Cortical Responsive Neurostimulation in a Baboon with Genetic Generalized Epilepsy

Abstract

Objective:

Evaluate the efficacy of cortical responsive neurostimulation (CRN) in an epileptic male baboon with genetic generalized epilepsy (GGE), as well as the alteration of seizure patterns and their circadian rhythms due to treatment.

Methods:

The baboon was implanted with two subdural frontoparietal strips, bridging the medial central sulci bilaterally. Electrocorticography (ECoG) data was downloaded daily during a three-month baseline, then every 2–3 days over a five-month treatment period. Long episodes, reflecting ictal or interictal epileptic discharges, were also quantified.

Results:

Twenty-three generalized tonic-clonic seizures (GTCS) and 2 episodes of nonconvulsive status epilepticus (NCSE) were recorded at baseline (median 8 events/month), whereas 26 GTCS were recorded under treatment (median 5/month). Similarly, daily indices of long episodes decreased from 0.46 at baseline to 0.29 with treatment. Ictal ECoG patterns and the circadian distribution of GTCS were also altered by RNS therapy.

Significance:

This case study provides the proof-of-concept for RNS therapy in the baboon model of GGE. CRN demonstrated a 38% median reduction in GTCS. Distinct ictal patterns were identified, which changed over the treatment period; the circadian pattern of his GTCS also shifted gradually from night to daytime with treatment. Future studies targeting the thalamic nuclei, or combining cortical and subcortical sites, may further improve detection and control of GTCS as well as other generalized seizure types. More broadly, this study demonstrates opportunities for evaluating seizure detection as well as chronic therapeutic interventions over long term in the baboon.

Graphical Abstract:

About 40% of people with epilepsy have idiopathic generalized epilepsy (IGE) [1]. While most IGEs respond to medical therapies, 35–40% remain poorly controlled. In contrast to focal epilepsies, there are no approved surgical therapies to treat medically refractory cases. For this reason, we utilized a natural nonhuman primate model of IGE to evaluate the potential use of responsive neurostimulation therapy (RNS® System; NeuroPace, CA).

Cortical responsive neurostimulation (CRN) and deep brain stimulation (DBS) delivered via the anterior nucleus of the thalamus have been approved to treat focal seizures in humans [2,3]. The patients selected for RNS System therapy have bitemporal epilepsy or dual pathology, and epileptogenic foci in functionally eloquent cortices, while DBS is frequently implemented in patients with multiregional epilepsy or large and poorly delineated epileptogenic zones. Despite these challenges, treatment with the RNS System demonstrated median seizure reduction of 41.5% in the first three months [2]. Median seizure reduction steadily improved to 70% after 6 years of treatment with the RNS System [4,5,]; similarly, there was 56% median seizure reduction after two years of DBS treatment compared to 26% after the first two months [3]. Smaller DBS case series from outside of the U.S. targeting the centromedian nucleus have also demonstrated seizure response in people with medically refractory IGE and Lennox-Gastaut syndromes [6].

The epileptic baboon provides a well-characterized, animal model of GGE [7]. The epilepsy is characterized by generalized myoclonic, absence and generalized tonic-clonic seizures (GTCS) as well as generalized ictal and interictal epileptic discharges on scalp EEG. The baboon also provides a model for photosensitivity, which is encountered in 40% of epileptic baboons. Similar to their human counterparts, epileptic baboons respond to antiseizure therapies [8], as well as Vagal Nerve Stimulation Therapy [9]. In this case study, we evaluated the use of cortical RNS therapy targeting the perirolandic cortices, and its effect on seizure expression.

Case Report:

This study was conducted at the Southwest National Primate Research Center (SNPRC, Texas Biomedical Research Institute, San Antonio, Texas), which houses the largest captive baboon pedigree in the world [10]. A ten-year old male baboon was selected on the basis of frequent primary GTCS, scalp EEG findings supporting the diagnosis of GGE, normal brain MRI, and the ability to cooperate for the interrogation and programing of the RNS® System. He did not reveal photosensitivity on scalp EEG. The baboon was conditioned to stay within reach of the interrogation wand, long enough to download electrocorticography (ECoG) data and for reprogramming the device (Figure S1). Bilateral craniotomies were performed to place one 1*4 contact cortical strip lead on each side, sampling the medial precentral cortex to the superior parietal lobule (Figure 1). The neurostimulator ferrule was mounted over the right centroparietal convexity. Electrode locations were confirmed at the necropsy following euthanasia. The study was approved by the IACUC at Texas Biomedical Research Institute strictly adhering to all rules and regulations governing the use of laboratory animals, as outlined in the United States Public Health Service’s Guide for the Care and Use of Laboratory Animals (Institute for Laboratory Animal Research) and the Animal Welfare Act (Amended, 2009) [11,12]. Principles outlined in the ARRIVE guidelines and in the Basel declaration (http://www.basel.declaration.org) were also followed.

Figure 1.

RNS strip electrode location reconstructed MRI with skull X-rays

Legend: L(left), cortical reconstruction of MRI on the left, and skull X-rays demonstrating neurstimulator and electrode placement.

After implantation, ECoG was downloaded daily during a three-month baseline period (during which no stimulation was delivered), and every 2–3 days during the subsequent five-month treatment period (during which stimulation was enabled). During the baseline, seizure detections were successfully correlated with simultaneous continuous video-recordings of GTCS. For adjustment of seizure detection and responsive stimulation parameters see supplementary Table 1 (Table S1).

Five ictal patterns were identified in 49 recorded GTCS (Figure 2, Samples 1–5):

Figure 2.

Categorization of Ictal Patterns

Legend: Ictal patterns demonstrated over 30 second samples using four channels (Channel 1 left precentral, contacts 1-L2, Channel L2 left postcentral contacts 3–4, Channel 3 right postcentral, contacts 1-L2, and Channel 4 right precentral, contacts 3–4). Markers indicate seizure detections or saturations (ictal patterns 1, L2, 4–6) and responsive stimulation (ictal patterns L2 and 5).

1. Onset with generalized 30–40 Hz low-voltage fast activity, which evolved over the right hemisphere, parietal before frontal, then emerging in the left parietal before the frontal channels, finally building up as 4–6 Hz spike-and-wave complexes, first lateralized to the right and generalizing with seconds (N=21).

2. Similar to above, but the paroxysmal fast activity (PFA) evolves first over the left hemisphere, then in right frontal before parietal channels, followed by generalized spike-and-wave complexes (GSWCs, N=7).

3. PFA begins over the left hemisphere for 2–3 seconds, better developed parietally than frontally, before being replaced by a generalized fast activity, evolving to 4–6 Hz GSWCs (N=8).

4. Onset similar to (1), with subsequent PFA evolving over both hemispheres but higher in amplitude on the right (N=5).

5. Onset with a generalized low-voltage fast activity (about 30–40 Hz), followed by generalized PFA, and 4–6 Hz generalized spiking (N=6).

Ictal onsets could not be accurately characterized in 2 post-treatment GTCS due to delayed seizure detection. Nonconvulsive status epilepticus (NCSE) was suspected on two additional occasions due to repeated samples of semi-periodic bursts of generalized, high-amplitude PFA lasting 1–2 seconds, followed by attenuation for a second, which extended beyond 15 minutes (Figure 2, Sample 6). The onset and duration of this pattern could not be determined, but no preceding GTCS was noted.

The baboon was tolerated the implantation well, and did not appear to have any adverse effects of stimulation. He had complied well with the downloading of ECoG data and the programing of stimulation settings the entire study. During the five-month treatment period, he suffered from an exacerbation of seizures due to an aggressive and dominant cage mate (seven GTCS in just three days), who was being vetted for the RNS® System implantation as well. After the eight months of close observation, he was moved to group cages. There he had experienced chronic skin infections, that required intermittent single housing for treatment. In one of the last group cages where he was housed, he experienced hostility from his male cage mates, again resulting in breakthrough seizures. At 25 months post-implantation, he was found with a scalp laceration and an inoperable injury to his right orbit possibly related to breakthrough seizures. He was euthanized and referred for necropsy. At the time of necropsy, the electrode placement was reconfirmed, and seemed to have been stable throughout his treatment period.

Results:

Of the 51 seizures, 31 occurred in clusters of multiple seizures per day on consecutive days: at baseline, the baboon had two clusters of 14 and 6 seizures in 6 and 3 days, respectively, while post-treatment, he demonstrated 7 and 4 seizures in 3 and 2 days, respectively. At baseline, 23 GTCS and two bouts of NCSE were recorded, with a median seizure rate of 8 (range 2–15) per month. Only 2 seizures were recorded in the first post-operative month, which may have reflected a post-implantation effect (Morrell et al., 2011). GTCS occurred mainly between 7pm-7am (69%), with <50% demonstrating a right hemispheric predominance. In 5 months of CRN, 26 GTCS were recorded with a median seizure rate of 5 (range 2–11) per month, reflecting a median seizure reduction from baseline of 38%. The seizures shifted to the daytime, with only 37% occurring between 7pm-7am, and 58% demonstrating right hemispheric lateralization. For the circadian distribution of the GTCS see Figure 3.

Figure 3.

Circadian Distribution of GTCS

The daily index of long episodes decreased from 0.46 at baseline to 0.29 post-treatment. Interictal epileptic discharges (IEDs) were mainly seen nocturnally, in sleep states, but occasional generalized polyspikes were also noted in awake states (Figure S2).

He had four GTCS documented by RNS in the last six months of his life, but he was not under continuous observation and downloads only occurred during veterinary exams.

Discussion:

This study provides a proof-of-concept for long-term RNS therapy in in the epileptic baboon. While this baboon was not photosensitive, his epilepsy was characterized as GGE before his implantation. The baboon cooperated with ECoG downloads and programing, but challenges became evident with stressors related to particular social settings. CRN resulted in a median seizure reduction of 38% in the first five months of treatment, with a similar reduction in epileptiform electrographic events, which is similar to the efficacy of RNS therapy in adults with medically refractory focal epilepsy (42%) [2]. Consistent with previous intracranial EEG recordings in epileptic baboons, GTCS were associated with a variable, often lateralized ictal EEG pattern, while IEDs were both generalized and multiregional [13]. Furthermore, ictal EEG onsets were noted more commonly in the postcentral/parietal than precentral/frontal lobe channels.

Due to the limited cortical coverage and the multiregional epileptogenicity in this model, the pattern of electrode involvement does not necessarily reflect the ictal onsets, rather a previously reported posterior-to-anterior ictal propagation [13]. The presence of lateralized or regional seizure onsets recorded with intracranial electrodes may also raise concern about the relevance of the baboon model for human GGE. Most of the seizure types (1,2,4,5; see Figure 2) were generalized in onset, some with lateralization to the right or left hemispheres as the seizures evolved; only 8 (16%) GTCS had a lateralized onset. While intracranial recordings in human GGE are rare, focal semiologies and scalp EEG findings are well-documented in people with GGE [14,15]. Finally, the relatively short treatment observation period of six months may not be sufficient to account for long term effects of RNS therapy; in studies monitoring patients with focal epilepsy up to 6 years, there was continued seizure reduction over time [4,5]. However, due to the shift in the ictal patterns and changes in the diurnal distribution of seizures, seizure detection settings may need to be monitored closely in IGE.

With its long-term recording capability, RNS® System therapy also offers a window to investigate diurnal patterns of seizures [16], and expression of IGE-related GTCS frequently conform to circadian cycles [17]. In this case study, nocturnal GTCS predominated at baseline and occurred from sleep, regardless of the time of day. With treatment, GTCS occurrences gradually shifted to the daytime, with seizures occurring mainly from wakefulness. Predominant nocturnal delivery of neurostimulation due to sleep-related activation of ictal and interictal discharges, or even due to stimulation-related sleep disruption, may have caused the circadian shift in seizure expression. This treatment effect may be particular to GGE, though a shift in the circadian seizure pattern was not noted with high-frequency microburst VNS Therapy [9]. Furthermore, ictal EEG lateralization also shifted from the left to the right hemisphere with treatment, which may have been caused by the alteration of circadian patterns. It would be interesting to see whether similar changes will occur in patients with GGE being treated with DBS.

In summary, this pilot study provides preliminary data on the use of RNS therapy in the baboon model of GGE. More importantly, this study also demonstrates how the baboon may be utilized in for the evaluation of long-term therapeutic interventions, such as neurostimulation therapies. Similarly, as the only large animal model associated with SUDEP [18], with similar cardiac complications as human epilepsy [19,20], long-term device studies could better elucidate the relationship of chronic GTCS with changes in autonomic regulation and cardiac function. Development of an implanted EEG recording system with live data streaming would provide an ideal platform to monitor seizure activity in epileptic baboons while remaining within their accustomed group, without having to move them to single cages or trying to cohabitate them in new, unfamiliar groups. The baboon model is also amenable to behavioral testing, and baboons can be trained to perform screen-based cognitive evaluations, such as the Cambridge Neuropsychological Test Automated Battery, or CANTAB [21]. Finally, in reference to RNS therapy, implantation of thalamic electrodes to treat GGE allows detection of ictal discharges originating from the cortices [22,23], whereas closed-loop stimulation combining cortical and thalamic electrodes may provide the optimal platform for the detection of ictal and interictal epileptic discharges and effective delivery of responsive neurostimulation to treat all seizure types associated with GGE [24].

Supplementary Material

1

Figure S1. Baboon Being Trained by Veterinary Staff to Comply with ECoG Downloads

2

Figure S2. Interictal ECoG Samples

Legend: (A) demonstrates normal awake sample, (B) activation of 4–6 Hz spike-and-waves complexes and polyspikes in sleep, multiregional and generalized, and (C) burst of generalized polyspikes in relaxed wakefulness leading to “saturation”, possibly representing the EEG correlate of a generalized myoclonic seizure.

3

Supplementary Table 1. Seizure Detection and Responsive Neurostimulation Programming

Legend: Ch(annel), L(eft), R(ight), L Line length, s(econds), currents either at the same or different outputs between bursts.

Highlights:

• This case study evaluated the use of CRN in a baboon IGE model.

• Monthly median seizure counts decreased by 38% in first 5 months of therapy.

• Long episode indices were also reduced by 37% in treatment period.

• Distinct ictal patterns were identified, which changed during the treatment period.

• Circadian pattern of GTCS shifted from night to daytime with treatment.

Highlights:

• The epileptic baboon provides an excellent model to evaluate seizure detection and neurostimulation therapies over long-term

• This case study evaluated the use of cortical responsive neurostimulation in the epileptic baboon