Managing drug-resistant epilepsy: challenges and solutions

Abstract

Despite the development of new antiepileptic drugs (AEDs), ~20%–30% of people with epilepsy remain refractory to treatment and are said to have drug-resistant epilepsy (DRE). This multifaceted condition comprises intractable seizures, neurobiochemical changes, cognitive decline, and psychosocial dysfunction. An ongoing challenge to both researchers and clinicians alike, DRE management is complicated by the heterogeneity among this patient group. The underlying mechanism of DRE is not completely understood. Many hypotheses exist, and relate to both the intrinsic characteristics of the particular epilepsy (associated syndrome/lesion, initial response to AED, and the number and type of seizures prior to diagnosis) and other pharmacological mechanisms of resistance. The four current hypotheses behind pharmacological resistance are the “transporter”, “target”, “network”, and “intrinsic severity” hypotheses, and these are reviewed in this paper. Of equal challenge is managing patients with DRE, and this requires a multidisciplinary approach, involving physicians, surgeons, psychiatrists, neuropsychologists, pharmacists, dietitians, and specialist nurses. Attention to comorbid psychiatric and other diseases is paramount, given the higher prevalence in this cohort and associated poorer health outcomes. Treatment options need to consider the economic burden to the patient and the likelihood of AED compliance and tolerability. Most importantly, higher mortality rates, due to comorbidities, suicide, and sudden death, emphasize the importance of seizure control in reducing this risk. Overall, resective surgery offers the best rates of seizure control. It is not an option for all patients, and there is often a significant delay in referring to epilepsy surgery centers. Optimization of AEDs, identification and treatment of comorbidities, patient education to promote adherence to treatment, and avoidance of triggers should be periodically performed until further insights regarding causative pathology can guide better therapies.

Individualized Dosing Algorithms and Therapeutic Monitoring for Antiepileptic Drugs

“…1,2 It is therefore acknowledged that rational prescribing of AEDs requires not only an understanding of the seizure type and of the drugs' pharmacodynamic (PD) properties, but also careful consideration of the factors known to affect drug disposition. 3,4 In fact, the impact of covariate factors on drug exposure and consequently on pharmacokinetic (PK) variability, efficacy, and tolerability profile of AEDs has been highlighted in a recent publication by our group. 5 Our findings confirm the concerns raised by previous authors on the importance of accounting for covariate factors, particularly in patients at the extreme range of age, such as infants and the elderly.…”

“…3 It may also allow the identification of individuals within the group of patients who would respond to optimized regimens, but currently remain refractory to treatment and are said to have drug-resistant epilepsy. 4 Finally, we aim to show how TDM procedures can be combined with inferential methods based on modeling and simulation to optimize doses and dosing regimens. These concepts have been increasingly applied to other therapeutic areas (e.g., antitumor, immunosuppressant, and antiinfective drugs) where favorable treatment outcome depends on the attainment and maintenance of target drug exposure.…”

“…Such interindividual variability in the response to AEDs is a consequence of multiple interacting factors, including differences in the pathophysiology, pharmacokinetics, pharmacodynamics, and genetic variation . It is therefore acknowledged that rational prescribing of AEDs requires not only an understanding of the seizure type and of the drugs' pharmacodynamic (PD) properties, but also careful consideration of the factors known to affect drug disposition . In fact, the impact of covariate factors on drug exposure and consequently on pharmacokinetic (PK) variability, efficacy, and tolerability profile of AEDs has been highlighted in a recent publication by our group .…”

“…Our approach may be of particular relevance for the 10–20% of patients who still show unresolved seizures when their target dose has been achieved . It may also allow the identification of individuals within the group of patients who would respond to optimized regimens, but currently remain refractory to treatment and are said to have drug‐resistant epilepsy …”

Epigenetic modifications of chromatin in epilepsy: a potential mechanism of pharmacoresistance?

“…Согласно рассматриваемой гипотезе, такие структурные изменения способствуют формированию патологической нейронной сети. Такая сеть становится нечувствительной к эндогенным противоэпилептическим механизмам и действию ПЭП [17].…”