Blood-brain barrier dysfunction and epilepsy: pathophysiologic role and therapeutic approaches

Abstract

The blood-brain barrier (BBB) is located within a unique anatomic interface and has functional ramifications to most of the brain and blood cells. In the past, the BBB was considered a pharmacokinetic impediment to antiepileptic drug penetration into the brain; nowadays it is becoming increasingly evident that targeting of the damaged or dysfunctional BBB may represent a therapeutic approach to reduce seizure burden. Several studies have investigated the mechanisms linking the onset and sustainment of seizures to BBB dysfunction. These studies have shown that the BBB is at the crossroad of a multifactorial pathophysiologic process that involves changes in brain milieu, altered neuroglial physiology, development of brain inflammation, leukocyte-endothelial interactions, faulty angiogenesis, and hemodynamic changes leading to energy mismatch. A number of knowledge gaps, conflicting points of view, and discordance between clinical and experimental data currently characterize this field of neuroscience. As more pieces are added to this puzzle, it is apparent that each mechanism needs to be validated in an appropriate clinical context. We now offer a BBB-centric view of seizure disorders, linking several aspects of seizures and epilepsy physiopathology to BBB dysfunction. We have reviewed the therapeutic, antiseizure effect of drugs that promote BBB repair. We also present BBB neuroimaging as a tool to correlate BBB restoration to seizure mitigation. Add-on cerebrovascular drug could be of efficacy in reducing seizure burden when used in association with neuronal antiepileptic drugs.

Figure 1

Blood–brain barrier (BBB) dysfunction in seizure disorders. The BBB represents the main vascular interface between brain and blood. Owing to its anatomic location and its unique physiologic properties, the BBB controls brain metabolism and cell- to-cell communication, and it maintains the composition of the extracellular brain milieu. BBB dysfunction has direct effects on virtually all brain cells; BBB dysfunction determines deviation from the physiologic crosstalk between the periphery and the brain. BBB dysfunction can be a cause or the result of seizure activity. Epilepsia © ILAE

Figure 2

Measurement of BBB integrity in animal models and patients with drug-resistant epilepsy (DRE). (A) MRI can be used to detect BBB damage. Contrast enhanced (Gd++) T₁ allows for the localization of cerebrovascular failure during periictal stages or at onset of seizures, when BBB damage is likely to be prominent. T₂-DWI and FLAIR are more sensitive and can be used to localize brain edema during interictal periods. In addition, serum markers (e.g., S100B) can be used to evaluate BBB permeability (see panel C). Postmortem brain specimens can be analyzed for the presence of serum protein extravasates (e.g., IgG and albumin). The dotted line in (A) indicates the predicted evolution of BBB damage during ictal, periictal, and interictal stages. (B) FITC-albumin brain extravasation is observed in rats at time of seizures, indicating BBB damage. (C) Blood S100B levels are elevated during the ictal stages in patients with DRE (*p < 0.05, analysis of variance [ANOVA]). Brain extravasates of serum IgG (arrow heads and dotted line) are detected in brain specimens obtained from patients with DRE. (D) T2-FLAIR shows reduction of edema (arrow heads) in a patient with DRE who responded to add-on glucocorticosteroid therapy. Epilepsia © ILAE