Decrease In Seizure Frequency Research Articles

Neurostimulation in people with drug-resistant epilepsy: Systematic review and meta-analysis from the ILAE Surgical Therapies Commission.

Summarize the current evidence on efficacy and tolerability of vagus nerve stimulation (VNS), responsive neurostimulation (RNS), and deep brain stimulation (DBS) through a systematic review and meta-analysis. We followed the Preferred Reporting Items of Systematic reviews and Meta-Analyses reporting standards and searched Ovid Medline, Ovid Embase, and the Cochrane Central Register of Controlled Trials. We included published randomized controlled trials (RCTs) and their corresponding open-label extension studies, as well as prospective case series, with ≥20 participants (excluding studies limited to children). Our primary outcome was the mean (or median, when unavailable) percentage decrease in frequency, as compared to baseline, of all epileptic seizures at last follow-up. Secondary outcomes included the proportion of treatment responders and proportion with seizure freedom. We identified 30 eligible studies, six of which were RCTs. At long-term follow-up (mean 1.3years), five observational studies for VNS reported a pooled mean percentage decrease in seizure frequency of 34.7% (95% confidence interval [CI]: -5.1, 74.5). In the open-label extension studies for RNS, the median seizure reduction was 53%, 66%, and 75% at 2, 5, and 9 years of follow-up, respectively. For DBS, the median reduction was 56%, 65%, and 75% at 2, 5, and 7 years, respectively. The proportion of individuals with seizure freedom at last follow-up increased significantly over time for DBS and RNS, whereas a positive trend was observed for VNS. Quality of life was improved in all modalities. The most common complications included hoarseness, and cough and throat pain for VNS and implant site pain, headache, and dysesthesia for DBS and RNS. Neurostimulation modalities are an effective treatment option for drug-resistant epilepsy, with improving outcomes over time and few major complications. Seizure-reduction rates among the three therapies were similar during the initial blinded phase. Recent long-term follow-up studies are encouraging for RNS and DBS but are lacking for VNS.

A Rare Presentation Characterized by Epileptic Spasms in ALDH7A1, Pyridox(am)ine-5'-Phosphate Oxidase, and PLPBP Deficiency.

Objective: To analyze the clinical feature, treatment, and prognosis of epileptic spasms (ES) in vitamin B6–dependent epilepsy, including patients with pyridoxine-dependent epilepsy (PDE) caused by ALDH7A1 mutation, pyridox(am)ine-5′-phosphate oxidase (PNPO) deficiency, and PLPBP deficiency. Methods: We analyzed data from a cohort of 54 cases with PDE, 13 cases with PNPO deficiency, and 2 cases with PLPBP deficiency and looked for the presentation of ES among them. Results: A total of 11 patients with the seizure presentation of ES have been collected. Among them, four patients carried mutations in ALDH7A1, six carried mutations in PNPO, and the remaining one carried mutation in PLPBP. The analysis of this cohort identified nine cases presenting as infantile spasms distributed in the three diseases and two cases presenting as Ohtahara syndrome diagnosed with PDE and PNPO deficiency, respectively. In the PDE and PLPBP deficiency groups, seizures were controlled by pyridoxine monotherapy, and the remaining one had refractory seizures due to secondary brain atrophy. In the groups with PNPO deficiency, one patient showed seizure-free when treated by PLP combined with valproic acid, three still had infrequent seizures treated by PLP monotherapy or pyridoxine or PLP combined with other antiseizure medications, and two died. In two cases presenting as Ohtahara syndrome, after regular treatment, one showed seizure-free, the others showed a marked decrease in seizure frequency, and they both showed an improvement in EEG. Significance: ES might be a common form of seizures in PNPO deficiency, and EEG presented as hypsarrhythmia or a burst suppression pattern. It is difficult for pyridoxine to control frequent seizures caused by secondary brain injury. In our PNPO deficiency cohort, patients with infantile spasms did not respond better to PLP than pyridoxine. Timely and correct treatment could prevent the transformation of the child’s disease from Ohtahara syndrome and infantile spasms to subsequent epileptic encephalopathy or refractory epilepsy.

Responsive Neurostimulation Targeting the Anterior, Centromedian and Pulvinar Thalamic Nuclei and the Detection of Electrographic Seizures in Pediatric and Young Adult Patients.

BackgroundResponsive neurostimulation (RNS System) has been utilized as a treatment for intractable epilepsy. The RNS System delivers stimulation in response to detected abnormal activity, via leads covering the seizure foci, in response to detections of predefined epileptiform activity with the goal of decreasing seizure frequency and severity. While thalamic leads are often implanted in combination with cortical strip leads, implantation and stimulation with bilateral thalamic leads alone is less common, and the ability to detect electrographic seizures using RNS System thalamic leads is uncertain.ObjectiveThe present study retrospectively evaluated fourteen patients with RNS System depth leads implanted in the thalamus, with or without concomitant implantation of cortical strip leads, to determine the ability to detect electrographic seizures in the thalamus. Detailed patient presentations and lead trajectories were reviewed alongside electroencephalographic (ECoG) analyses.ResultsAnterior nucleus thalamic (ANT) leads, whether bilateral or unilateral and combined with a cortical strip lead, successfully detected and terminated epileptiform activity, as demonstrated by Cases 2 and 3. Similarly, bilateral centromedian thalamic (CMT) leads or a combination of one centromedian thalamic alongside a cortical strip lead also demonstrated the ability to detect electrographic seizures as seen in Cases 6 and 9. Bilateral pulvinar leads likewise produced reliable seizure detection in Patient 14. Detections of electrographic seizures in thalamic nuclei did not appear to be affected by whether the patient was pediatric or adult at the time of RNS System implantation. Sole thalamic leads paralleled the combination of thalamic and cortical strip leads in terms of preventing the propagation of electrographic seizures.ConclusionThalamic nuclei present a promising target for detection and stimulation via the RNS System for seizures with multifocal or generalized onsets. These areas provide a modifiable, reversible therapeutic option for patients who are not candidates for surgical resection or ablation.

Effects of Obstructive Sleep Apnea on Epilepsy, and Continuous Positive Airway Pressure as a Treatment Option.

Purpose: To compare the characteristics of obstructive sleep apnea (OSA) between patients with epilepsy and patients without epilepsy and to investigate CPAP (Continuous Positive Airway Pressure) effect on seizures. Methods: Medical and polysomnography (PSG) data from 235 adult OSA patients with epilepsy (OE; 183 males; mean age, 49.8 years) and 268 age- and sex-matched OSA patients without epilepsy (OSE; 216 males; mean age, 51.3 years), obtained between March 2014 and May 2020 and housed in a database in a university-affiliated hospital, were retrospectively reviewed. All subjects completed surveys addressing comorbidities and medications, and sleep-related questionnaires including the Insomnia Severity Index, Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, and Beck Depression Inventory-II. Results: Compared with the OSE group, the OE group reported fewer sleep-related complaints and less severe OSA-related PSG parameters, with a lower apnea-hypopnea index (24.9 vs. 33.4 events/h; p < 0.003), arousal index (23.3 vs. 30.8 events/h; p < 0.001), and oxygen desaturation index (19.6 vs. 28.8; p < 0.002). The OE group had fewer smokers and lower alcohol consumption but a higher body mass index (27.0 vs. 25.9 kg/m2; p < 0.001). No correlations were observed between OSA-related PSG parameters and epilepsy-related factors, such as age at seizure onset, seizure type, frequency of seizures, presence of nocturnal seizures, and number of antiseizure medications, in the OE group. Patients with OE who demonstrated good compliance with CPAP therapy exhibited a decrease in seizure frequency. Conclusions: The OE group exhibited less severe disease characteristics than their age- and sex-matched OSE counterparts. Nevertheless, because the coexistence of OSA and epilepsy is high, CPAP therapy can reduce the frequency of seizures. Therefore, it is important to evaluate the presence of OSA in patients with epilepsy and to treat the conditions concurrently.

Vagus nerve stimulation for treatment of drug-resistant epilepsy: a systematic review and meta-analysis.

To analyze the efficacy and safety of high-frequency VNS versus control (low-frequency VNS or no VNS) in patients with DRE using data from randomized controlled trials (RCTs). An electronic literature search was conducted on PubMed, EMBASE, and Cochrane Controlled Register of Trials (CENTRAL); 12 RCTs reporting seizure frequency or treatment response in studies containing a high-frequency VNS treatment arm (conventional VNS or transcutaneous VNS [tVNS]) compared to control (low-frequency VNS or no VNS) were included. Seizure frequency, treatment response (number of patients with ≥ 50% reduction in seizure frequency), quality of life (QOL), and adverse effects were analyzed. Seizure frequency was reported in 9 studies (718 patients). Meta-analysis with random-effects models favored high-frequency VNS over control (standardized mean difference = 0.82, 95%-CI = 0.39-1.24, p < .001). This remained significant for subgroup analyses of low-frequency VNS as the control, VNS modality, and after removing studies with moderate-to-high risk of bias. Treatment response was reported in 8 studies (758 patients). Random-effects models favored high-frequency VNS over control (risk ratio = 1.57, 95%-CI = 1.19-2.07, p < .001). QOL outcomes were reported descriptively in 4 studies (363 patients), and adverse events were reported in 11 studies (875 patients). Major side effects and death were not observed to be more common in high-frequency VNS compared to control. High-frequency VNS results in reduced seizure frequency and improved treatment response compared to control (low-frequency VNS or no VNS) in patients with drug-resistant epilepsy. Greater consideration for VNS in patients with DRE may be warranted to decrease seizure frequency in the management of these patients.

Pregabalin for Recurrent Seizures in Critical Illness: A Promising Adjunctive Therapy, Especially for cyclic Seizures.

Pregabalin (PGB) is an effective adjunctive treatment for focal epilepsy and acts by binding to the alpha2-delta subunit of voltage-gated calcium channels to reduce excitatory neurotransmitter release. Limited data exist on its use in the neurocritical care setting, including cyclic seizures-a pattern of recurrent seizures occurring at nearly regular intervals. Although the mechanism underpinning cyclic seizures remains elusive, spreading excitation linked to spreading depolarizations may play a role in seizure recurrence and periodicity. PGB has been shown to increase spreading depolarization threshold; hence,we hypothesized that the magnitude of antiseizure effect from PGB is more pronounced in patients with cyclic versus noncyclic seizures in a critically ill cohort with recurrent seizures. We conducted a retrospective case series of adults admitted to two academic neurointensive care units between January 2017 and March 2019 who received PGB for treatment of seizures. Data collected included demographics, etiology of brain injury, antiseizure medications, and outcome. Continuous electroencephalogram recordings 48hours before and after PGB administration were reviewed by electroencephalographers blinded to the administration of antiseizure medications to obtain granular data on electrographic seizure burden. Cyclic seizures were determined quantitatively (i.e., < 50% variation of interseizure intervals for at least 50% of consecutive seizures). Coprimary outcomes were decrease in hourly seizure burden in minutes and decrease in seizure frequency in the 48hours after PGB initiation. We used nonparametric tests for comparison of seizure frequency and burden and segmented linear regression to assess PGB effect. We included 16 patients; the median age was 69years, 11 (68.7%) were women, three (18.8%) had undergone a neurosurgical procedure, and five (31%) had underlying epilepsy. All seizures had focal onset; ten patients (62.5%) had cyclic seizures. The median hourly seizure burden over the 48hours prior to PGB initiation was 1.87min/hour (interquartile range 1.49-8.53), and the median seizure frequency was 1.96 seizures/hour (interquartile range 1.06-3.41). In the 48hours following PGB (median daily dose 300mg, range 75-300mg), the median number of seizures per hour was reduced by 0.80 seizures/hour (95% confidence interval 0.19-1.40), whereas the median hourly seizure burden decreased by 1.71min/hour (95% confidence interval 0.38-3.04). When we compared patients with cyclic versus noncyclic seizures, there was a relative decrease in hourly seizure frequency (- 86.7% versus - 2%, p = 0.04) and hourly seizure burden (- 89% versus - 7.8%, p = 0.03) at 48hours. PGB was associated with a relative reduction in seizure burden in neurocritically ill patients with recurrent seizures, especially those with cyclic seizures, and may be considered in the therapeutic arsenal for refractory seizures. Whether this effect is mediated via modulation of spreading depolarization requires further study.

A neuromorphic spiking neural network detects epileptic high frequency oscillations in the scalp EEG

Interictal High Frequency Oscillations (HFO) are measurable in scalp EEG. This development has aroused interest in investigating their potential as biomarkers of epileptogenesis, seizure propensity, disease severity, and treatment response. The demand for therapy monitoring in epilepsy has kindled interest in compact wearable electronic devices for long-term EEG recording. Spiking neural networks (SNN) have emerged as optimal architectures for embedding in compact low-power signal processing hardware. We analyzed 20 scalp EEG recordings from 11 pediatric focal lesional epilepsy patients. We designed a custom SNN to detect events of interest (EoI) in the 80–250 Hz ripple band and reject artifacts in the 500–900 Hz band. We identified the optimal SNN parameters to detect EoI and reject artifacts automatically. The occurrence of HFO thus detected was associated with active epilepsy with 80% accuracy. The HFO rate mirrored the decrease in seizure frequency in 8 patients (p = 0.0047). Overall, the HFO rate correlated with seizure frequency (rho = 0.90 CI [0.75 0.96], p < 0.0001, Spearman’s correlation). The fully automated SNN detected clinically relevant HFO in the scalp EEG. This study is a further step towards non-invasive epilepsy monitoring with a low-power wearable device.

Complementary and Alternative Medicine (CAM) use in Children with Epilepsy.

Complementary and alternative medicine (CAM) use by the pediatric population with epilepsy in rural Pennsylvania was studied to characterize the prevalence, perceived effectiveness, and reasons for CAM use. This study additionally assessed the adequacy of parent-physician communication regarding CAM usage. A telephone survey was administered to 200 parents/caregivers of children with epilepsy followed at Hershey Medical Center. Thirteen percent of respondents indicated CAM use by their child. Common types of CAM used were cannabis-related products such as CBD oil and medical marijuana. Forty-eight percent of CAM users chose to initiate CAM owing to dissatisfaction with the outcomes of antiseizure drugs. Fifty-nine percent noticed a decrease in seizure frequency with CAM use, and more than 11% of CAM users reported side effects from CAM. Eighty percent of CAM users had discussions regarding CAM with their child's neurologist. CAM use was found to be associated with increased seizure severity (P = .004) and the prior use of cannabidiol (Epidiolex) (P < .001) or the ketogenic diet (P = .001). Increased seizure severity and the prior use of Epidiolex or the ketogenic diet may be used as predictors for the identification of patients with a higher likelihood of using CAM. Interest in future CAM use, especially cannabis-related products, was expressed in a large percentage of non-CAM users. Given the high parental or caregiver interest in CAM, providers are encouraged to be proactive in initiating discussions about CAM and collaborate with parents/caregivers to ensure the safe usage of CAM among pediatric patients.

Monoamine neurotransmitters in early epileptic encephalopathies: New insights into pathophysiology and therapy

AimTo study neurotransmitter status in children with early epileptic and developmental and epileptic encephalopathy (DEE) and to explore the clinical response to dopaminergic and serotoninergic therapies in a group of patients.MethodTwo hundred and five patients (111 males [54.1.%] and 94 females [45.9%], mean age 10 months at the onset of epilepsy [SD 1 year 1 month], range 0–3 year) with epileptic encephalopathy/DEE were recruited, including those with West syndrome, Ohtahara syndrome, early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, myoclonic encephalopathy in non‐progressive disorders, infantile spasms, Doose syndrome, Lennox–Gastaut syndrome, Landau–Kleffner syndrome, and those unclassified. Cerebrospinal fluid (CSF) neurotransmitter studies and patients' medical records were reviewed. Additionally, we present clinical data of 10 patients with low CSF neurotransmitter levels who received dopaminergic/serotoninergic treatments.ResultsAbnormal neurotransmitter values were identified in 68 (33%) patients. 5‐Hydroxyindoleacetic acid (5‐HIAA) deficit was the most prevalent alteration (91%). Low CSF 5‐HIAA levels were significantly higher in 1‐ to 3‐year‐old children. A negative significant correlation was found between 5‐HIAA levels and epilepsy duration before CSF study (Spearman's ρ=−0.191, p=0.007). Abnormalities in deep grey matter were associated with low levels of CSF homovanillic acid and 5‐HIAA. Ten patients with low CSF neurotransmitter levels received dopamine and/or serotonin therapies. Six of them showed initial decrease of seizure frequency and severity and maintained improvement in some neurodevelopmental skills.InterpretationA considerable number of patients showed neurotransmitter abnormalities. Age at seizure onset and duration of epilepsy before CSF study were the principal factors related to neurotransmitter depletion. Early monoamine supplementation would seem advisable as a neuroprotective strategy.What this paper adds 5‐Hydroxyindoleacetic acid homeostasis is especially vulnerable in patients with epileptic encephalopathy/developmental and epileptic encephalopathy. Age of seizure onset and duration of epilepsy are determinants of neurotransmitter depletion.

Long-term use of cannabidiol-enriched medical cannabis in a prospective cohort of children with drug-resistant developmental and epileptic encephalopathy

ObjectiveWe report our findings regarding effectiveness, safety, and tolerability of cannabidiol (CBD)-enriched medical cannabis as add-on therapy in children with drug-resistant epileptic encephalopathies (DEEs) after a median follow-up of 20 months. MethodsA prospective cohort study was conducted to assess effectiveness, safety, and tolerability of CBD-enriched medical cannabis oil added to standard antiseizure medications in children with drug-resistant DEE seen at a single center. ResultsBetween October 2018 and March 2020, 59 patients were enrolled. Mean age at enrollment was 10.5 years (range, 2–17 years). Median treatment duration was 20 months (range, 12–32). Median age at first seizure was 8 months (range, 1 day – 10 years). At the end of follow-up, 78% of the children had a ≥ 50% decrease in seizure frequency and 47.5% had a > 75% decrease. Seven patients (11.9%) were seizure free. The number of seizures was reduced from a median of 305/month to 90/month, amounting to a mean reduction of 57% and a median reduction of 71% (p < 0.0001). Adverse effects were mostly mild or moderate. CBD was discontinued in 17 patients (28.8%) due to lack of response to treatment, increased seizure frequency, intolerance to the drug, or poor compliance. ConclusionIn children with drug-resistant DEEs, long-term treatment of CBD-enriched medical cannabis as an adjuvant therapy to antiseizure therapy was found to be safe, well tolerated, and effective. Sustained reductions in seizure frequency and improvement of aspects of daily living were observed compared to our preliminary findings.

Long-term therapeutic effect of eslicarbazepine acetate in children: An open-label extension of a cognition study in children aged 6–16 years

ObjectiveIn Europe, eslicarbazepine acetate (ESL) is approved as adjunctive therapy for the treatment of focal seizures (FS) in children aged >6 years. In the US, ESL is approved as both monotherapy and adjunctive therapy for the treatment of FS in patients aged ≥4 years. In a phase II study of children aged 6–16 years with FS, ESL had no significant effects on attention or behavioral functioning and decreased seizure frequency during double-blind therapy and a 1-year open-label extension (OLE). This report presents data from an additional 2-year OLE of the phase II study. MethodsPrevious recipients of ESL or placebo were treated with open-label ESL (10–30 mg/kg/day, adjusted for clinical response and/or adverse events [AEs]). Safety was assessed by incidence of treatment-emergent AEs (TEAEs). Efficacy endpoints were treatment retention time and change from baseline in Clinical Global Impression-Severity (CGI-S) scale scores. ResultsForty-two patients entered and 31 (73.8%) completed the 2-year OLE. Median treatment retention time was 735 (95% confidence interval 728–741) days. Seven patients (17% of total, 23% of completed) experienced ≥1 TEAE during the 2-year OLE, mostly of mild or moderate intensity. The incidence of serious TEAEs was low (n = 2; 5% of total, 6% of completed) and none were related to ESL. One child was withdrawn because of splenomegaly that was considered possibly related to ESL. The only change from baseline in CGI-S was a 0.5-point reduction in the severity of illness score. All findings were consistent across patient subgroups based on previous double-blind treatment (placebo or ESL) and patient age (6–11 or 12–16 years). ConclusionsThe majority of patients remained on ESL during the 2-year OLE, and treatment efficacy was maintained. Adverse events were consistent with the known safety profile of ESL, and no new safety signals were identified.

Evaluation of the efficacy and tolerability of levetiracetam as add-on therapy in intractable epilepsy of children.

Objective One-third of epilepsy of children is refractory, and this study was conducted to evaluate the efficacy and adverse events of levetiracetam as add-on therapy in the treatment of refractory epilepsy of children. Materials & Methods In this quasi-experimental study, seizures frequency and side effects of 314 children aged 1-14 years with refractory epilepsy were referred to the Pediatric Neurology Clinic of Shahid Sadoughi Medical Sciences University, Yazd, Iran, and treated with levetiracetam for six months, were evaluated. Results: We evaluated 142 girls and 172 boys with a mean age of 6.78±2.12 years. At the end of six months of treatment with levetiracetam, 20% became seizure-free, 28% had more than 50% decrease in seizure frequency, 38% did not have a notable change in seizure frequency, and 14% experienced an increase in seizure frequency. Good response (stopping of all seizures or more than 50% reduction in seizure frequency) was seen in 51% of mixed types, 61% of myoclonic seizures, 64% of generalized tonic-clonic seizures, 69 % of partial seizures, 100 % of tonic seizures, and in 40 % of atonic seizures. Levetiracetam was significantly more effective in partial seizures, idiopathic epilepsies, and children with normal developmental status and normal brain MRI. Twelve children discontinued the treatment due to severe drowsiness, restlessness, and exacerbation of seizures. Transient and mild side effects, including somnolence, anorexia, fatigue, headache, ataxia, and diplopia, were seen in 9% (N=28) of patients.Conclusion:Levetiracetam could be considered an efficient and safe adjunct therapy in treating refractory epilepsy in children.

Epilepsy surgery in patient with monogenic epilepsy related to SCN8A mutation.

Epilepsy surgery is superior to prolonged medical therapy in patients with drug-resistant focal epilepsy, but reports on epilepsy surgery outcomes for patients with a genetic etiology are limited, especially in adults. This is the first documented report of a stereoelectroencephalography (SEEG) evaluation and resective surgery outcome in an adult patient with epilepsy related to SCN8A mutation. We describe a patient with epilepsy related to SCN8A mutation which was reported as a variant of uncertain significance at time of his pre-surgical evaluation and reclassified as likely pathogenic about 3years after resective epilepsy surgery. Most of his pre-surgical evaluation results suggested right temporal lobe epilepsy, but few reported semiological symptoms, ictal SPECT, and neuropsychology results were discordant, and brain MRI was non-lesional. Therefore, SEEG was recommended; ultimately, seizures were localized to the right hippocampus. He was seizure-free for 1.5years after right anterior temporal lobectomy, then reported three focal to bilateral tonic-clonic (FBTC) seizures in the subsequent 12months (preoperatively, 6 focal impaired awareness seizures and 4-6 FBTC per year). This case demonstrates that epilepsy surgery reduced seizure burden in a patient with SCN8A-related epilepsy granting him short-term seizure freedom after resection, and then decreased seizure frequency after relapse compared to the preoperative baseline.

Effects of perampanel on cognitive behavior and GluR1 expression in immature mice of temporal lobe epilepsy

Temporal lobe epilepsy (TLE) has a low antiepileptic drug (AED) treatment response rate, and about 70% of patients eventually progress to refractory epilepsy. Perampanel (PER) is a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist, which is used clinically for the treatment of partially refractory epilepsy, but its mechanism of action is not completely clear. In this study, kainic acid (KA) was successfully used to induce TLE in 3-week-old C57BL/6 immature mice, and the effects of PER on the cognitive behavior of the epileptic mice were characterized using the Morris water maze paradigm. To determine the mechanism underlying the therapeutic effects of PER, the morphological evolution of the hippocampus and the expression of AP-1 and GluR1 were systematically evaluated. Compared to control TLE mice, escape latency was reduced and the number of target platform crossings was increased in the Morris water maze by treatment with PER. The therapeutic effects of PER were mediated mainly via inhibition of the expression of AP-1 and GluR1, as the TLE mice showed significantly improved learning and memory and decreased seizure frequency after treatment with PER.

Magnetic resonance-guided laser interstitial thermal therapy for pediatric periventricular nodular heterotopia-related epilepsy.

Periventricular nodular heterotopia (PVNH) is a result of disrupted neuronal migration from the ventricular system and can be a rare cause of refractory focal epilepsy. The goal of this case series was to describe the treatment of pediatric PVNH-related epilepsy with MR-guided laser interstitial thermal ablation. Patients treated at a single institution with MR-guided laser interstitial thermal therapy (MRgLITT) for PVNH-related epilepsy were identified. Preoperative and postoperative seizure outcomes and procedural information were evaluated. Five children with PVNH treated with MRgLITT were reviewed; 1 child was treated twice. Three patients were female; the median age was 10.9 years. Five of 6 treatments were preceded by stereoelectroencephalography phase II monitoring. Three children experienced unilateral PVNH, and 2 had bilateral seizures. The median number of seizures recorded during phase II monitoring was 2; the median number of ablation targets was 2 (range 1-4). All patients experienced a decrease in seizure frequency; 4 patients (80%) had an Engel class ≤ III at the last follow-up (range I-IV). One child experienced right hemianopia posttreatment. This case series investigation has illustrated a novel, minimally invasive approach for treating pediatric PVNH-related epilepsy. Further study of this technique with comparison with other surgical techniques is warranted.

Pilot study of focused ultrasound for drug-resistant epilepsy.

ObjectiveThe neuromodulatory effects of focused ultrasound (FUS) have been demonstrated in animal epilepsy models; however, the safety and efficacy of FUS in humans with epilepsy have not been well established. Patients with drug‐resistant epilepsy (DRE) undergoing stereo‐electroencephalography (SEEG) provide an opportunity to investigate the neuromodulatory effects of FUS in humans.MethodsPatients with DRE undergoing SEEG for localization of the seizure onset zone (SOZ) were prospectively enrolled. FUS was delivered to the SOZ using a neuronavigation‐guided FUS system (ceiling spatial‐peak temporal‐average intensity level = 2.8 W/cm2, duty cycle = 30%, modulating duration = 10 min). Simultaneous SEEG recordings were obtained during sonication and for 3 days after treatment. Seizures, interictal epileptiform discharges, and adverse events after FUS were monitored.ResultsSix patients met the eligibility criteria and completed FUS treatment. A decrease in seizure frequency was observed in two patients within the 3‐day follow‐up; however, one patient presented an increase in the frequency of subclinical seizures. Posttreatment magnetic resonance imaging revealed neither lesion nor brain edema. Significant changes in spectral power of SEEG were noted at the targeted electrodes during FUS treatment. One patient reported subjective scalp heating during FUS, and one patient developed transient naming and memory impairment that resolved within 3 weeks after FUS.SignificanceFUS can be safely delivered to the SOZ of patients with DRE, resulting in significant changes in spectral power of SEEG. A larger sample cohort and pursuing optimal sonication parameters will be required to elucidate the neuromodulatory effects of FUS when used for seizure control.

Long-term effectiveness and adverse effects of ketogenic diet therapy in infants with drug-resistant epilepsy treated at a single center in Argentina

IntroductionKetogenic diet therapy (KDT) is a metabolic treatment with proven effectiveness for the treatment of drug-resistant epilepsy in children. Although previously not used in infants under 2 years of age, recent studies have shown KDT to be highly effective and well tolerated in infants with epilepsy, especially those with epileptic encephalopathies. Here, we describe the effectiveness and tolerability of the diet in infants up to 2 years of age. Material and methodsA prospective study was conducted in a cohort of infants younger than 2 years of age with drug-resistant epilepsy who received the classic ketogenic diet using a specific protocol at a single center in Argentina. Results56 infants with treatment-refractory epilepsy were evaluated. The etiology was genetic in 21.4%, structural in 28.6%, unknown in 44.7%, and metabolic in 5.4%. At 3 months, a > 50% decrease in seizure frequency was observed in 35 patients (62.4%), of whom 11 (19.6%) became seizure free. At 6 months, 34 patients (60.7%) had a decrease in seizure frequency of > 50%, of whom 10 (17.8%) were seizure free. At the one-year follow-up, 27 patients (48.2%) had a > 50% decrease in seizure frequency, of whom six (10.7%) were seizure free. At two years, 14 patients (25%) had a > 50% seizure control, of whom four (7.1%) were seizure free. The most common early adverse effects were hypoglycemia and vomiting, while after 1 month and beyond metabolic acidosis, vomiting, and constipation more commonly found. A trend towards a higher rate of acute adverse events in infants younger than 1 year was observed. ConclusionsCKD showed to be a useful option in infants with treatment-resistant epilepsy. Adverse effects were common, but not a reason to discontinue the diet. Further studies are necessary to evaluate in which epilepsy syndromes and etiologies KDT is most effective.

Cannabidiol-enriched medical cannabis as add-on therapy in children with treatment-resistant West syndrome: A study of eight patients

ObjectiveHere we present a series of patients with WS that were refractory to antiseizure medications and the ketogenic diet and who were treated with cannabidiol-enriched cannabis oil (CBD) as add-on therapy analyzing efficacy, safety, and tolerability. Material and methodsMedical records of eight patients with WS treated with CBD at a ratio of cannabidiol:Δ-9-tetrahydrocannabinol (CBD:THC) of 25:1 seen between May 2020 and March 2021 were retrospectively analyzed. In all patients CBD was started as add-on therapy. ResultsEight patients (six female and two male) who received CBD for treatment-resistant WS were evaluated. Ages ranged from 16 to 22 months. The etiology was unknown in five and structural in three. Initial CBD dose was 2 mg/kg/day which was uptitrated to a median dose of 12 mg/kg/day (range, 2–25). Prior to CBD initiation, patients had a mean of 63 seizures per day (range, 31–79). After a follow-up of between 6 and 13 months, a 75–99% decrease in seizure frequency was observed in two patients, a 50–74% decrease in two, a less than 50% decrease in three, and no changes in seizure frequency were seen in the remaining patient. The index of EEG abnormalities improved between 20 and 80% in seven patients concurrently with the reduction in seizures. Adverse effects were mild and transient. Somnolence was observed in one patient, nausea and vomiting in one, and behavior disturbances and irritability in another patient. ConclusionThis study evaluating the use of cannabidiol-enriched cannabis oil in children with WS showed that four (50%) of eight had a more than 50% seizure reduction with good tolerability.

Anterior Nucleus of the Thalamus Deep Brain Stimulation with Concomitant Vagus Nerve Stimulation for Drug-Resistant Epilepsy.

The Food and Drug Administration approved the deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS) as an adjunctive therapy for drug-resistant epilepsy (DRE) in the United States in 2018. The DBS Therapy for Epilepsy Post-Approval Study is further evaluating the safety and effectiveness of ANT-DBS among different patients' groups. For this study, devices for vagus nerve stimulation (VNS) must be removed prior to enrolment. To investigate the outcomes of concomitant ANT-DBS and VNS treatment for DRE. A retrospective analysis was performed for 33 patients who underwent ANT-DBS using previous VNS to define distinct subgroups: standard ANT-DBS (9 subjects), ANT-DBS with functional VNS (12 subjects), and ANT-DBS with the VNS implantable pulse generator explanted or turned off at the time of the DBS (12 subjects). Effectiveness and safety data were analyzed across the whole population and among subgroups. A mean decrease in seizure frequency of 55% was observed after a mean follow-up of 25.5 mo. Approximately 67% of patients experienced ≥50% reduction in seizure frequency. Seizure reduction percentage was not significantly different among groups. Approximately 50% of subjects with no appreciable improvement and 75% of those who showed benefit after VNS (including improvement in seizure frequency, seizure severity, and seizure duration or quality of life) achieved a seizure reduction ≥50% after ANT-DBS surgery. There were no complications related to concomitant VNS and ANT-DBS. ANT-DBS for DRE provides excellent results despite previous and ongoing VNS therapy. Removal of VNS does not appear to be necessary before ANT-DBS.

Therapeutic Effects of Time-Limited Treatment with Brivaracetam on Posttraumatic Epilepsy after Fluid Percussion Injury in the Rat.

Mounting evidence suggests the synaptic vesicle glycoprotein 2A (SV2A) targeted by levetiracetam may contribute to epileptogenesis. Levetiracetam has shown anti-inflammatory, antioxidant, neuroprotective, and possible antiepileptogenic effects in brain injury and seizure/epilepsy models, and a phase 2 study has signaled a possible clinical antiepileptogenic effect. Brivaracetam shows greater affinity and specificity for SV2A than levetiracetam and broader preclinical antiseizure effects. Thus, we assessed the antiepileptogenic/disease-modifying potential of brivaracetam in an etiologically realistic rat posttraumatic epilepsy model optimized for efficient drug testing. Brivaracetam delivery protocols were designed to maintain clinical moderate-to-high plasma levels in young (5-week-old) male Sprague-Dawley rats for 4 weeks. Treatment protocols were rapidly screened in 4-week experiments using small groups of animals to ensure against rigorous testing of futile treatment protocols. The antiepileptogenic effects of brivaracetam treatment initiated 30 minutes, 4 hours, and 8 hours after rostral parasagittal fluid percussion injury (rpFPI) were then compared with vehicle-treated controls in a fully powered blind and randomized 16-week validation. Seizures were evaluated by video-electrocorticography using a 5-electrode epidural montage. Endpoint measures included incidence, frequency, duration, and spread of seizures. Group sizes and recording durations were supported by published power analyses. Three months after treatment ended, rats treated with brivaracetam starting at 4 hours post-FPI (the best-performing protocol) experienced a 38% decrease in overall incidence of seizures, 59% decrease in seizure frequency, 67% decrease in time spent seizing, and a 45% decrease in the proportion of spreading seizures that was independent of duration-based seizure definition. Thus, brivaracetam shows both antiepileptogenic and disease-modifying properties after rpFPI. SIGNIFICANCE STATEMENT: The rpFPI model, which likely incorporates epileptogenic mechanisms operating after human head injury, can be used to efficiently screen investigational treatment protocols and assess antiepileptogenic/disease-modifying effects. Our studies 1) support a role for SV2A in epileptogenesis, 2) suggest that brivaracetam and other drugs targeting SV2A should be considered for human clinical trials of prevention of post-traumatic epilepsy after head injury, and 3) provide data to inform the design of treatment protocols for clinical trials.