-9 concentrations in cerebral spinal fluid (CSF) are associated with BBB disruption in patients after epileptic seizures.MethodsThirty-one patients with generalized tonic-clonic (GTC) seizures were included in the study: 20 had recurrent GTC seizures (RS), and 11 had a single GTC seizure (SS) episode. Twenty-five adult non-seizure patients were used as controls. CSF samples were collected by lumbar puncture within 24 h after seizure cessation (range: 3–15 h, mean 6.2 h). CSF MMP-9 levels were determined by an enzyme-linked immunosorbent assay (ELISA). MMP enzyme activity was measured by gelatin zymography. The CSF/serum albumin ratio (albumin quotient, QAlb) was used as a measure of blood–brain barrier permeability.ResultsWe found significantly higher CSF MMP-9 concentrations in seizure patients compared with controls (P < 0.001). CSF MMP-9 levels and QAlb values were higher in RS patients compared with SS and controls. Moreover, CSF MMP-9 concentration showed strong correlation between QAlb values (r = 0.76, P < 0.0001) and between CSF leukocyte counts (r = 0.77, P < 0.0001) in patients after seizures. Gelatin zymography showed MMP-9 proteolytic activity only in GTC seizure patients.ConclusionsOur results suggest MMP-9 plays a role in BBB dysfunction, characterized by invasion of leukocytes into the CSF during seizures.

Highlights

Increasing evidence suggests seizures cause blood–brain barrier (BBB) dysfunction including decreased seizure threshold and higher onset potential of future seizures
Thirty-one patients with either tonic-clonic or partial secondarily generalized seizures were included in the study: 20 had recurrent generalized tonic-clonic (GTC) seizures (RS), and 11 had a single GTC seizure (SS) episode confirmed by an eyewitness that occurred within 3 h before admission
We found that neither cerebral spinal fluid (CSF) matrix metalloproteinase-9 (MMP-9) levels nor QAlb values correlated with seizure frequency (Figure 3C-D)

Summary

Introduction

Increasing evidence suggests seizures cause blood–brain barrier (BBB) dysfunction including decreased seizure threshold and higher onset potential of future seizures. Evidence in human and animal models shows BBB disruption is associated with activation of matrix metalloproteinase-9 (MMP-9) after cerebral ischemia and inflammation. The objective of this study was to determine whether MMP-9 concentrations in cerebral spinal fluid (CSF) are associated with BBB disruption in patients after epileptic seizures. Animal models and human clinical data have described a central epileptic patients are consistent with the animal data, showing an increase in BBB permeability during seizures [7,8]. There is evidence in human and animal stroke models that BBB disruption is associated with activation of matrix metalloproteinases (MMPs) [12,13,14]

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