Emerging approaches in neurostimulation for epilepsy.

PURPOSE OF REVIEW: Neurostimulation is a quickly growing treatment approach for epilepsy patients. We summarize recent approaches to provide a perspective on the future of neurostimulation. RECENT FINDINGS: Invasive stimulation for treatment of focal epilepsy includes vagus nerve stimulation, responsive neurostimulation of the cortex and deep brain stimulation of the anterior nucleus of the thalamus. A wide range of other targets have been considered, including centromedian, central lateral and pulvinar thalamic nuclei; medial septum, nucleus accumbens, subthalamic nucleus, cerebellum, fornicodorsocommissure and piriform cortex. Stimulation for generalized onset seizures and mixed epilepsies as well as increased efforts focusing on paediatric populations have emerged. Hardware with more permanently implanted lead options and sensing capabilities is emerging. A wider variety of programming approaches than typically used may improve patient outcomes. Finally, noninvasive brain stimulation with its favourable risk profile offers the potential to treat increasingly diverse epilepsy patients. SUMMARY: Neurostimulation for the treatment of epilepsy is surprisingly varied. Flexibility and reversibility of neurostimulation allows for rapid innovation. There remains a continued need for excitability biomarkers to guide treatment and innovation. Neurostimulation, a part of bioelectronic medicine, offers distinctive benefits as well as unique challenges.

Responsive neurostimulation with low-frequency stimulation.

Deep brain stimulation and responsive neurostimulation (RNS) use high-frequency stimulation (HFS) per the pivotal trials and manufacturer-recommended therapy protocols. However, not all patients respond to HFS. In this retrospective case series, 10 patients implanted with the RNS System were programmed with low-frequency stimulation (LFS) to treat their seizures; nine of these patients were previously treated with HFS (100 Hz or greater). LFS was defined as frequency < 10 Hz. Burst duration was increased to at least 1000 ms. With HFS, patients had a median seizure reduction (MSR) of 13% (interquartile range [IQR] = -67 to 54) after a median of 19 months (IQR = 8-49). In contrast, LFS was associated with a 67% MSR (IQR = 13-95) when compared to HFS and 76% MSR (IQR = 43-91) when compared to baseline prior to implantation. Charge delivered per hour and pulses per day were not significantly different between HFS and LFS, although time stimulated per day was longer for LFS (228 min) than for HFS (7 min). There were no LFS-specific adverse effects reported by any of the patients. LFS could represent an alternative, effective method for delivering stimulation in focal drug-resistant epilepsy patients treated with the RNS System.

Neurodevelopmental and Epilepsy Phenotypes in Individuals With Missense Variants in the Voltage-Sensing and Pore Domains of KCNH5.

BACKGROUND AND OBJECTIVES: KCNH5 encodes the voltage-gated potassium channel EAG2/Kv10.2. We aimed to delineate the neurodevelopmental and epilepsy phenotypic spectrum associated with de novo KCNH5 variants. METHODS: We screened 893 individuals with developmental and epileptic encephalopathies for KCNH5 variants using targeted or exome sequencing. Additional individuals with KCNH5 variants were identified through an international collaboration. Clinical history, EEG, and imaging data were analyzed; seizure types and epilepsy syndromes were classified. We included 3 previously published individuals including additional phenotypic details. RESULTS: We report a cohort of 17 patients, including 9 with a recurrent de novo missense variant p.Arg327His, 4 with a recurrent missense variant p.Arg333His, and 4 additional novel missense variants. All variants were located in or near the functionally critical voltage-sensing or pore domains, absent in the general population, and classified as pathogenic or likely pathogenic using the American College of Medical Genetics and Genomics criteria. All individuals presented with epilepsy with a median seizure onset at 6 months. They had a wide range of seizure types, including focal and generalized seizures. Cognitive outcomes ranged from normal intellect to profound impairment. Individuals with the recurrent p.Arg333His variant had a self-limited drug-responsive focal or generalized epilepsy and normal intellect, whereas the recurrent p.Arg327His variant was associated with infantile-onset DEE. Two individuals with variants in the pore domain were more severely affected, with a neonatal-onset movement disorder, early-infantile DEE, profound disability, and childhood death. DISCUSSION: We describe a cohort of 17 individuals with pathogenic or likely pathogenic missense variants in the voltage-sensing and pore domains of Kv10.2, including 14 previously unreported individuals. We present evidence for a putative emerging genotype-phenotype correlation with a spectrum of epilepsy and cognitive outcomes. Overall, we expand the role of EAG proteins in human disease and establish KCNH5 as implicated in a spectrum of neurodevelopmental disorders and epilepsy.

Invasive neuromodulation for epilepsy: Comparison of multiple approaches from a single center.

BACKGROUND: Drug-resistant epilepsy (DRE) patients not amenable to epilepsy surgery can benefit from neurostimulation. Few data compare different neuromodulation strategies. OBJECTIVE: Compare five invasive neuromodulation strategies for the treatment of DRE: anterior thalamic nuclei deep brain stimulation (ANT-DBS), centromedian thalamic nuclei DBS (CM-DBS), responsive neurostimulation (RNS), chronic subthreshold stimulation (CSS), and vagus nerve stimulation (VNS). METHODS: Single center retrospective review and phone survey for patients implanted with invasive neuromodulation for 2004-2021. RESULTS: N = 159 (ANT-DBS = 38, CM-DBS = 19, RNS = 30, CSS = 32, VNS = 40). Total median seizure reduction (MSR) was 61 % for the entire cohort (IQR 5-90) and in descending order: CSS (85 %), CM-DBS (63 %), ANT-DBS (52 %), RNS (50 %), and VNS (50 %); p = 0.07. The responder rate was 60 % after a median follow-up time of 26 months. Seizure severity, life satisfaction, and quality of sleep were improved. Cortical stimulation (RNS and CSS) was associated with improved seizure reduction compared to subcortical stimulation (ANT-DBS, CM-DBS, and VNS) (67 % vs. 52 %). Effectiveness was similar for focal epilepsy vs. generalized epilepsy, closed-loop vs. open-loop stimulation, pediatric vs. adult cases, and high frequency (>100 Hz) vs. low frequency (<100 Hz) stimulation settings. Delivered charge per hour varied widely across approaches but was not correlated with improved seizure reduction. CONCLUSIONS: Multiple invasive neuromodulation approaches are available to treat DRE, but little evidence compares the approaches. This study used a uniform approach for single-center results and represents an effort to compare neuromodulation approaches.

Subclinical seizures on stereotactic EEG: characteristics and prognostic value.

OBJECTIVE: Although stereotactic EEG (sEEG) has become a widely used intracranial EEG technique, the significance of subclinical seizures (SCS) recorded on sEEG is unclear and studies examining this finding on sEEG are limited. We investigated (1) the prevalence of SCS in patients undergoing sEEG and clinical factors associated with their presence, (2) how often the subclinical seizure onset zone (SOZ) colocalizes with clinical SOZ, (3) the association of SCS and surgical outcomes, and (4) the influence of resection of the subclinical SOZ on surgical outcome. METHODS: We reviewed all patients who underwent intracranial monitoring with sEEG at our institution from 2015 through 2020 (n=169). Patient and seizure characteristics were recorded, as was concordance of subclinical and clinical seizures and post-surgical outcomes. RESULTS: SCS were observed during sEEG monitoring in 84 of 169 patients (50%). There was no difference in the prevalence of SCS based on imaging abnormalities, temporal vs extratemporal SOZ, number of electrodes, or pathology. SCS were more common in females than males (62% vs 40%, p=0.0054). SCS had complete concordance with clinical SOZ in 40% of patients, partial concordance in 29%, overlapping in 19%, and discordant in 12%. Eighty-three patients had surgery, 44 of whom had SCS. There was no difference in excellent outcome (ILAE 12 or 2) based on the presence of SCS or SCS concordance with clinical SOZ; however, there were improved outcomes in patients with complete resection of the subclinical SOZ compared with patients with incomplete resection (p =0.013). SIGNIFICANCE: These findings demonstrate that SCS are common during sEEG and colocalize with the clinical SOZ in most patients. Discordance with clinical SOZ does not necessarily predict poor surgical outcome; rather, complete surgical treatment of the subclinical SOZ correlates with excellent outcome. For unclear reasons, subclinical seizures occurred more commonly in females than males.

Centromedian Nucleus of the Thalamus Deep Brain Stimulation for Genetic Generalized Epilepsy: A Case Report and Review of Literature.

There is a paucity of treatment options for cognitively normal individuals with drug resistant genetic generalized epilepsy (GGE). Centromedian nucleus of the thalamus (CM) deep brain stimulation (DBS) may be a viable treatment for GGE. Here, we present the case of a 27-year-old cognitively normal woman with drug resistant GGE, with childhood onset. Seizure semiology are absence seizures and generalized onset tonic clonic (GTC) seizures. At baseline she had 4-8 GTC seizures per month and weekly absence seizures despite three antiseizure medications and vagus nerve stimulation. A multidisciplinary committee recommended off-label use of CM DBS in this patient. Over 12-months of CM DBS she had two GTC seizure days, which were in the setting of medication withdrawal and illness, and no GTC seizures in the last 6 months. There was no significant change in the burden of absence seizures. Presently, just two studies clearly document CM DBS in cognitively normal individuals with GGE or idiopathic generalized epilepsy (IGE) [in contrast to studies of cognitively impaired individuals with developmental and epileptic encephalopathies (DEE)]. Our results suggest that CM DBS can be an effective treatment for cognitively normal individuals with GGE and underscore the need for prospective studies of CM DBS.

Case Report: Prolonged Effects of Short-Term Transcranial Magnetic Stimulation on EEG Biomarkers, Spectral Power, and Seizure Frequency.

Transcranial magnetic stimulation (TMS) is a non-invasive modality of focal brain stimulation in which a fluctuating magnetic field induces electrical currents within the cortex. It remains unclear to what extent TMS alters EEG biomarkers and how EEG biomarkers may guide treatment of focal epilepsy. We present a case of a 48-year-old man with focal epilepsy, refractory to multiple medication trials, who experienced a dramatic reduction in seizures after targeting the area of seizure onset within the left parietal-occipital region with low-frequency repetitive TMS (rTMS). Prior to treatment, he experienced focal seizures that impacted cognition including apraxia at least 50-60 times daily. MRI of the brain showed a large focal cortical dysplasia with contrast enhancement involving the left occipital-parietal junction. Stimulation for 5 consecutive days was well-tolerated and associated with a day-by-day reduction in seizure frequency. In addition, he was monitored with continuous video EEG, which showed continued and progressive changes in spectral power (decreased broadband power and increased infraslow delta activity) and a gradual reduction in seizure frequency and duration. One month after initial treatment, 2-day ambulatory EEG demonstrated seizure-freedom and MRI showed resolution of focal contrast enhancement. He continues to receive 2-3 days of rTMS every 2-4 months. He was seizure-free for 6 months, and at last follow-up of 17 months was experiencing auras approximately every 2 weeks without progression to disabling seizures. This case demonstrates that rTMS can be a well-tolerated and effective means of controlling medication-refractory seizures, and that EEG biomarkers change gradually in a fashion in association with seizure frequency. TMS influences cortical excitability, is a promising non-invasive means of treating focal epilepsy, and has measurable electrophysiologic effects.

Presurgical Evaluation Strategies for Intractable Epilepsy of Childhood.

For children who continue to experience seizures despite treatment with antiseizure medications, epilepsy surgery can be considered. The goals of the presurgical evaluation are to determine the best surgical approach to render a good outcome. In patients with drug resistant focal epilepsy, the epileptogenic zone defines the minimal brain volume which must be resected for surgical success and to delineate the relationship of this region with functional cortex. A number of noninvasive tools for these tasks have emerged over the past decade, and existing technologies have been revised and improved. In this review, we examine the recent published evidence for these techniques, specifically as applied to the pediatric population. Discussed herein are the diagnostic value of methods such as video electroencephalography, magnetic resonance imaging, and supportive neuroimaging techniques including single photon emission tomography, photon emission tomography, and magnetoencephalography. Functional testing including functional magnetic resonance imaging, electrical stimulation mapping, and transcranial magnetic stimulation are considered in the context of pediatric epilepsy. The application of emerging techniques to preoperative testing such as source localization, image post-processing, and artificial intelligence is covered. We summarize the relative value of presurgical testing based on patient characteristics, including lesional or nonlesional MRI, temporal or extratemporal epilepsy, and other factors relevant in pediatric epilepsy such as pathological substrate and age.

A Review of Neurostimulation for Epilepsy in Pediatrics.

Neurostimulation for epilepsy refers to the application of electricity to affect the central nervous system, with the goal of reducing seizure frequency and severity. We review the available evidence for the use of neurostimulation to treat pediatric epilepsy, including vagus nerve stimulation (VNS), responsive neurostimulation (RNS), deep brain stimulation (DBS), chronic subthreshold cortical stimulation (CSCS), transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). We consider possible mechanisms of action and safety concerns, and we propose a methodology for selecting between available options. In general, we find neurostimulation is safe and effective, although any high quality evidence applying neurostimulation to pediatrics is lacking. Further research is needed to understand neuromodulatory systems, and to identify biomarkers of response in order to establish optimal stimulation paradigms.