The role of chronobiology in drug-resistance epilepsy: The potential use of a variability and chronotherapy-based individualized platform for improving the response to anti-seizure drugs

Abstract

Despite progress in the development of anti-seizure drugs, drug-resistant epilepsy (DRE) occurs in a third of patients. DRE is associated with poor quality of life and increased risk of sudden, unexplained death. The autonomic nervous system and chronobiology play a role in DRE. In the present paper, we provide a narrative review the mechanisms that underlie DRE and characterize some of the autonomic-and chronotherapy-associated parameters that contribute to the degree of response to therapy. Variability describes the functions of many biological systems, which are dynamic and continuously change over time. These systems are required for responses to continuing internal and external triggers, in order to maintain homeostasis and normal function. Both intra-and inter-subject variability in biological systems have been described. We present a platform, which comprises a personalized-based machine learning closed loop algorithm built on epilepsy-related signatures, autonomic signals, and chronotherapy, as a means for overcoming DRE, improving the response, and reducing the toxicity of current therapies.

Improving Diuretic Response in Heart Failure by Implementing a Patient-Tailored Variability and Chronotherapy-Guided Algorithm

“…This enables the overcoming of intra-and inter-patient variability, which prevents the "single bullet for all" concept from being applicable to the majority of patients. This concept is being introduced for overcoming drug resistance in several chronic diseases (142,143,(145)(146)(147)(148)(149)(150)(151)(152)(153)(154)(155)(156). In the last step, signatures based on parameters relevant to the pathogenesis of HF, mechanisms of action, and the cardio renal axis are introduced in a personalized approach for tailoring the appropriate dosing in a continuous and consistent manner (143, 144) (Figure 2).…”

Sleep Disruption Worsens Seizures: Neuroinflammation as a Potential Mechanistic Link

“…Chronotherapies and personalization of treatment schedules to accommodate sleeprelated epilepsy also provides a useful avenue for personalized seizure prevention [126,353,354]. For example, Guilhoto et al [132] observed that a higher dose of antiepileptic drugs (AEDs) at night led to seizure freedom in 64.7% (11/17) of patients, and 88.2% (15/17) experienced reduced seizure frequency.…”

Wearables bei Epilepsien

“…B. alle 3-6 Monate) beziehen [52]. Das Wissen um solche Zyklen ermöglicht zum einen Vorsorgemaßnahmen und die Etablierung individueller Therapieanpassungen (Chronopharmakotherapie) [54][55][56]. Zum anderen können Vorhersage-Algorithmen durch Berücksichtigung der zyklischen Muster relevant verbessert werden [57].…”

“…Erst die Validierung solcher Technologien nach höchsten Gütekriterien auch unter nicht kontrollierten Bedingungen (Phase 4-Studie nach [12]) wird den zuverlässigen Einsatz im häuslichen Umfeld und in Einrichtungen, aber auch in randomisierten klinischen Studien zur Wirksamkeitsprüfung von Medikamenten, implantierten Neurostimulation-Systemen und epilepsiechirurgischen Eingriffen erlauben. Eine objektive, automatisierte Zählung über einen längeren Zeitraum könnte auch neue Erkenntnisse zu individuellen zyklischen Mustern epileptischer Anfälle liefern und chronopharmakologische Therapieansätze ermöglichen [52,[54][55][56]. Die unmittelbare Kopplung von Detektions-und Vorhersagetechnologien mit Interventionsmöglichkeiten in einer Closed-Loop könnte auch beginnende Anfälle unterbrechen, wie es bereits bspw.…”