Circadian distribution of autostimulations in rVNS therapy in patients with refractory focal epilepsy

Highlights

• Autostimulation clustering is a new and useful way to analyze autostimulations.

• The probability of an autostimulation cluster occurrence is higher in the morning.

• Autostimulation cluster occurrence resembles the rhythmicity of cortisol concentration.

• Autostimulations may be used as a biomarker of ANS dysfunctions.

Abstract

Background

Responsive vagus nerve stimulation (rVNS) utilizes an electrocardiograph (ECG)-based algorithm to detect rapid sympathetic activations associated with the onset of a seizure. Abrupt sympathetic activation may also be associated with nocturnal arousals between sleep cycles or transitioning from sleep to wakefulness, a period in which many patients with epilepsy experience seizures. Because of circadian changes in autonomic function, we hypothesized that the autostimulation feature might also behave in a circadian fashion.

Objective

The aim of this study was to assess the circadian rhythmicity of autostimulations in rVNS treatment in patients with drug-resistant epilepsy (DRE).

Materials and methods

We performed a retrospective follow-up study of 30 patients with DRE treated with rVNS including 17 new implantations and 13 battery replacements at a single center in Finland. After initiation of autostimulation mode, the exact rVNS stimulation parameters and the timestamps of all individual autostimulations delivered were registered. A clustered autostimulation was defined as any autostimulation that occurred within the duration of the therapeutic cycle during the therapy “OFF” time compared with both the previous autostimulation and the following autostimulation.

Results

Autostimulations and especially autostimulation clusters show a higher probability of occurring in the morning and less at night. This trend appeared to follow the circadian rhythm of cortisol concentration.

Conclusions

Early morning peaks of autostimulations at low thresholds may reflect awakening-induced activation of the cardiovascular system, which is associated with a shift towards the dominance of the sympathetic branch of the autonomic nervous system. Cortisol release occurs in parallel driven by wakening-induced activation of the hypothalamic–pituitary–adrenal axis, which is fine-tuned by direct sympathetic input to the adrenal gland. This is of interest considering the known sympathetic hyperactivity in patients with epilepsy.

Introduction

Epilepsy is a chronic neurological disease associated with frequent seizures that affect approximately 1% of the world's population [1]. While a number of pharmaceutical therapies exist for epilepsy, approximately one in every three patients does not achieve seizure freedom with antiepileptic drugs (AEDs) and requires nonpharmacological therapies such as resective surgeries, diet therapies, or device-based therapies such as vagus nerve stimulation (VNS), deep brain stimulation, or responsive neurostimulation (Neuropace) [2]. The criteria for drug-resistant epilepsy (DRE) are fulfilled when sustained seizure freedom is not achieved with at least two tolerated, appropriately chosen, and used AED trials. According to the definition, AEDs can be used in combination or as monotherapies [3].

In 1994, VNStherapy received European approval followed by 1997 US Food and Drugs Administration (FDA) approval for DRE, with subsequent approvals expanding the base of indications for seizures and age ranges of prospective patients. In 2005, similar approval was granted for treatment-resistant depression.

Recent studies have begun to explore VNStherapy in chronic autoimmune disorders such as rheumatoid arthritis [4,5] and Crohn's disease [6] and other diseases with strong inflammatory components such as fibromyalgia [7]. It is possible that one of the likely multiple underlying therapeutic mechanisms is shared between all of these indications: chronic inflammation and autonomic dysfunction. Chronic inflammation and sympathetic hyperactivity are linked by a vicious circle, driving oxidative stress and multiple comorbidities such as heart disease and sudden cardiac death (SCD) [8]. Antiinflammatory therapies that pass the blood–brain barrier are known to be effective treatments for epilepsies that are resistant to typical AEDs. Specifically, adrenocorticotropic hormone (ACTH) therapies are known to regulate neurosteroid and melanocortin levels and have been shown to be therapeutic in DRE [9,10].

The vagus nerve is the key mediator of gut-brain communication and is critical in monitoring systemic inflammation. The nerve's afferent connections detect levels of inflammatory cytokines and transmit information about systemic inflammation to the hypothalamus, which in turn activates the vagovagal cholinergic antiinflammatory pathway, vagosympathetic antiinflammatory pathway, and the hypothalamic–pituitary–adrenal (HPA) axis. The vagovagal pathway corresponds to the vagus nerve's efferent connections, which are largely cholinergic and are believed to modulate an antiinflammatory pathway through nicotinic acetylcholine receptors, which in turn activate several cellular antiinflammatory mechanisms [[11], [12], [13], [14]], in addition to modulating autonomic control of other organs such as the heart, lungs, and gastrointestinal tract. Furthermore, the vagosympathetic antiinflammatory pathway suggests that sympathetic efferent innervation of multiple organs via the greater splanchnic nerve can mediate a significant reduction in inflammatory cytokines [[15], [16], [17]]. In addition to these pathways, the HPA axis represents a slower hormonal response to long-term or circadian patterns of inflammation. Tracking the activity of the HPA axis can be done in a minimally invasive fashion by assessing serum cortisol levels [18], and cortisol levels are gaining attention as a circadian covariate with some seizure types [19].

Responsive vagus nerve stimulation (rVNS) utilizes a proprietary algorithm to detect rapid changes in cardiac sympathetic activations,which are associated with the onset of a seizure. This detection feature is then paired with a responsive stimulation mode which allows the rVNS generator to deliver an additional “dose” of stimulation, referred to henceforth as an autostimulation, which ideally contains spatial propagation of a focal-onset seizure thereby also containing the sympathetic cardiac consequences (ictal tachycardia and repolarization abnormalities) of the seizure [20]. Because of circadian changes in autonomic function, we hypothesized that the autostimulation feature might also behave in a circadian fashion. Thus, we collected autostimulation logs from rVNS devices in 30 patients in order to understand the underlying circadian patterns in autostimulation delivery.