The Concept of Drug-Resistant Epileptogenic Zone

Abstract

Resective surgery is the most effective way to treat drug-resistant epilepsy. Despite extensive pre-surgical evaluation, only 30–70% patients would become seizure-free after surgery. New approaches and strategies are needed to improve the outcome of epilepsy surgery. It is commonly observed in clinical practice that antiepileptic drugs (AEDs) could maintain seizure freedom in a large proportion of patients after surgery, who were uncontrolled before the operation. In some patients cessation of AEDs leads to seizure recurrence which, in most cases, can be controlled by resuming AEDs. These observations suggest that the surgery has converted the epilepsy from drug-resistant to drug-responsive, implying that the operation has removed the brain tissue accounting for pharmacoresistance, rather than the pathological substrate of epilepsy (at least not completely). Based on these observations, it is hypothesized that there is a drug-resistant epileptogenic zone (DREZ) which overlaps with the epileptogenic zone (EZ), and has both epileptogenic and drug-resistant properties. DREZ is necessary and sufficient to cause drug-resistant epilepsy, and its remove would render the epilepsy drug-responsive. Testing the hypothesis requires the development of new methods to define the DREZ, which may be used to guide surgical planning when the epileptogenic zone cannot be completely excised. This concept can also help understand the mechanisms of drug-resistant epilepsy, leading to new therapeutic strategies.

Finding a Fragile Piece to End the Seizure War

“…Surgical resection of potentially epileptic brain tissue does not always result in seizure freedom in patients with drug-resistant epilepsy, 1 pointing to the importance and difficulty of successfully identifying the brain regions responsible for initiating seizures (seizure onset zone; SOZ). This is why so much research continues to focus on identifying reliable biomarkers that can help clinicians optimally localize the SOZ.…”

Neuroanatomical and psychological considerations in temporal lobe epilepsy

“…The most common surgical procedure is the removal of the anterior temporal cortex ( Engel and Shewmon, 1993 ), most of the amygdala and the anterior portion of the hippocampal formation ( Penfield and Jasper, 1954 ; Falconer, 1971 ; Olivier, 1992 ; Fried and Spencer, 1993 ; Wieser et al, 1993 ; see Feindel et al, 2009 for a review of the history of the development of surgery for epilepsy). About 60–70% of these patients can be seizure-free with relatively few problems after surgery (e.g., McIntosh et al, 2001 ; Engel et al, 2003 ; Sola et al, 2005 ; Aull-Watschinger et al, 2008 ; Spencer and Huh, 2008 ; Thom et al, 2010 ; Ryvlin and Rheims, 2016 ; for recent reviews see West et al, 2019 ; Zhang and Kwan, 2019 ).…”

Bypassing the Blood–Brain Barrier: Direct Intracranial Drug Delivery in Epilepsies

“…Indeed, according to the drug transporter hypothesis, sysDRE is in part due to inadequate ASD passage across the BBB. Localized upregulation of multidrug efflux transporters such as P-glycoprotein in brain capillary endothelium and astrocytes of the BBB [21] in the drug-resistance epileptogenic zone [22,23] results in limited access of ASDs to the brain parenchyma, i.e., in lower extracellular concentration of ASDs at the drug target sites in the epileptogenic zone. The overexpression of these efflux transporters has been shown in the brain of DRE patients [21] as well as rodent models of refractory epilepsy [24,25].…”