Closed-loop control of seizure activity via real-time seizure forecasting by reservoir neuromorphic computing

Reliable seizure forecasting has important implications in epilepsy treatment and improving the quality of lives for people with epilepsy. High-frequency activity (HFA) is a biomarker that has received significant attention over the past 2 decades, but its predictive value in seizure forecasting remains uncertain. This work aimed to determine the utility of HFA in seizure forecasting. We used seizure data and HFA (80-170 Hz) data obtained from long-term, continuous intracranial EEG recordings of patients with drug-resistant epilepsy. Instantaneous rates and phases of HFA cycles were used as features for seizure forecasting. Seizure forecasts based on each individual HFA feature, and with the use of a combined approach, were generated pseudo-prospectively (causally). To compute the instantaneous phases for pseudo-prospective forecasting, real-time phase estimation based on an autoregressive model was used. Features were combined with a weighted average approach. The performance of seizure forecasting was primarily evaluated by the area under the curve (AUC). Of 15 studied patients (median recording duration 557 days, median seizures 151), 12 patients with >10 seizures after 100 recording days were included in the pseudo-prospective analysis. The presented real-time phase estimation is feasible and can causally estimate the instantaneous phases of HFA cycles with high accuracy. Pseudo-prospective seizure forecasting based on HFA rates and phases performed significantly better than chance in 11 of 12 patients, although there were patient-specific differences. Combining rate and phase information improved forecasting performance compared to using either feature alone. The combined forecast using the best-performing channel yielded a median AUC of 0.70, a median sensitivity of 0.57, and a median specificity of 0.77. These findings show that HFA could be useful for seizure forecasting and represent proof of concept for using prior information of patient-specific relationships between HFA and seizures in pseudo-prospective forecasting. Future seizure forecasting algorithms might benefit from the inclusion of HFA, and the real-time phase estimation approach can be extended to other biomarkers. This study provides Class IV evidence that HFA (80-170 Hz) in long-term continuous intracranial EEG can be useful to forecast seizures in patients with refractory epilepsy.

Epilepsy affects approximately 1% of the world population. Patients have recurrent seizures, increased physical and psychiatric comorbidities, and higher mortality rate than the general population. Over the last 40 years, research has resulted in 20 new antiseizure medications (ASMs) approved between 1990 and 2018. In spite of this, up to one-third of patients (~ 1 million patients in the USA) have drug-resistant epilepsy (DRE), with little change between 1982 and 2018, a period of intense new ASM development. A minority of patients with DRE may benefit from surgical treatment, but this specialized care remains challenging to scale. Therefore, the greatest hope for breakthroughs for patients with DRE is in pharmacologic therapies.Recently, several advances promise to change the outcomes for patients with DRE. Cenobamate, a drug with dual mechanisms of modulating sodium channel currents and GABA-A receptors, achieves 90-100% seizure reduction in 25-33% of patients with focal DRE, a response not observed with other ASMs. Fenfluramine, a serotonin-acting drug, dramatically reduces the frequency ofconvulsive seizuresin Dravet syndrome, a devastating developmental epileptic encephalopathy with severe DRE.Both drugs reduce mortality.In addition, the possibility of DRE prevention was recently raised in patients with tuberous sclerosis complex, a relatively common genetic form of epilepsy. A paradigm shift is emerging in the treatment of epilepsy. Seizure freedom has become attainable in a significant proportion of patients with focal DRE, and dramatic seizure reduction has been achieved in a developmental encephalopathy. Coupled with a rich pipeline of new compounds under clinical development, the long sought-after breakthrough in the treatment of epilepsy may finally be in sight.

While the efficacy of repetitive transcranial magnetic stimulation (rTMS) has been explored in humans and, to a lesser extent, in dogs with epilepsy, further clinical studies are required to assess the potential antiseizure effect of this non-invasive neurostimulation technique. The objective was to assess the antiseizure effect and safety of a novel three-day rTMS protocol in dogs with drug-resistant idiopathic epilepsy. A single-blinded, randomized, sham-controlled clinical trial was conducted by randomly allocating 20 dogs with drug-resistant idiopathic epilepsy or epilepsy of unknown origin into active (n = 10) or sham (n = 10) rTMS. The monthly seizure frequency (MSF), monthly seizure day frequency (MSDF), and number of cluster seizures (CS) were recorded and comparisons between the two groups were analysed. The safety of the rTMS protocol was also evaluated. Statistically significant differences were identified between the groups in median MSF (active, 8 [0–24]; sham, 17 [7–46]; p = 0.04), MSDF (active, 8 [0–24]; sham, 11 [6–23]; p = 0.04), and number of CS (active, 10 [5–23]; sham, 16 [10–25]; p = 0.005). No adverse events were reported. The current protocol indicates that active rTMS is safe, can reduce seizure frequency, and prevent CS in dogs with drug-resistant idiopathic epilepsy or epilepsy of unknown origin. An “one-size-fits-all” rTMS protocol for epilepsy in dogs is likely to provide suboptimal outcomes because the effect of rTMS is highly dependent on the duration and parameters of stimulation as well as individual variability. Therefore, future studies are needed to explore further specific stimulation parameters so they can be better tailored to the individual dog.

Rufinamide add-on therapy for drug-resistant epilepsy.

Despite the considerable advances of epileptology drug-resistant epilepsies consist about 30% among all forms of epilepsy. Authors represent the review of the literature devoted to efficacy and tolerability of zonisamide in the treatment of drug-resistant epilepsy. The current review of studies devoted to efficacy and safety of a new antiepileptic drug zonisamide in the treatment of epilepsy is proposed. The mechanism of action and pharmacokinetic of zonisamide are described; the questions of efficacy and tolerability in the treatment of drug-resistant focal epilepsies and other types of seizures and forms of epilepsy are considered. The possibilities of the use of the drug in the treatment of comorbid disorders are considered

Background. Detected temporal lobe focal cortical dysplasia (FCD) often results in developing drug-resistant epilepsy requiring surgical treatment. In turn, temporal lobectomy, despite its high efficiency, can cause a certain deficit associated with direct or indirect damage to the brain pathways.Objective: to describe the main anatomical features of temporal lobe brain pathways and clinical outcomes of surgical treatment of drug-resistant epilepsy that developed in temporal lobe FCD.Material and methods. A retrospective analysis of the treatment of 14 patients with drug-resistant structural focal epilepsy (temporal lobe FCD) who underwent surgery (anterior temporal lobectomy) was carried out. To localize the epileptogenic zone, specialists of the multidisciplinary group performed a comprehensive presurgical examination in all participants. The surgical material was examined by a neuromorphologist, the diagnosis was verified. In the postoperative period, patients underwent a series of control examinations at standard time points (after 3, 6, 12, 36 months). The minimum follow-up period was 12 months. As a part of the anatomical study, 6 brain hemispheres were investigated prepared for the white matter fibers dissection using Klingler technique. The main pathways that run within or near the temporal lobe were selectively examined: the lower longitudinal, medial longitudinal, lower fronto-occipital and uncinate fasciculi.Results. In the postoperative period, no complications were observed in 14.3% of patients after 4 cm resection of the temporal lobe subdominant hemisphere. Speech disorders (mostly transient) were detected in 35.7% of the subjects, visual field disorders (mainly transient) – in 21.4%, neuropsychiatric disorders – in 43.9%. Overall seizure control: 93% of patients achieved class I according to Engel Epilepsy Surgery Outcome Scale.Conclusion. Anterior temporal lobectomy can be considered as a highly effective method of surgical treatment of drug-resistant structural focal epilepsy with a high rate of achieving control over epileptic seizures in the postoperative period. However, the mandatory conditions for maintaining the quality of life for patients after such a surgical intervention include preoperative analysis of the risk of adverse effects performed by a multidisciplinary team as well as postoperative management and rehabilitation.

BackgroundIn 1997 Vagus Nerve Stimulation (VNS) received approval from the US Food and Drug Administration (FDA) as an adjunctive therapy in the treatment of medically intractable partial epilepsy in people aged 12 years and older who are ineligible for resective epilepsy surgery. Although the exact mechanisms of action are unknown, the use of VNS with children has increased, including those younger than 12 years of age, or those with generalized epilepsy.MethodsWe describe the outcome for the first group of nine patients, aged 8-28 years, who had pharmaco-resistant epilepsy and were treated with VNS. During the follow up, we gradually and slowly increased the parameters of the stimulation in order to assess the efficacy of VNS even at parameters which would usually be considered "non-therapeutic", along with possible side effects and changes in quality of life.ResultsAt the last follow, up 1 patient was "seizures free", 3 were "very good responders", 3 were "good responders" and 2 were "non responders". We obtained an initial seizure reduction with low stimulation parameters, the highest current reached being 2.00 mA. This observation supports the possibility that, for younger patients, lower stimulation intensities than those commonly used in clinical practice for adults can be therapeutic. We also wanted to underline the reduction in seizure frequency (~91,7%) and the reduction in seizure duration (> 50%) in the patients affected by drug-resistant absence epilepsy. Adverse effects were mild, tolerable and, in most of cases, easily resolved by adjusting the stimulation parameters. Hoarseness of voice was the most frequent side effect. The improvements in the quality of life are relevant and seem to be independent of the VNS effect in controlling seizures.ConclusionsOur small experience seems to confirm the efficacy and safety of VNS in drug resistant partial and generalized epilepsy in developing age groups.

Transcutaneous vagus nerve stimulation in the treatment of drug-resistant epilepsy.

Editor's evaluation: Disease-modifying effects of sodium selenate in a model of drug-resistant, temporal lobe epilepsy

One of the most disabling aspects of living with chronic epilepsy is the unpredictability of seizures. Cumulative research in the past decades has advanced our understanding of the dynamics of seizure risk. Technological advances have recently made it possible to record pertinent biological signals, including electroencephalogram (EEG), continuously. We aimed to assess whether patient-specific seizure forecasting is possible using remote, minimally invasive ultra-long-term subcutaneous EEG. We analyzed a two-center cohort of ultra-long-term subcutaneous EEG recordings, including six patients with drug-resistant focal epilepsy monitored for 46-230days with median 18h/day of recorded data, totaling >11000h of EEG. Total electrographic seizures identified by visual review ranged from 12 to 36 per patient. Three candidate subject-specific long short-term memory network deep learning classifiers were trained offline and pseudoprospectively on preictal (1 h before) and interictal (>1 day from seizures) EEG segments. Performance was assessed relative to a random predictor. Periodicity of the final forecasts was also investigated with autocorrelation. Depending on each architecture, significant forecasting performance was achieved in three to five of six patients, with overall mean area under the receiver operating characteristic curve of .65-.74. Significant forecasts showed sensitivity ranging from 64% to 80% and time in warning from 10.9% to 44.4%. Overall, the output of the forecasts closely followed patient-specific circadian patterns of seizure occurrence. This study demonstrates proof-of-principle for the possibility of subject-specific seizure forecasting using a minimally invasive subcutaneous EEG device capable of ultra-long-term at-home recordings. These results are encouraging for the development of a prospective seizure forecasting trial with minimally invasive EEG.

Expression and cellular distribution of multidrug resistance-related proteins in patients with focal cortical dysplasia

Intravenous immunoglobulin G as adjuvant treatment in drug-resistant childhood epilepsy

The review is dedicated to the problems of current neurosurgical treatment for drug-resistant epilepsy in the adult population of Russia and foreign countries. The literature published in the period 2010–2017 was sought in Russian and foreign databases. This review included 58 only full-text publications. The search results have shown that despite advances in neurosurgery for drug-resistant epilepsy and the development of new surgical procedures, the problem of this disease has not yet been fully resolved today. This is evidenced by fairly high global prevalence rates in patients with postoperative epilepsy resistant to antiepileptic therapy. The literature analysis has revealed that the mean prevalence of postoperative epilepsy is 69%. This indicator may vary according to the type of an epileptogenic structural lesion and its location in the brain. However, despite the rapid development of epilepsy surgery, currently there is still a low surgical activity in the treatment of patients with drugresistant epilepsy. Of importance is also the presence of postoperative complications, including various infectious complications and neurological deficit. Taking into account the high rate of postoperative epilepsy, it is concluded that it is appropriate to develop postoperative rehabilitation methods for patients with drug-resistant epilepsy.

<h3>Objective:</h3> To determine the efficacy and safety of RNS in the treatment of drug-resistant epilepsy and to determine the potential complications. <h3>Background:</h3> Epilepsy Surgery is an effective treatment for patients with drug-resistant epilepsy (DRE). Although resection/ablation of the epileptogenic zone is the preferred method to achieve seizure freedom, many patients are not appropriate for resection/ablation due to potential neurologic risks or limited benefits. Responsive Neurostimulation System (RNS) was approved by the US Food and Drug Administration FDA as an adjunctive treatment of drug-resistant focal epilepsy. <h3>Design/Methods:</h3> A database search was performed for patients who underwent RNS placement between 01/01/2014–04/01/2022 at our institution. Patients with &gt;12 months follow-up duration were included in the final data analysis. The primary outcome is seizure freedom as defined by Engel/ILAE seizure outcome classification systems. Variables were reported as mean or median for numerical variables and percentage for categorical variables. The Chi-square and Fisher’s exact tests were applied to compare independent groups for categorical variables. <h3>Results:</h3> A total of 50 patients fit the inclusion criteria during this time period. 19 were excluded as they had less than one-year follow-up. Overall, 22.6% reached a state of freedom from disabling seizures (Engel 1 or ILAE I/II). With 28 total patients getting RNS alone or as a final procedure, 21.4% achieved freedom from debilitating seizures (Engel 1 or ILAE I/II), and 60.7% had a &gt;50% reduction in seizure frequency (ILAE III/IV). There was no difference regarding seizure freedom in patients based on electrode placement (p = 0.645). Four patients (8%) had complications (1 encephalopathy, 2 scalp infections, and 1 scalp infection with meningitis). The other 92% had no major complications. <h3>Conclusions:</h3> Overall, RNS provides worthwhile seizure reduction in most of the population seen at the University of Kansas Medical Center. The outcome from our center is comparable to the outcomes reported in literature. <b>Disclosure:</b> Dr. Beattie has nothing to disclose. Dr. Ortiz Guerrero has nothing to disclose. Dr. Uysal has nothing to disclose.

Evaluating prodromal symptoms and health locus of control as predictors of seizure reactivity and neuropsychiatric outcomes in drug-resistant epilepsy: a cross-sectional study.