Drug-resistant epilepsy and the hypothesis of intrinsic severity: What about the high-frequency oscillations?

Abstract

Drug-resistant epilepsy (DRE) affects approximately one-third of the patients with epilepsy. Based on experimental findings from animal models and brain tissue from patients with DRE, different hypotheses have been proposed to explain the cause(s) of drug resistance. One is the intrinsic severity hypothesis that posits that drug resistance is an inherent property of epilepsy related to disease severity. Seizure frequency is one measure of epilepsy severity, but frequency alone is an incomplete measure of severity and does not fully explain basic research and clinical studies on drug resistance; thus, other measures of epilepsy severity are needed. One such measure could be pathological high-frequency oscillations (HFOs), which are believed to reflect the neuronal disturbances responsible for the development of epilepsy and the generation of spontaneous seizures. In this manuscript, we will briefly review the intrinsic severity hypothesis, describe basic and clinical research on HFOs in the epileptic brain, and based on this evidence discuss whether HFOs could be a clinical measure of epilepsy severity. Understanding the mechanisms of DRE is critical for producing breakthroughs in the development and testing of novel strategies for treatment.

Keywords: EEG; drug-resistant epilepsy; epilepsy; epilepsy severity.

FIGURE 1

High‐frequency oscillations (HFOs) as a potential marker of epilepsy severity. After an epileptogenic insult, the appearance of HFOs precedes and contributes to the development of clinical seizures (denoted by outer arc). In some cases, HFOs could appear immediately after injury, and lead to the formation of a more extensive HFO network, and soon thereafter the appearance of clinical seizures (inner arc). Once epilepsy is established, the rate of HFOs or the number of HFO‐generating sites or both increases to generate more frequent seizures (denoted by black dashed arrow). If the intrinsic severity hypothesis is correct and HFOs are a measure of epilepsy severity, then a high burden of HFOs would predict a severe form of epilepsy with high seizure frequency (solid blue arrow) that could be unresponsive to medication, that is, drug‐resistant epilepsy (DRE) (blue dashed arrow)