High-frequency burst vagal nerve simulation therapy in a natural primate model of genetic generalized epilepsy

Abstract

Purpose Since the approval of Vagal Nerve Stimulation (VNS) Therapy for medically refractory focal epilepsies in 1997, it has been also reported to be effective for a wide range of generalized seizures types and epilepsy syndromes. Instead of conventional VNS Therapy delivered at 20–30 Hz signal frequencies, this study evaluates efficacy and tolerability of high-frequency burst VNS in a natural animal model for genetic generalized epilepsy (GGE), the epileptic baboon. Methods Two female baboons (B1 P.h. Hamadryas and B2 P.h. Anubis × Cynocephalus) were selected because of frequently witnessed generalized tonic-clonic seizures (GTCS) for VNS implantation. High-frequency burst VNS Therapy was initiated after a 4–5 week baseline; different VNS settings (0.25, 2 or 2.5 mA, 300 Hz, 4 vs 7 pulses, 0.5–2.5 sec interburst interval, and intermittent stimulation for 1–2 vs for 24 hours per day) were tested over the subsequent 19 weeks, which included a 4–6 week wash-out period. GTCS frequencies were quantified for each setting, while seizure duration and postictal recovery times were compared to baseline. Scalp EEG studies were performed at almost every setting, including intermittent light stimulation (ILS) to evaluate photosensitivity. Pre-ILS ictal and interictal discharge rates, as well as ILS responses were compared between trials. The Novel Object test was used to assess potential treatment effects on behavior. Results High-frequency burst VNS Therapy reduced GTCS frequencies at all treatment settings in both baboons, except when output currents were reduced (0.25 mA) or intermittent stimulation was restricted (to 1–2 hours/day). Seizure duration and postictal recovery times were unchanged. Scalp EEG studies did not demonstrate treatment-related decrease of ictal or interictal epileptic discharges or photosensitivity, but continuous treatment for 120–180 seconds during ILS appeared to reduce photoparoxysmal responses. High-frequency burst VNS Therapy was well-tolerated by both baboons, without cardiac or behavioral changes. Repetitive muscle contractions involving the neck and left shoulder girdle were observed intermittently, most commonly at 0.5 interburst intervals, but these were transient, resolving with a few cycles of stimulation and not noted in wakefulness. Conclusions This preclinical pilot study demonstrates efficacy and tolerability of high-frequency burst VNS Therapy in the baboon model of GGE. The muscle contractions may be due to aberrant propagation of the stimulus along the vagal nerve or to the ansa cervicalis, but can be reduced by minimal adjustment of current output or stimulus duration.

Epilepsy in nonhuman primates

“…There are surprisingly no studies evaluating the effects of chronic ASMs on spontaneous seizure activity in the epileptic baboon. Nonetheless, in a recent study, high‐frequency microburst VNS therapy demonstrated efficacy in reducing spontaneous GTCS frequency in epileptic baboons monitored continuously by video …”

“…The seizures are mainly myoclonic seizures, and rarely convulsive in character. If convulsive seizures occur, they are usually briefer than the spontaneous GTCS, and may be repetitive . Intramuscular ketamine exceeding 8 mg/kg raises seizure thresholds and suppresses photosensitivity .…”

“…Nonetheless, in a recent study, high-frequency microburst VNS therapy demonstrated efficacy in reducing spontaneous GTCS frequency in epileptic baboons monitored continuously by video. 22 The ASM, ketamine, on the other hand, may induce spontaneous IEDs and reduce seizure threshold at subtherapeutic doses (intramuscular injections of 4-6 mg/kg). 13 The seizures are mainly myoclonic seizures, and rarely convulsive in character.…”

“…If convulsive seizures occur, they are usually briefer than the spontaneous GTCS, and may be repetitive. 13,22,23 Intramuscular ketamine exceeding 8 mg/kg raises seizure thresholds and suppresses photosensitivity. 23 Inhibition of the negative feedback influencing glutamatergic activity via antagonism of presynaptic glutamate receptor activity results in a proconvulsive effect, while at higher ketamine doses, the glutamatergic effects may be suppressed by saturation of the postsynaptic glutamate receptors.…”

Semiology of spontaneous generalized tonic‐clonic seizures in the epileptic baboon

“…All of the baboons had normal gross brain pathology on necropsy. The baboons were participating in three different funded studies at the time of their recordings: two baboons, B1 and B5, were recorded as part of an RNS implantation study, 14 four baboons, B2‐B4 and B7, were recorded as part of a high‐frequency microburst VNS Therapy trial, 15 and one baboon, B6, was implanted with intracranial depth, strip and grid electrodes 9 . The differences between the protocols underlie the disparity of the recording times.…”