Understanding the pathophysiology of epilepsy implies elucidating the neurovascular modifications occurring before or at time of seizures. Cerebrovascular dysfunction provokes or sustains seizures and loss of selective blood–brain barrier (BBB) permeability is a modulator of seizure threshold. However, cerebrovascular pathology in epilepsy extends beyond BBB “leakage” to encompass vascular and parenchymal events. Whenever abnormal accumulation of protein is observed surrounding brain blood vessels, BBB disruption (BBBD) was invoked. Recent clinical and laboratory findings challenged an exclusive role of BBBD in perivascular accumulation of serum-derived products. The circulation of interstitial fluid (ISF) and its bulk flow have emerged as candidate mechanisms which play a role in clearance of CNS waste. Although controversy exists, changes of ISF flow may contribute to CNS disorders through a mechanism encompassing incomplete parenchymal clearance and accompanying accumulation of toxic byproducts.

We summarize the evidence in favor and against ISF bulk flow and propose a scenario where abnormal ISF in the epileptic brain allows accumulation of brain protein, sustaining pathophysiology and altering the pharmacology of antiepileptic drugs. We also describe the methods routinely used to dissect out the contribution of BBB-dependent, vascular or paracellular mechanisms to altered neuronal excitability.