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Clinical aspects and biological bases of drug-resistant epilepsies
1Department of Neurology, Epilepsy Center, San Martino Hospital, Genova, Italy. divneurologia@smartino.ge.it
Abstract:
The definition of drug-resistant epilepsy (DRE) is elusive and still controversial owing to some unresolved questions such as: how many drugs should be tried before a patient is considered intractable; to which extent side-effects may be acceptable; how many years are necessary before establishing drug resistance. In some cases, the view of epilepsy as a progressive disorder constitutes another important issue. Despite the use of new antiepileptic drugs (AEDs), intractable epilepsy represents about 20-30% of all cases, probably due to the multiple pathogenetic mechanisms underlying refractoriness. Several risk factors for pharmacoresistance are well known, even if the list of clinical features and biological factors currently accepted to be associated with difficult-to-treat epilepsy is presumably incomplete and, perhaps, disputable. For some of these factors, the biological basis may be common, mainly represented by mesial temporal sclerosis or by the presence of focal lesions. In other cases, microdysgenesis or dysplastic cortex, with abnormalities in the morphology and distribution of local-circuit (inhibitory) neurons, may be responsible for the severity of seizures. The possible influence of genes in conditioning inadequate intraparenchimal drug concentration, and the role of some cytokines determining an increase in intracellular calcium levels or an excessive growth of distrophic neurites, constitute other possible mechanisms of resistance. Several hypotheses on the mechanisms involved in the generation of DRE have been indicated: (a) ontogenic abnormalities in brain maturation; (b) epilepsy-induced alterations in network, neuronal, and glial properties in seizure-prone regions such as the hippocampus; (c) kindling phenomenon; (d) reorganization of cortical tissue in response to seizure-induced disturbances in oxygen supply. Such hypotheses need to be confirmed with suitable experimental models of intractable epilepsy that are specifically dedicated, which have until now been lacking.
Insights
Defining drug-resistant epilepsy (DRE) remains challenging due to unresolved questions about treatment duration and acceptable side effects. Understanding the complex mechanisms of pharmacoresistance is crucial for improving patient outcomes in intractable epilepsy cases.
Area of Science:
- Neuroscience
- Epileptology
- Pharmacology
Background:
- The definition of drug-resistant epilepsy (DRE) is controversial, with ongoing debate regarding treatment thresholds, acceptable side effects, and the timeframe for diagnosing resistance.
- Intractable epilepsy affects 20-30% of cases despite new antiepileptic drugs (AEDs), likely due to diverse pathogenetic mechanisms of refractoriness.
- Known risk factors for pharmacoresistance may be incomplete, with potential contributions from genetic factors, cytokines, and underlying brain abnormalities.
Purpose of the Study:
- To review the current understanding and unresolved questions surrounding the definition and mechanisms of drug-resistant epilepsy (DRE).
- To explore potential biological and clinical factors contributing to pharmacoresistance in epilepsy.
- To highlight the need for dedicated experimental models to investigate hypotheses on DRE generation.
Main Methods:
- Literature review and synthesis of existing research on drug-resistant epilepsy.
- Analysis of proposed mechanisms underlying pharmacoresistance, including genetic, cellular, and network-level factors.
- Discussion of clinical and biological risk factors associated with difficult-to-treat epilepsy.
Main Results:
- The definition of DRE lacks consensus on critical parameters like the number of drugs to try and acceptable side effects.
- Potential mechanisms of resistance include mesial temporal sclerosis, focal lesions, microdysgenesis, dysplastic cortex, genetic influences on drug concentration, and cytokine activity.
- Hypothesized mechanisms for DRE generation involve developmental abnormalities, epilepsy-induced network alterations, kindling, and cortical reorganization.
Conclusions:
- The definition and diagnosis of drug-resistant epilepsy require further clarification and standardization.
- Multiple, complex mechanisms contribute to pharmacoresistance, necessitating further research into their biological basis.
- The development of specific experimental models is essential to validate hypotheses and advance our understanding of intractable epilepsy.