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

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 20-30Hz 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 x 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 2.5mA, 300Hz, 4 vs 7 pulses, 0.5-2.5s interburst interval, and intermittent stimulation for 1-2 vs for 24h 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 (0.25mA) or intermittent stimulation was restricted (to 1-2h/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 120-180s 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.

Subdural electrode recording of generalized photoepileptic responses.

We evaluated the spatiotemporal distribution of photic driving (PDR), photoparoxysmal (PPR), and photoconvulsive (PCR) responses recorded by intracranial electrodes (ic-EEG) in a patient with generalized photosensitivity and right frontal lobe cortical dysplasia. Intermittent light stimulation (ILS) was performed thirteen times in nine days. Cortical responses to ILS recorded by ic-EEG were reviewed and classified as PDRs, PPRs, and PCRs. Photic driving responses were restricted to the occipital lobe at ILS frequencies below 9 Hz, spreading to the parietal and central regions at > 9 Hz. Photoparoxysmal responses commonly presented as focal, medial occipital, and parietal interictal epileptic discharges (IEDs), the latter propagating to the sensorimotor cortices. Generalized IEDs were also generated in the setting of PPRs. Photoconvulsive responses, characterized by repetitive bilateral upper extremity myoclonus sustained until the end of the stimulus, were associated with propagation of the medial parieto-occipital discharge to the primary sensorimotor and supplementary area cortices, while generalized myoclonic seizures were associated with a generalized spike-and-wave discharge with an interhemispheric posterior cingulate onset sparing the sensorimotor cortices. Both types of PCR could occur during the same stimulus. Regardless of the pathway, PCRs only occurred when PDRs involved the parietal cortices. While there may be more than one pathway underlying PCRs, parietal lobe association cortices appear to be critical to their generation.