Focal Cortex Stimulation With a Novel Implantable Device and Antiseizure Outcomes in 2 Prospective Multicenter Single-Arm Trials.

Importance: For the large population of people with drug-refractory epilepsy, alternative treatment approaches are needed. Clinical trial outcomes of a novel stimulation device, which is newly available in Europe for the treatment of patients with a predominant seizure focus, are reported for the first time. Objective: To perform a pooled analysis of the results of 2 prospective, multicenter, single-arm trials, A Pilot Study to Assess the Feasibility of Neurostimulation With the EASEE System to Treat Medically Refractory Focal Epilepsy (EASEE II) and A Pilot Study to Assess the Feasibility of Patient-Controlled Neurostimulation With the EASEE System to Treat Medically Refractory Focal Epilepsy (PIMIDES I), assessing the safety and efficacy of epicranial focal cortex stimulation (FCS) with a novel implantable device (EASEE [Precisis]) as adjunctive treatment for adult patients with drug-refractory focal epilepsy. Design, Setting, and Participants: This study was a pooled analysis of 2 nonrandomized uncontrolled trials, EASEE II and PIMIDES I, which began on January 15, 2019, and January 14, 2020, respectively, and ended on July 28, 2021. EASEE II and PIMIDES I were the first in-human, prospective, single-arm trials with an 8-month evaluation period. Patients were recruited at 7 European epilepsy centers. Consecutive participants with drug-refractory focal epilepsy were enrolled. Study data were analyzed from September 29, 2021, to February 2, 2022. Interventions: After a 1-month prospective baseline period, patients were implanted with the neurostimulation device. After a 1-month postimplantation recovery period, unblinded FCS was activated using both high-frequency and direct current (DC)-like components performed via electrode arrays placed epicranially above the individual epileptic focus region. Main Outcomes and Measures: Efficacy was prospectively assessed by the responder rate in the sixth month of stimulation compared with baseline; safety and additional end points were assessed after device implantation and during the stimulation period. Results: Of the 34 adult patients enrolled at 6 German and 1 Belgian investigational site, 33 (mean [SD] age, 34.6 [13.5] years; 18 male patients [54.5%]) received the neurostimulation device implant. A total of 32 patients underwent combined high-frequency direct current-like stimulation at least until the 8-month postimplant follow-up visit. After 6 months of stimulation, 17 of 32 patients (53.1%) were responders to treatment with at least a 50% reduction in seizure frequency compared with baseline, corresponding to a significant median seizure reduction by 52% (95% CI, 0.37%-0.76%; P < .001). No device- or procedure-related serious adverse events were reported (0; 95% CI, 0%-10.58%). There were no significant alterations in cognition, mood, or overall quality of life. Conclusions and Relevance: Results of this pooled analysis of 2 nonrandomized uncontrolled trials suggest that FCS with a novel neurostimulation device was associated with an effective reduction in seizure frequency in patients with drug-refractory focal epilepsy and may offer a promising treatment option for patients with a predominant epileptic focus. Trial Registration: German Clinical Trials Register: DRKS00015918 and DRKS00017833, respectively, and jointly under PROSPERO: CRD42021266440.

Using chronic recordings from a closed-loop neurostimulation system to capture seizures across multiple thalamic nuclei.

We report the case of a patient with unilateral diffuse frontotemporal epilepsy in whom we implanted a responsive neurostimulation system with leads spanning the anterior and centromedian nucleus of the thalamus. During chronic recording, ictal activity in the centromedian nucleus consistently preceded the anterior nucleus, implying a temporally organized seizure network involving the thalamus. With stimulation, the patient had resolution of focal impaired awareness seizures and secondarily generalized seizures. This report describes chronic recordings of seizure activity from multiple thalamic nuclei within a hemisphere and demonstrates the potential efficacy of closed-loop neurostimulation of multiple thalamic nuclei to control seizures.

Improved seizure burden and cognitive performance in a child treated with responsive neurostimulation (RNS) following febrile infection related epilepsy syndrome (FIRES).

Responsive neurostimulation (RNS) is an emerging therapy for patients with refractory focal epilepsy who are not candidates for surgical resection, with limited published experience in the pediatric population. We report a case of refractory multifocal epilepsy following febrile infection related epilepsy syndrome (FIRES) in which surgical resection was not feasible due to multifocal independent seizures and risk of cognitive deficit, and RNS was pursued. Relevant RNS data and neuropsychological testing results were reviewed. By eight months after implantation, decreased frequency and severity of clinical seizures were noted, and RNS data revealed decreased "long episodes," reduced spread of electrographic seizures, and fewer detections. Neuropsychological assessment, though potentially confounded by stimulant medication, revealed significant improvement in multiple cognitive domains, particularly working memory and processing speed, at six months. These findings illustrate success in detecting and aborting seizures, and additionally suggest a neuromodulatory effect of RNS stimulation. Our case demonstrates feasibility, efficacy and safety of RNS in a pediatric patient with FIRES, with evidence to also suggest cognitive improvement.

Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy.

OBJECTIVE: To prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years. METHODS: Adults treated with brain-responsive neurostimulation in 2-year feasibility or randomized controlled trials were enrolled in a long-term prospective open label trial (LTT) to assess safety, efficacy, and quality of life (QOL) over an additional 7 years. Safety was assessed as adverse events (AEs), efficacy as median percent change in seizure frequency and responder rate, and QOL with the Quality of Life in Epilepsy (QOLIE-89) inventory. RESULTS: Of 256 patients treated in the initial trials, 230 participated in the LTT. At 9 years, the median percent reduction in seizure frequency was 75% (p < 0.0001, Wilcoxon signed rank), responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency. We found that 18.4% (47 of 256) experienced ≥1 year of seizure freedom, with 62% (29 of 47) seizure-free at the last follow-up and an average seizure-free period of 3.2 years (range 1.04-9.6 years). Overall QOL and epilepsy-targeted and cognitive domains of QOLIE-89 remained significantly improved (p < 0.05). There were no serious AEs related to stimulation, and the sudden unexplained death in epilepsy (SUDEP) rate was significantly lower than predefined comparators (p < 0.05, 1-tailed χ2). CONCLUSIONS: Adjunctive brain-responsive neurostimulation provides significant and sustained reductions in the frequency of FOS with improved QOL. Stimulation was well tolerated; implantation-related AEs were typical of other neurostimulation devices; and SUDEP rates were low. CLINICALTRIALSGOV IDENTIFIER: NCT00572195. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that brain-responsive neurostimulation significantly reduces focal seizures with acceptable safety over 9 years.

Real-world experience with direct brain-responsive neurostimulation for focal onset seizures.

OBJECTIVE: The RNS System is a direct brain-responsive neurostimulation system that is US Food and Drug Administration-approved for adults with medically intractable focal onset seizures based on safety and effectiveness data from controlled clinical trials. The purpose of this study was to retrospectively evaluate the real-world safety and effectiveness of the RNS System. METHODS: Eight comprehensive epilepsy centers conducted a chart review of patients treated with the RNS System for at least 1 year, in accordance with the indication for use. Data included device-related serious adverse events and the median percent change in disabling seizure frequency from baseline at years 1, 2, and 3 of treatment and at the most recent follow-up. RESULTS: One hundred fifty patients met the criteria for analysis. The median reduction in seizures was 67% (interquartile range [IQR] = 33%-93%, n = 149) at 1 year, 75% (IQR = 50%-94%, n = 93) at 2 years, 82% (IQR = 50%-96%, n = 38) at ≥3 years, and 74% (IQR = 50%-96%, n = 150) at last follow-up (mean = 2.3 years). Thirty-five percent of patients had a ≥90% seizure frequency reduction, and 18% of patients reported being clinically seizure-free at last follow-up. Seizure frequency reductions were similar regardless of patient age, age at epilepsy onset, duration of epilepsy, seizure onset in mesial temporal or neocortical foci, magnetic resonance imaging findings, prior intracranial monitoring, prior epilepsy surgery, or prior vagus nerve stimulation treatment. The infection rate per procedure was 2.9% (6/150 patients); five of the six patients had an implant site infection, and one had osteomyelitis. Lead revisions were required in 2.7% (4/150), and 2.0% (3/150) of patients had a subdural hemorrhage, none of which had long-lasting neurological consequences. SIGNIFICANCE: In this real-world experience, safety was similar and clinical seizure outcomes exceeded those of the prospective clinical trials, corroborating effectiveness of this therapy and suggesting that clinical experience has informed more effective programming.

Responsive neurostimulation for regional neocortical epilepsy.

OBJECTIVE: Surgical resection of seizure-producing brain tissue is a gold standard treatment for drug-resistant focal epilepsy. However, several patient-specific factors can preclude resective surgery, including a spatially extensive ("regional") seizure-onset zone (SOZ). For such patients, responsive neurostimulation (RNS) represents a potential treatment, but its efficacy has not been investigated in this population. METHODS: We performed a multicenter retrospective cohort study of patients (N = 30) with drug-resistant focal epilepsy and a regional neocortical SOZ delineated by intracranial monitoring who were treated with the RNS System for at least 6 months. RNS System leads were placed at least 1-cm apart over the SOZ, and most patients were treated with a lead-to-lead stimulation pathway. Five patients underwent partial resection of the SOZ concurrent with RNS System implantation. We assessed change in seizure frequency relative to preimplant baseline and evaluated correlation between clinical outcome and stimulation parameters. RESULTS: Median follow-up duration was 21.5 months (range 6-52). Median reduction in clinical seizure frequency was 75.5% (interquartile range [IQR] 40%-93.9%). There was no significant difference in outcome between patients treated with and without concurrent partial resection. Most patients were treated with low charge densities (1-2.5 µC/cm2 ), but charge density, interlead distance, and duration of treatment were not significantly correlated with outcome. SIGNIFICANCE: RNS is a feasible and effective treatment in patients with drug-resistant regional neocortical seizures. Prospective studies in larger cohorts are necessary to determine optimal lead configuration and stimulation parameters, although our results suggest that lead-to-lead stimulation and low charge density may be effective in some patients.

Neurofeedback impacts cognition and quality of life in pediatric focal epilepsy: An exploratory randomized double-blinded sham-controlled trial.

OBJECTIVE: Children with epilepsy experience cognitive deficits and well-being issues that have detrimental effects on their development. Pharmacotherapy is the standard of care in epilepsy; however, few interventions exist to promote cognitive development and to mitigate disease burden. We aimed to examine the impact of two different modalities of neurofeedback (NFB) on cognitive functioning and quality-of-life (QOL) measurements in children and adolescents with controlled focal epilepsy. The study also explored the effects of NFB on clinical outcomes and electroencephalography (EEG) quantitative analysis. METHODS: Participants (n = 44) with controlled focal epilepsy were randomized to one of three arms: sensorimotor rhythm (SMR) NFB (n = 15), slow cortical potentials (SCP) NFB (n = 16), or sham NFB (n = 13). All participants received 25 sessions of intervention. The attention switching task (AST), Liverpool Seizure Severity Scale (LSSS), seizure frequency (SF), EEG power spectrum, and coherence were measured at baseline, postintervention, and at 3-month follow-up. RESULTS: In children and adolescents with controlled focal epilepsy, SMR training significantly reduced reaction time in the AST (p = 0.006), and this was correlated with the difference of change for theta power on EEG (p = 0.03); only the SMR group showed a significant decrease in beta coherence (p = 0.03). All groups exhibited improvement in QOL (p = <0.05). CONCLUSIONS: This study provides the first data on two NFB modalities (SMR and SCP) including cognitive, neurophysiological, and clinical outcomes in pediatric epilepsy. Sensorimotor rhythm NFB improved cognitive functioning, while all the interventions showed improvements in QOL, demonstrating a powerful placebo effect in the sham group.

Electrical cortical stimulation for refractory focal epilepsy: A long-term follow-up study.

OBJECTIVE: To report the long-term seizure control and safety of open-loop electrical cortical stimulation in patients with refractory focal epilepsy of diverse etiologies. METHODS: Six patients who received a therapeutic trial of cortical stimulation were included retrospectively. The frequency of seizures was recorded before and after implantation. Surgical procedure- and stimulation-related adverse effects were also recorded. RESULTS: The mean reductions in seizures were 61% at 1 year, 68% at 2 years, and 80% at 3-7 years post-implantation. The median follow-up time was 54 months (range 36-156 months). The etiologies of epilepsy included polymicrogyria in two patients, post-traumatic in one patient, and periventricular heterotopia, post-encephalitis, and familial lateral temporal lobe epilepsy in the remaining three patients. Status epilepticus stopped immediately after stimulation in three patients with focal status epilepticus or epilepsia partialis continua at baseline, with a long-term reduction in seizures of more than 90% and improvements in conscious level. Tissue incompatibility with the connection wire was noted in one patient, which subsided after the system was removed. CONCLUSIONS: Open-loop cortical stimulation of epileptic foci improved seizure control in our patients with refractory focal epilepsy of diverse etiologies. Electrical cortical stimulation stopped epilepsia partialis continua/focal status epilepticus immediately after the intervention and exhibited a sustained effect in reducing seizures. No procedure-related complications were observed. Further case cohort studies are needed to clarify which patients respond to open-loop cortical stimulation.

Parametric subtracted post-ictal diffusion tensor imaging for guiding direct neurostimulation therapy.

Parametric subtracted post-ictal diffusion tensor imaging (pspiDTI) is a novel imaging technique developed at our center to visualize transient, patient-specific, ictal-associated water diffusion abnormalities in hippocampal-associated axonal tissue. PspiDTI can elucidate putative connectivity patterns, tracing ictal propagation following a partial-onset seizure without generalization secondarily. PspiDTI compares two DTI volumes acquired during the early post-ictal period (<4 hr), and baseline inter-ictal interval (>24 hr post-seizure). This technique performs a voxel-wise parametric test to identify statistically significant transient ictal-associated changes in water diffusivity involving white matter (WM). Our technique was applied to six patients with refractory partial-onset epilepsy who were candidates for direct cortical responsive neurostimulation (RNS) therapy. Global and region-specific fractional anisotropy decreases, relative to baseline, were detected in all patients with a 17.01% (p < .01) relative mean decrement, while trace increases were found in 6/6 (100%) patients with a 13.30% (p < .01) relative global mean increment. Changes in diffusivity were anatomically compared with transient hyper-perfusion as detected by subtracted ictal SPECT co-registered to MRI (SISCOM). In 5/6 (83.33%) patients, alterations in WM diffusivity were detected adjacent to the SISCOM signal localized predominantly in gray matter. In 4/6 patients, post-implant RNS electrocorticography revealed early ictal propagation between implanted RNS depth leads guided by pspiDTI, hence validating concordant abnormal diffusivity regions detected by our technique. PspiDTI can complement the conventional pre-surgical evaluation to provide additional crucial information regarding WM ictal-propagation pathways between predominantly gray matter ictal-onset zones. When incorporated into a multi-modality pre-surgical workflow, pspiDTI can aid in defining critical nodes between ictogenic regions. This information can be used to strategically implant a limited set of two RNS depth leads for maximizing the extent to which direct cortical RNS can modulate a potentially extensive epileptogenic network.

Electroencephalographic findings in patients with circumscribed thalamic lesions.

INTRODUCTION: Thalamo-cortical networks have mainly been studied in the generation of idiopathic (genetic) epilepsies. The purpose of this study was to analyze EEG patterns and the occurrence of focal (symptomatic) epileptic seizures in patients with acquired circumscribed thalamic lesions. PATIENTS AND METHODS: Among 596 patients with thalamic lesions, we identified 47 patients in whom circumscribed thalamic lesions were detected by MRI and who underwent an EEG examination at the same stay at hospital. EEG findings were divided into normal findings, unspecific pathological changes and epileptiform discharges. The EEG findings were correlated to the localisation of the lesion within the thalamus and to the patients symptoms. RESULTS: In 32 patients (68%) pathological EEG findings were observed. They were heterogeneous and comprised regional and generalized slowing, triphasic waves, generalized periodic and regional epileptiform discharges. However, some characteristic findings were seen: Regional slowing was associated with ipsilateral thalamic lesions independent of the thalamic subarea, epileptiform discharges were related to lesions in the ipsilateral medial thalamus and periodic generalized discharges/triphasic waves with lesions in the anterior-ventromedial thalamus. Epileptic seizures were also more common in patients with medial thalamic lesions. Patients with regional epileptiform discharges responded to antiepileptic treatment whereas patients with triphasic waves and generalized periodic patterns did not. In some cases, it remained difficult to decide whether the thalamic lesion was the cause or consequence of epileptic activity. CONCLUSION: Pathological EEG findings are common in patients with acute and chronic thalamic lesions. EEG patterns associated with circumscribed thalamic lesions were influenced by the affected thalamic subregion. As in idiopathic generalized epilepsy, also in symptomatic epilepsy, the medial thalamus revealed to play a role in the generation of epileptiform discharges. In the patients with generalized periodic discharges and acute lesions in the ventral-anterior-medial thalamus, however, EEG changes were more likely caused by a disinhibition of cortico-thalamic networks than by a status epilepticus and thus risks and benefits of an aggressive antiepileptic treatment must be thoroughly balanced.

Hypothalamic hamartoma with epilepsy: Review of endocrine comorbidity.

The most common, and usually the only, endocrine disturbance in patients with hypothalamic hamartoma (HH) and epilepsy is central precocious puberty (CPP). The mechanism for CPP associated with HH may relate to ectopic generation and pulsatile release of gonadotropin-releasing hormone (GnRH) from the HH, but this remains an unproven hypothesis. Possible regulators of GnRH release that are intrinsic to HH tissue include the following: (1) glial factors (such as transforming growth factor α[TGFα) and (2) γ-aminobutyric acid (GABA)-mediated excitation. Both are known to be present in surgically-resected HH tissue, but are present in patients with and without a history of CPP, suggesting the possibility that symptoms related to HH are directly associated with the region of anatomic attachment of the HH to the hypothalamus, which determines functional network connections, rather than to differences in HH tissue expression or pathophysiology. CPP associated with HH presents with isosexual development prior to the age of 8 years in girls and 9 years in boys. It is not uncommon for CPP with HH to present in children at an earlier age in comparison to other causes of CPP, including in infancy. Surgical resection of the HH can be effective for treating CPP, but is reserved for patients with intractable epilepsy, since GnRH agonists are widely available and effective treatment. Other endocrine disturbances with HH are rare, but can include growth hormone deficiency, hypothyroidism, and adrenal insufficiency. Diabetes insipidus is commonly encountered postoperatively, but is not observed with HH prior to surgical intervention.

Chronic subthreshold cortical stimulation: a therapeutic and potentially restorative therapy for focal epilepsy.

INTRODUCTION: Approximately one third of patients with focal epilepsy continue to have ongoing seizures despite adequate trials of anti-seizure medications. Surgery to remove the epileptogenic zone remains the most efficacious treatment option for focal drug-resistant epilepsy. However, when cortical areas are eloquent or there are multiple epileptogenic zones, surgical resection is not an ideal approach. Cortical stimulation provides an attractive alternative. Area covered: Here, the authors describe Chronic Subthreshold Cortical Stimulation (CSCS), which uses continuous intracranial electrical stimulation applied near the epileptogenic zone to lower seizure probability. The authors review literature related to CSCS. One challenge is finding the most efficacious set of stimulation parameters for each patient. Expert commentary: Data supporting CSCS are limited but promising for the treatment of patients with focal drug resistant epilepsy who are not surgical candidates. Additional electrophysiological biomarkers to estimate cortical excitability are needed.

Brain-responsive neurostimulation in patients with medically intractable seizures arising from eloquent and other neocortical areas.

OBJECTIVE: Evaluate the seizure-reduction response and safety of brain-responsive stimulation in adults with medically intractable partial-onset seizures of neocortical origin. METHODS: Patients with partial seizures of neocortical origin were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. Additional analyses considered safety and seizure reduction according to lobe and functional area (e.g., eloquent cortex) of seizure onset. RESULTS: There were 126 patients with seizures of neocortical onset. The average follow-up was 6.1 implant years. The median percent seizure reduction was 70% in patients with frontal and parietal seizure onsets, 58% in those with temporal neocortical onsets, and 51% in those with multilobar onsets (last observation carried forward [LOCF] analysis). Twenty-six percent of patients experienced at least one seizure-free period of 6 months or longer and 14% experienced at least one seizure-free period of 1 year or longer. Patients with lesions on magnetic resonance imaging (MRI; 77% reduction, LOCF) and those with normal MRI findings (45% reduction, LOCF) benefitted, although the treatment response was more robust in patients with an MRI lesion (p = 0.02, generalized estimating equation [GEE]). There were no differences in the seizure reduction in patients with and without prior epilepsy surgery or vagus nerve stimulation. Stimulation parameters used for treatment did not cause acute or chronic neurologic deficits, even in eloquent cortical areas. The rates of infection (0.017 per patient implant year) and perioperative hemorrhage (0.8%) were not greater than with other neurostimulation devices. SIGNIFICANCE: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including adults with seizures of neocortical onset, and those with onsets from eloquent cortex.

Brain-responsive neurostimulation in patients with medically intractable mesial temporal lobe epilepsy.

OBJECTIVE: Evaluate the seizure-reduction response and safety of mesial temporal lobe (MTL) brain-responsive stimulation in adults with medically intractable partial-onset seizures of mesial temporal lobe origin. METHODS: Subjects with mesial temporal lobe epilepsy (MTLE) were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. RESULTS: There were 111 subjects with MTLE; 72% of subjects had bilateral MTL onsets and 28% had unilateral onsets. Subjects had one to four leads placed; only two leads could be connected to the device. Seventy-six subjects had depth leads only, 29 had both depth and strip leads, and 6 had only strip leads. The mean follow-up was 6.1 ± (standard deviation) 2.2 years. The median percent seizure reduction was 70% (last observation carried forward). Twenty-nine percent of subjects experienced at least one seizure-free period of 6 months or longer, and 15% experienced at least one seizure-free period of 1 year or longer. There was no difference in seizure reduction in subjects with and without mesial temporal sclerosis (MTS), bilateral MTL onsets, prior resection, prior intracranial monitoring, and prior vagus nerve stimulation. In addition, seizure reduction was not dependent on the location of depth leads relative to the hippocampus. The most frequent serious device-related adverse event was soft tissue implant-site infection (overall rate, including events categorized as device-related, uncertain, or not device-related: 0.03 per implant year, which is not greater than with other neurostimulation devices). SIGNIFICANCE: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including patients with unilateral or bilateral MTLE who are not candidates for temporal lobectomy or who have failed a prior MTL resection.

Comparing neurostimulation technologies in refractory focal-onset epilepsy.

For patients with pharmacoresistant focal epilepsy in whom surgical resection of the epileptogenic focus fails or was not feasible in the first place, there were few therapeutic options. Increasingly, neurostimulation provides an alternative treatment strategy for these patients. Vagal nerve stimulation (VNS) is well established. Deep brain stimulation (DBS) and cortical responsive stimulation (CRS) are newer neurostimulation therapies with recently published long-term efficacy and safety data. In this literature review, we introduce these therapies to a non-specialist audience. Furthermore, we compare and contrast long-term (5-year) outcomes of newer neurostimulation techniques with the more established VNS. A search to identify all studies reporting long-term efficacy (>5 years) of VNS, CRS and DBS in patients with refractory focal/partial epilepsy was conducted using PubMed and Cochrane databases. The outcomes compared were responder rate, percentage seizure frequency reduction, seizure freedom, adverse events, neuropsychological outcome and quality of life. We identified 1 study for DBS, 1 study for CRS and 4 studies for VNS. All neurostimulation technologies showed long-term efficacy, with progressively better seizure control over time. Sustained improvement in quality of life measures was demonstrated in all modalities. Intracranial neurostimulation had a greater side effect profile compared with extracranial stimulation, though all forms of stimulation are safe. Methodological differences between the studies mean that direct comparisons are not straightforward. We have synthesised the findings of this review into a pragmatic decision tree, to guide the further management of the individual patient with pharmacoresistant focal-onset epilepsy.

[Neurofeedback therapy influence on clinical status and some EEG parameters in children with localized epilepsy]. / Wplyw terapii neurofeedback na stan kliniczny i wybrane parametry zapisu EEG u dzieci chorych na padaczke z napadami czesciowymi.

UNLABELLED: Neurofeedback (EEG biofeedback, NF) is one of the methods of non-pharmacological instrumental therapy. In the treatment of epilepsy it is considered as a complementary method, reducing the number of seizures. The aim of this study was to investigate the effect of NF on the incidence of clinical attacks and bioelectrical activity of the brain in children with epilepsy with partial seizures and secondarily generalized seizures. MATERIAL AND METHODS: The study involved a group of 78 children with partial seizures, additionally 30 of them had second-ry generalized seizures. There were 35 girls and 43 boys ranging in age from 5 to 17.5 years. They were treated with NF in the Neuromedica Institute in Krakow, in the period 2005-2015. Treatment time ranged from 6 months to 3 years. We have evaluated the incidence of seizures before and after NF therapy. Visual analysis of EEG recordings with assessment of background activity, location of focal changes, presence of paroxysmal pattern and epileptic graphoelements. RESULTS: In 41/78 children seizures occurred 1-2 times a month, in 19/78 every day and 9 children were diagnosed with epileptic syndrome. During NF therapy 52/78 children experienced resolution of clinical seizures. NF therapy was ineffective in only one child. In 18 child withdrawal of antiepileptic treatment was achieved and in 22 reduction of drug doses. Epileptic graphoelements occurred in 46/78 children before treatment and in 21/78 children after treatment. Before NF therapy irregular bio-electrical activity was found in 51 children versus 27 children with regular bioelectric activity and in 27 children versus 51 children after the therapy. The amplitude of this activity returned to normal in 19 children, and in 29 children the frequency of background activity. Particularly surprising was to restore synchrony and symmetry of EEG pattern in 44 children (11 children before NF treatment to 55 children after the treatment). Even more significant effect of NF therapy was observed in EEG patterns, abolition of paroxysmal pattern and reduction of continuous, localized and generalized changes. NF therapy also advantageously reduced the number of localized changes and decreased sensitivity of EEG pattern to hyperventilation and photostimulation. CONCLUSIONS: During NF therapy in almost all children with epileptic partial seizures and secondarily generalized seizures resolution or reduction of clinical seizures was observed. In nearly 1/4 of children withdrawal of antiepileptic treatment was achieved and in higher number reduction of pharmacotherapy. All parameters of the background EEG bioelectric activity in these children have improved, especially synchrony and symmetry of EEG pattern and paroxysmal changes subsided.

Day-Night Patterns of Epileptiform Activity in 65 Patients With Long-Term Ambulatory Electrocorticography.

PURPOSE: To characterize cyclic day-night patterns of electrocorticographic epileptiform activity (EA) in patients with focal onset seizures. METHODS: Epileptiform events as defined by the physician (also termed more generally as "epileptiform activity" or EA) were recorded in 65 patients with partial onset (also referred to as "focal onset") seizures using the RNS System, which includes a cranially implanted neurostimulator connected to 1 or two 4-contact leads placed at the seizure focus. The neurostimulator is programmed to detect specific patterns of electrocorticographic activity and to provide responsive stimulation. The 24-hour periodicity of detections of EA was analyzed for individual patients and for subgroups of patients according to the type of EA, laterality, lobe of onset, and whether the onset was neocortical or hippocampal. The time of day when peaks in EA occurred was also analyzed. RESULTS: There were robust circadian patterns of detections of EA in most patients, with a primary peak in detections at night and a secondary peak in the late afternoon in some cases. Subset analyses were performed by lobe, region of the brain, and type of cortex (neocortical vs. hippocampal); significant circadian rhythmicity was present in all subsets. CONCLUSIONS: This is the first report of circadian cycles of EA as assessed through chronic ambulatory electrocorticographic recordings in adults with focal onset seizures. Epileptiform activity displayed circadian patterns in the majority of these patients. These findings suggest that epilepsy therapies might be optimized by adjusting the timing of therapy according to each patient's unique circadian pattern of EA.

Low-frequency electroacupuncture suppresses focal epilepsy and improves epilepsy-induced sleep disruptions.

BACKGROUND: The positive effects of acupuncture at Feng-Chi acupoints on treating epilepsy and insomnia have been well-documented in ancient Chinese literature. However, there is a lack of scientific evidence to elucidate the underlying mechanisms behind these effects. Our previous study demonstrated that high-frequency (100 Hz) electroacupuncture (EA) at Feng-Chi acupoints deteriorates both pilocarpine-induced focal epilepsy and sleep disruptions. This study investigated the effects of low-frequency (10 Hz) EA on epileptic activities and epilepsy-induced sleep disruptions. RESULTS: In rats, the Feng-Chi acupoint is located 3 mm away from the center of a line between the two ears. Rats received 30 min of 10 Hz EA stimuli per day before each day's dark period for three consecutive days. Our results indicated that administration of pilocarpine into the left CeA at the beginning of the dark period induced focal epilepsy and decreased both rapid eye movement (REM) sleep and non-REM (NREM) sleep during the consequent light period. Low-frequency (10 Hz) EA at Feng-Chi acupoints suppressed pilocarpine-induced epileptiform EEGs, and this effect was in turn blocked by naloxone (a broad-spectrum opioid receptor antagonist), but not by naloxonazine (a µ-receptor antagonist), naltrindole (a δ-receptor antagonist) and nor-binaltorphimine (a κ-receptor antagonist). Ten Hz EA enhanced NREM sleep during the dark period, and this enhancement was blocked by all of the opioid receptor antagonists. On the other hand, 10 Hz EA reversed pilocarpine-induced NREM suppression during the light period, and the EA's effect on the sleep disruption was only blocked by naloxonazine. CONCLUSIONS: These results indicate that low-frequency EA stimulation of Feng-Chi acupoints is beneficial in improving epilepsy and epilepsy-induced sleep disruptions, and that opioid receptors in the CeA mediate EA's therapeutic effects.

A Single-Center Experience with the NeuroPace RNS System: A Review of Techniques and Potential Problems.

INTRODUCTION: The clinical results for the RNS System (NeuroPace, Mountain View, California, USA) closed-loop responsive neurostimulator for the treatment of medically intractable partial-onset seizures have been encouraging. The University of Southern California (USC) Neurorestoration Center and the Keck Hospital of USC have become the world's first institutions to implant an RNS System post U.S. Food and Drug Administration (FDA) approval. As one of the study centers, we review our experience with our group of patients who have been implanted with the RNS System. METHODS: A total of 40 surgeries by a single surgeon were performed on 10 patients (7 male and 3 female) with an average age of 39.2 years (24-66 years) and were followed for an average of 45 months (30-54 months). The average age at seizure onset was 14 years (birth-37 years) with an average of 4.7 (3-12) failed antiepileptic drugs. We reviewed the patients' charts for complications from the surgeries including infections requiring surgical intervention, hematomas, hardware failures, and death. RESULTS: Of the 40 surgeries, there were 10 initial implantations of the neurostimulator and leads, 24 neurostimulator replacements for expected end of neurostimulator service, 2 incision and drainage procedures (I & Ds) for soft tissue infection followed by 1 explantation and 1 reimplantation (same patient), and 2 revisions because of one lead that was damaged at the exit point between the skull and a titanium mesh and the second lead that was damaged at an acute bend over the skull (same patient). Eight of the patients had no complications and underwent an average of 2.7 neurostimulator replacements over 7 consecutive years to date. Each patient underwent routine postoperative computed tomography imaging of the brain, and none had any intracranial hematomas or misplaced leads requiring revision surgery. Finally, there were no deaths in our patient population. CONCLUSIONS: Our experience with the NeuroPace RNS System over an average follow-up of 45 months suggests that the surgery and device are safe when placed by an experienced surgeon. Although there were no clinically significant hematomas or patient deaths, we did have 1 patient each with infection and lead damage at the point of exit from the skull. We compare the results of this study with other neuromodulation procedures for epilepsy to evaluate the safety and complications associated with the RNS System. Our initial experience suggests that the RNS System can be readily incorporated into an active epilepsy surgical center.

On-demand pulsatile intracerebral delivery of carisbamate with closed-loop direct neurostimulation therapy in an electrically induced self-sustained focal-onset epilepsy rat model.

OBJECT: The authors evaluated the preclinical feasibility of acutely stabilizing an active bihemispheric limbic epileptic circuit using closed-loop direct neurostimulation therapy in tandem with "on-demand'" convection-enhanced intracerebral delivery of the antiepileptic drug (AED) carisbamate. A rat model of electrically induced self-sustained focal-onset epilepsy was employed. METHODS: A 16-contact depth-recording microelectrode was implanted bilaterally in the dentate gyrus (DG) of the hippocampus of Fischer 344 rats. The right microelectrode array included an integrated microcatheter for drug delivery at the distal tip. Bihemispheric spontaneous self-sustained limbic status epilepticus (SSLSE) was induced in freely moving rats using a 90-minute stimulation paradigm delivered to the right medial perforant white matter pathway. Immediately following SSLSE induction, closed-loop right PP stimulation therapy concurrent with on-demand nanoboluses of the AED [(14)C]-carisbamate (n = 4), or on-demand [(14)C]-carisbamate alone (n = 4), was introduced for a mean of 10 hours. In addition, 2 reference groups received either closed-loop stimulation therapy alone (n = 4) or stimulation therapy with saline vehicle only (n = 4). All animals were sacrificed after completing the specified therapy regimen. In situ [(14)C]-autoradiography was used to determine AED distribution. RESULTS: Closed-loop direct stimulation therapy delivered unilaterally in the right PP aborted ictal runs detected in either ipsi- or contralateral hippocampi. Freely moving rats receiving closed-loop direct stimulation therapy with ondemand intracerebral carisbamate delivery experienced a significant reduction in seizure frequency (p < 0.001) and minimized seizure frequency variability during the final 50% of the therapy/recording session compared with closed-loop stimulation therapy alone. CONCLUSIONS: Unilateral closed-loop direct stimulation therapy delivered to afferent hippocampal white matter pathways concurrent with on-demand ipsilateral intracerebral delivery of nano-bolused carisbamate can rapidly decrease the frequency of electrographic seizures in an active bihemispheric epileptic network. Additionally, direct pulsatile delivery of carisbamate can stabilize seizure frequency variability compared with direct stimulation therapy alone.