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Published on: May 16, 2019
Drug resistance in epilepsy: putative neurobiologic and clinical mechanisms
Dieter Schmidt1, Wolfgang Löscher
1Epilepsy Research Group, Berlin, Germany. dbschmidt@t-online.de
Abstract:
Drug-resistant epilepsy with uncontrolled severe seizures despite state-of-the-art medical treatment continues to be a major clinical problem for up to one in three patients with epilepsy. Although drug resistance may emerge or remit in the course of epilepsy or its treatment, in most patients, drug resistance seems to be continuous and to occur de novo. Unfortunately, current antiepileptic drugs (AEDs) do not seem to prevent or to reverse drug resistance in most patients, but add-on therapy with novel AEDs is able to exert a modest seizure reduction in as many as 50% of patients in short-term clinical trials, and a few become seizure free during the trial. It is not known why and how epilepsy becomes drug resistant, while other patients with seemingly identical seizure types can achieve seizure control with medication. Several putative mechanisms underlying drug resistance in epilepsy have been identified in recent years. Based on experimental and clinical studies, two major neurobiologic theories have been put forward: (a) removal of AEDs from the epileptogenic tissue through excessive expression of multidrug transporters, and (b) reduced drug-target sensitivity in epileptogenic brain tissue. On the clinical side, genetic and clinical features and structural brain lesions have been associated with drug resistance in epilepsy. In this article, we review the laboratory and clinical evidence to date supporting the drug-transport and the drug-target hypotheses and provide directions for future research, to define more clearly the role of these hypotheses in the clinical spectrum of drug-resistant epilepsy.
Insights
Drug-resistant epilepsy affects many patients despite advanced treatments. Research explores mechanisms like drug transport and target sensitivity to understand and combat this condition.
Area of Science:
- Neurology
- Pharmacology
- Epileptology
Background:
- Drug-resistant epilepsy impacts up to one-third of patients, presenting a significant clinical challenge.
- Current antiepileptic drugs (AEDs) often fail to prevent or reverse drug resistance.
- Understanding the mechanisms of drug resistance is crucial for developing effective treatments.
Purpose of the Study:
- To review laboratory and clinical evidence for major neurobiologic theories of drug resistance in epilepsy.
- To explore the roles of drug-transport and drug-target mechanisms in treatment-resistant epilepsy.
- To identify future research directions for drug-resistant epilepsy.
Main Methods:
- Review of experimental and clinical studies on epilepsy drug resistance.
- Analysis of evidence supporting the drug-transport hypothesis (multidrug transporters).
- Analysis of evidence supporting the drug-target hypothesis (reduced drug-target sensitivity).
Main Results:
- Two primary neurobiologic theories for drug resistance are proposed: excessive expression of multidrug transporters and reduced drug-target sensitivity.
- Clinical factors such as genetic and structural brain lesions are associated with drug resistance.
- Novel AEDs offer modest seizure reduction in some patients, but a cure for resistance remains elusive.
Conclusions:
- Further research is needed to clarify the roles of drug-transport and drug-target mechanisms in drug-resistant epilepsy.
- Defining these mechanisms more clearly could lead to improved therapeutic strategies for patients with uncontrolled seizures.
- Addressing drug resistance requires a deeper understanding of its underlying neurobiologic and clinical factors.
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