Functional network dynamics between the anterior thalamus and the cortex in deep brain stimulation for epilepsy.

Owing to its unique connectivity profile with cortical brain regions, and its suggested role in the subcortical propagation of seizures, the anterior nucleus of the thalamus (ANT) has been proposed as a key deep brain stimulation (DBS) target in drug-resistant epilepsy. However, the spatio-temporal interaction dynamics of this brain structure, and the functional mechanisms underlying ANT DBS in epilepsy remain unknown. Here, we study how the ANT interacts with the neocortex in vivo in humans and provide a detailed neurofunctional characterization of mechanisms underlying the effectiveness of ANT DBS, aiming at defining intraoperative neural biomarkers of responsiveness to therapy, assessed at 6 months post-implantation as the reduction in seizure frequency. A cohort of 15 patients with drug-resistant epilepsy (n = 6 males, age = 41.6 ± 13.79 years) underwent bilateral ANT DBS implantation. Using intraoperative cortical and ANT simultaneous electrophysiological recordings, we found that the ANT is characterized by high amplitude θ (4-8 Hz) oscillations, mostly in its superior part. The strongest functional connectivity between the ANT and the scalp EEG was also found in the θ band in ipsilateral centro-frontal regions. Upon intraoperative stimulation in the ANT, we found a decrease in higher EEG frequencies (20-70 Hz) and a generalized increase in scalp-to-scalp connectivity. Crucially, we observed that responders to ANT DBS treatment were characterized by higher EEG θ oscillations, higher θ power in the ANT, and stronger ANT-to-scalp θ connectivity, highlighting the crucial role of θ oscillations in the dynamical network characterization of these structures. Our study provides a comprehensive characterization of the interaction dynamic between the ANT and the cortex, delivering crucial information to optimize and predict clinical DBS response in patients with drug-resistant epilepsy.

Neurological function and drug-refractory epilepsy in Sturge-Weber syndrome children: a retrospective analysis.

Epilepsy in Sturge-Weber syndrome (SWS) is common, but drug-refractory epilepsy (DRE) in SWS has rarely been studied in children. We investigated the characteristics of epilepsy and risk factors for DRE in children with SWS. A retrospective study was conducted to analyze the clinical characteristics of children with SWS with epilepsy in our hospital from January 2013 to October 2022. Univariate and multivariate logistic analyses were performed to investigate the factors influencing DRE in children with SWS. A total of 35 SWS children with epilepsy were included (51% male; mean age of presentation 3.6 ± 0.5 years), 71% of children with SWS had their first seizure within the first year of life, and the most common type of seizure was focal seizure (77%). Eleven (31%) patients developed DRE. The median age of onset for the first seizure was 1.0 years and all these cases were of SWS type I. Multivariate logistic analysis revealed that stroke-like episodes and seizure clusters were risk factors for DRE in SWS children. A poor neurological function group was observed in twenty-five children with SWS. Status epilepticus was a risk factor that affected the neurological function of SWS children with epilepsy.  Conclusion: The study explored the epileptic features of children with SWS. The results revealed that stroke-like episodes and seizure clusters are risk factors for DRE in children with SWS. The occurrence of status epilepticus impacts the neurological function of SWS children with epilepsy. Thus, long-term follow-up is necessary to monitor outcomes. What is Known: • Sturge-Weber syndrome (SWS) is a rare neurocutaneous disorder, over 75% of children with SWS experience seizures, and 30-57% develop drug-refractory epilepsy (DRE), which leads to a poor outcome. • Drug-refractory epilepsy in SWS has been rarely studied in children, and the risk factors associated with DRE are unclear. What is New: • Clinical features of SWS children with drug-refractory epilepsy. • In SWS, stroke-like episodes and seizure clusters are risk factors of DRE, the occurrence of status epilepticus impacts the neurological function.

SEW2871 reduces seizures via the sphingosine 1-phosphate receptor-1 pathway in the pentylenetetrazol and phenobarbitone kindling model of drug-refractory epilepsy.

Epilepsy is a prevalent neurological disorder characterized by neuronal hypersynchronous discharge in the brain, leading to central nervous system (CNS) dysfunction. Despite the availability of anti-epileptic drugs (AEDs), resistance to AEDs is the greatest challenge in treating epilepsy. The role of sphingosine-1-phosphate-receptor 1 (S1PR1) in drug-resistant epilepsy is unexplored. This study investigated the effects of SEW2871, a potent S1PR1 agonist, on a phenobarbitone (PHB)-resistant pentylenetetrazol (PTZ)-kindled Wistar rat model. We measured the messenger ribonucleic acid (mRNA) expression of multi-drug resistance 1 (MDR1) and multi-drug resistance protein 5 (MRP5) as indicators for drug resistance. Rats received PHB + PTZ for 62 days to develop a drug-resistant epilepsy model. From day 48, SEW2871 (0.25, 0.5, 0.75 mg/kg, intraperitoneally [i.p.]) was administered for 14 days. Seizure scoring, behaviour, oxidative markers like reduced glutathione, catalase, superoxide dismutase, inflammatory markers like interleukin 1 beta tumour necrosis factor alpha, interferon gamma and mRNA expression (MDR1 and MRP5) were assessed, and histopathological assessments were conducted. SEW2871 demonstrated dose-dependent improvements in seizure scoring and neurobehavioral parameters with a reduction in oxidative and inflammation-induced neuronal damage. The S1PR1 agonist also downregulated MDR1 and MRP5 gene expression and significantly decreased the number of dark-stained pyknotic nuclei and increased cell density with neuronal rearrangement in the rat brain hippocampus. These findings suggest that SEW2871 might ameliorate epileptic symptoms by modulating drug resistance through downregulation of MDR1 and MRP5 gene expression.

Management of autoimmune temporal lobe epilepsy with GAD65 antibody: four case reports.

AIM OF STUDY: Glutamate decarboxylase (GAD) enzyme can be a target intracellular antigen in autoimmune focal epilepsy. GAD65 antibody is in found patients diagnosed with drug-refractory temporal lobe epilepsy (TLE). We explore the clinical features of the disease and therapeutic options. MATERIAL AND METHODS: We present the cases of four TLE patients, two of them with type 1 diabetes. All of them were drug-resistant and therefore underwent presurgical evaluation, which revealed GAD65 antibody positivity. We discuss the four GAD65 antibody positive temporal lobe epilepsy patients' electroclinical data, the treatments, and their effectiveness. RESULTS: One of them became seizure-free after right anterior temporal lobe resection, two of them did not show significant improvement with immunmodulatory agents, and the fourth patient with the shortest duration of disease had significant improvement in seizure status and normalisation of cognitive status with IVIg therapy. CONCLUSIONS AND CLINICAL IMPLICATIONS: Our cases show that the earlier a GAD65 antibody is detected, the greater the chance of achieving seizure freedom or improvements in both seizure and cognitive status with immunomodulatory agents. However, in some cases, surgery may also bring seizure freedom, but with a risk of cognitive deterioration.

Strategic targeting of the temporal lobe with orthogonal placement of responsive neurostimulation leads.

Responsive neurostimulation (RNS) is an effective treatment modality for refractory temporal lobe epilepsy (TLE). However, the optimal placement of RNS leads is not known. We use an orthogonal approach to lead placement instead of the more common longitudinal approach to target the entorhinal cortex (EC), given its potential for modulating activity entering and leaving the hippocampus. An orthogonal approach allows for coverage of the EC as well as the anterior lateral temporal cortex, which may be particularly beneficial for patients with mesial-lateral TLE and may also enable greater modulation of the limbic network. The objective of this study was to determine treatment outcomes for orthogonally placed RNS depth leads targeting the EC. We performed a retrospective analysis of prospectively collected data on a cohort of 13 patients. Mean follow-up duration was 57.3 months, and the 50% responder rate was 76.9%. These results show that orthogonally placed RNS leads are safe and effective for the treatment of refractory TLE. Larger cohorts are needed to further delineate the clinical utility of this novel targeting strategy.

Outcomes following cardiac sympathetic denervation in patients with structural heart disease and refractory ventricular arrhythmia.

AIM: Cardiac sympathetic denervation (CSD) has been introduced as a bailout therapy in patients with structural heart disease and refractory ventricular arrhythmias (VAs), but available data are scarce. Purpose of this study was to estimate immediate results, complications, and mid-term outcomes of CSD following recurrent VA after catheter ablation. METHODS AND RESULTS: Adult patients who underwent CSD in the Heart Center Leipzig from March 2017 to February 2021 were retrospectively analysed. Follow-up (FU) was executed via implantable cardioverter defibrillator (ICD) interrogation, telephone interviews, and reviewing medical records. Twenty-one patients (age 63.7 ± 14.4 years, all men, 71.4% non-ischaemic cardiomyopathy, left ventricular ejection fraction 31.6 ± 12.6%) received CSD via video-assisted thoracoscopic surgery (90.5% bilateral, 9.5% left-sided only). Indication for CSD was monomorphic ventricular tachycardia in 76.2% and ventricular fibrillation in 23.8 with 71.4% of patients presenting with electrical storm before index hospitalization. Procedure-related major complications occurred in 9.5% of patients. In-hospital adverse events not related to surgery were common (28.6%) and two patients died during the index hospital stay. During FU (mean duration 9.1 ± 6.5 months), five more patients died. Of the remaining patients, 38.5 and 76.9% were free from any VA or ICD shocks, respectively. CONCLUSIONS: The CSD showed additional moderate efficacy to suppress VAs, when performed as a bailout therapy after previously unsuccessful catheter ablation. At 9 months, it was associated with freedom of ICD shocks in two-thirds of patients. In a population with many comorbidities, the rate of CSD-related complications was acceptable, although there was an overall high risk of procedure unrelated adverse events and death.

Perampanel add-on therapy for drug-refractory epilepsy: A single-center retrospective study based on 6-month treatment outcomes in Central China.

OBJECTIVE: To systematically evaluate the efficacy, tolerability and retention of perampanel (PER) for treating drug-refractory epilepsy (DRE), and to investigate the independent factors affecting efficacy and retention. We hope this will provide clinicians with guidelines for the use of PER to treat patients with DRE. METHODS: We conducted a single-center retrospective observational study of patients with DRE who received PER as add-on therapy at the Epilepsy Center of the People's Hospital of Henan Province, China, between 2020 Mar. and 2021 Sep. We collected clinical data from these patients. The observation period was 6 months. The observation endpoint is the drug response and retention rate at 6 months of PER use. Regression analyses were used to compare the differences in efficacy and retention rates, respectively. RESULTS: Clinical data were obtained for 72 patients with DRE (mean duration of treatment: 10.6 months). At 6 months, 25% of patients (n = 18) were seizure free; 18.1% of patients (n = 13) remained seizure free for 6 months after the addition of PER. 22.2% of patients (n = 16) had a response (One of the patients was withdrawn 5 months after adding PER due to financial difficulties). The retention rate of PER at 6 months was 77.8%. Adverse effects tended to be dominated by neuropsychiatric symptoms. Multifactorial logistic regression analysis showed significant differences in whether the baseline seizure frequency exceeded 4 seizures/month (OR = 0.232, 95%CI: 0.077-0.702, p = 0.01) and whether the number of previously failed ASMs exceeded 3 (OR = 0.316; 95%CI:0.109-0.920, p = 0.035). This indicates that the risk of experiencing a nonresponse is higher with a higher baseline seizure frequency as well as with a higher number of previous ASM failures. Therefore, a baseline frequency exceeding four seizures/month and more than three previous ASM failures were independent influencing factors for PER addition treatment for patients with DRE. Multifactorial COX regression showed that patients with DRE due to infection had a lower retention rate (OR = 15.957, 95% CI: 3.692-68.972, P < 0.001) than patients with DRE due to other noninfectious etiologies. Patients with DRE who only had a single seizure type (OR = 0.053, 95% CI:0.006-0.476, P = 0.009), and patients who did not have cognitive impairment (OR = 134.253, 95% CI:5.623-3205.104, P = 0.002) showed longer durations of PER use. Infection-related epilepsy etiology, experiencing multiple types of seizures, and with cognitive impairment were independent influencing factors on PER use retention in patients with DRE. CONCLUSION: Our study demonstrated the efficacy of PER for reducing seizure frequency in patients with DRE and found significant differences in efficacy and retention rate, respectively. This provides a basis for assessing the expected efficacy and duration of use of PER for patients with DRE.

Secukinumab and acitretin as a combination therapy for three clinical forms of severe psoriasis in multi-drug refractory patients: A case series of high efficacy and safety profile.

Secukinumab, the first monoclonal antibody that inhibits interleukin-17A, has been shown to have rapid and long-lasting efficacy in the treatment of moderate-to-severe psoriasis. However, there are still difficult-to-treat cases in which even dose-escalation fails to provide a clinical response. In such cases, combining secukinumab with a conventional systemic agent may be a rational approach. Although methotrexate is most commonly preferred, acitretin may also be considered a good alternative, with its lower hepatotoxic potential. Data are limited regarding the use of combination therapy of secukinumab and acitretin for psoriasis. We herein present three patients with chronic plaque, generalized pustular and erythrodermic psoriasis, respectively, accompanied by multiple comorbidities, in whom skin clearance could not be achieved with several conventional and biologic therapies (including escalated dose regimens of secukinumab in two patients). Alternatively, we used a combination of secukinumab with low-dose acitretin, which resulted in a complete or almost complete skin clearance in all patients, with no adverse events or increased toxicity. Based on our real-life clinical experience with those patients, acitretin seems an effective and safe option to be used in combination with secukinumab. Even in patients who are refractory to multiple drugs including escalated doses of secukinumab, the addition of low-dose acitretin may be helpful in achieving treatment goals, decreasing the need for switching to another biologic therapy.

Epilepsy surgery in COVID times-a unique conundrum.

The COVID-19 pandemic has forced hospitals to prioritize admissions. Epilepsy surgeries have been postponed at most centers. As the pandemic continues with no definite end in sight in the near future, the question arises until when such patients should be denied appropriate treatment. A 12-year-old child with left-sided Rasmussen's encephalitis with drug refractory epilepsy (DRE) presented at the height of the pandemic, with worsening of seizure frequency from 4-5/day to 20/day, with new-onset epilepsia partialis continua. She demonstrated features of progressive cognitive decline. The pros and cons of operating during the pandemic were discussed with the parents by a multidisciplinary team. She underwent endoscopic left hemispherotomy. Postoperatively she became seizure free but developed hospital-acquired mild COVID infection for which she was treated accordingly. Chosen cases of severe DRE, as the one illustrated above, who are deemed to benefit from surgery by a multidisciplinary team of physicians, should be re-categorized into the most severe class of patients and scheduled for surgery as soon as possible. The risk benefit ratio of the seizures being mitigated by surgery on one hand and possibility of acquiring COVID infection during hospital stay has to be balanced and a decision made accordingly.

Efficacy and safety of corpus callosotomy and ketogenic diet in children with Lennox Gastaut syndrome: a systematic review and meta-analysis.

BACKGROUND: Both corpus callosotomy (CC) and the ketogenic diet (KD) are commonly used in patients with Lennox Gastaut syndrome (LGS), as a significant proportion of these patients develop pharmacoresistant epilepsy. But no systematic review has yet compared the efficacy and safety of these two measures. METHODS: We conducted a systematic search on various databases to collating all available literature until 30th November 2020 with a primary objective to compare the efficacy of KD and CC in terms of the proportion of patients with complete seizure freedom, at least 75% and 50% reduction in seizure frequency at various time points after the institution of these modalities. We also attempted to compare the proportion and nature of adverse effects, impact on EEG, cognition, and behavior with these modalities. We only included original articles enrolling at least 10 patients with CC or KD for quantitative synthesis to determine a pooled estimate. We used a fixed or random effects model, depending on the degree of heterogeneity. RESULTS: We selected 23 and 7 articles describing the efficacy of CC and KD in 436 and 185 LGS patients out of 217 search items, but none of the studies compared directly these two entities. The indirect comparison between the pooled estimate of all patients with individual modalities revealed more patients with CC had seizure freedom, at least 75% and 50% reduction in seizure frequency (p=0.0001, 0.01, and 0.04 respectively). The proportion of patients with adverse effects was also higher for CC patients (p=0.01), although the proportion with serious adverse effects was not significantly different between the two modalities. Patients selected for CC were older, had higher seizure burden, more lag time after the onset of seizures, and received more number of antiseizure medications previously. Due to the availability of limited data, a firm conclusion could not be determined regarding the effect on EEG, cognition, and behavior with CC and KD. CONCLUSION: CC is more efficacious than KD in reducing seizure frequency in patients with LGS, although it has relatively more adverse effects during the immediate perioperative period.

A large deletion in RYR2 exon 3 is associated with nadolol and flecainide refractory catecholaminergic polymorphic ventricular tachycardia.

We report a 17-year-old boy with a large RYR2 exon 3 deletion who has a severe catecholaminergic polymorphic ventricular tachycardia (CPVT) phenotype characterized by refractoriness to both nadolol and flecainide which has previously not been reported in this subgroup of CPVT patients. Treatment options in a patient like ours are therefore limited and sympathectomy and implantable cardioverter-defibrillator implantation should be considered early in the treatment course as was done in this patient. In contrast to other CPVT patients who do not usually have structural cardiac abnormalities, these patients are at a high risk of developing left ventricular noncompaction or dilated cardiomyopathy and therefore might benefit from cardiac imaging at regular intervals.

Investigation of altered microstructure in patients with drug refractory epilepsy using diffusion tensor imaging.

PURPOSE: The risk of refractory epilepsy can be more dangerous than the adverse effect caused by medical treatment. In this study, we employed voxel-wise analysis (VWA) and tract-based spatial statistics (TBSS) methods to measure microstructural changes using diffusion tensor imaging (DTI) in patients of drug refractory epilepsy (DRE) who had been epileptic for more than 10 years. METHODS: To examine the specific microstructural abnormalities in DRE patients and its difference from medically controlled epilepsy (MCE), we acquired DTI data of 7 DRE patients, 37 MCE patients, and 31 healthy controls (HCs) using a 3 T MRI scanner. Comparisons between epileptic patients and HCs between MCE and DRE patients were performed based on calculated diffusion anisotropic indices data using VWA and TBSS. RESULTS: Compared to HCs, epileptic patients (including MCE and DRE) showed significant DTI changes in the common affected regions based on VWA, whereas TBSS found that widespread DTI changes in parts of microstructures of bilateral hemispheres were more obvious in the DRE patients than that in the MCE patients when compared with HCs. In contrast, significant reduction of fractional anisotropy values of thalamo-cortical fibers, including left superior temporal gyrus, insular cortex, pre-/post-central gyri, and thalamus, were further found in DRE patients compared with MCE. CONCLUSION: The results of multiple diffusion anisotropic indices data provide complementary information to understand the dysfunction of thalamo-cortical pathway in DRE patients, which may be contributors to disorder of language and motor functions. Our current study may shed light on the pathophysiology of DRE.

Right ventricular endomyocardial biopsy in children and adolescents with drug-refractory arrhythmia.

Purpose This study aimed to assess the results of endomyocardial biopsy from the right ventricle to establish the possible cause for drug-refractory arrhythmias in children. Materials and methods We enrolled 19 consecutive young patients with drug-refractory arrhythmia, from 2010 to 2013, who underwent endomyocardial biopsy. Inclusion criteria were as follows: age <18 years with a structurally normal heart or mild changes in a structure of the heart initially diagnosed as arrhythmia-induced cardiomyopathy. Overall, 86 biopsies were performed in 19 patients. Histopathological analysis, immunohistochemistry, and polymerase chain reaction were used for the interpretation of the endomyocardial biopsy. RESULTS: The mean age of the patient population was 14.1±2.9 year (range from 7 to 17 years). All these patients had a history of drug-refractory arrhythmia for >5 months (mean 30 months). Patients underwent a complete history investigation, physical examination, laboratory studies, echocardiography, electrocardiography, treadmill test, and Holter monitoring before endomyocardial biopsy; two patients with arrhythmogenic right ventricular dysplasia had implantable cardioverter defibrillator implantation and further appropriate successful device shocks. Myocarditis was diagnosed based on histopathological and immunohistological analyses in nine (47.4%) patients. Polymerase chain reaction was positive for viral genome in four of them; five patients had active myocarditis. Radiofrequency ablation was performed in 17 patients; five out of six (83%) endomyocardial biopsy-proved myocarditis patients had successful radiofrequency ablation. No significant complication was reported during ablation and endomyocardial biopsy. CONCLUSIONS: Approximately half of the children with drug-refractory arrhythmia had unsuspected myocarditis according to the results of the endomyocardial biopsy.

RNA-seq analysis of hippocampal tissues reveals novel candidate genes for drug refractory epilepsy in patients with MTLE-HS.

Array-based profiling studies have shown implication of aberrant gene expression patterns in epileptogenesis. We have performed transcriptome analysis of hippocampal tissues resected from patients with MTLE-HS using RNAseq approach. Healthy tissues from tumour margins obtained during tumour surgeries were used as non-epileptic controls. RNA sequencing was performed using standard protocols on Illumina HiSeq 2500 platform. Differential gene expression analysis of the RNAseq data revealed 56 significantly regulated genes in MTLE patients. Gene cluster analysis identified 3 important hubs of genes mostly linked to, neuroinflammation and innate immunity, synaptic transmission and neuronal network modulation which are supportive of intrinsic severity hypothesis of pharmacoresistance. This study identified various genes like FN1 which is central in our analysis, NEUROD6, RELN, TGFßR2, NLRP1, SCRT1, CSNK2B, SCN1B, CABP1, KIF5A and antisense RNAs like AQP4-AS1 and KIRREL3-AS2 providing important insight into the understanding of the pathophysiology or genomic basis of drug refractory epilepsy due to MTS.

Perampanel as add-on treatment in refractory focal epilepsy. The Dianalund experience.

BACKGROUND: Perampanel (PER) is an antagonist of AMPA receptors that has been approved for adjunctive treatment of partial-onset seizures. AIMS: To evaluate effectiveness and safety of PER as add-on treatment in patients with severely refractory focal epilepsy. METHODS: PER was introduced as add-on treatment in 22 consecutive patients with drug-resistant focal epilepsy. PER was started with 2 mg/day at bedtime and was up-titrated by 2 mg/day every 2-4 weeks. RESULTS: All patients suffered from severely refractory focal epilepsy (86% took 2 or more AEDs prior PER initiation; 40% had been submitted to surgery or were surgery candidates; 7 had VNS). After 12 months since PER initiation, the retention rate was 54.5% and the responder rate was 27.2%, including 9.1% seizure-free patients. Mean PER dose in the responders was 8 mg/day (range 4-10). Most common side effects were tiredness, behavioral changes (primarily aggressivity), dizziness and were reported in 59.1% of patients, leading to PER discontinuation in 31.8% of subjects. CONCLUSIONS: PER as add-on treatment can achieve clinically meaningful improvement in patients suffering from severely refractory focal epilepses. Further studies are warranted to explore the tolerability profile, with particular focus on psychiatric adverse events.

[Invasive stimulation procedures and EEG diagnostics in epilepsy]. / Invasive Stimulationsverfahren und EEG-Diagnostik bei Epilepsien.

Stimulation has been performed experimentally and in small case series to treat epilepsy since the 1970s. Since the introduction of vagus nerve stimulation in 1997 and intracranial stimulation methods in 2011 into patient care, invasive stimulation has become a rapidly developing but infrequently used therapeutic option in Europe. Whereas vagus nerve stimulation is frequently used, particularly in the USA, intracranial stimulation differs in its regional availability. In order to improve the efficacy of stimulation, develop criteria for its use and assure low complication rates, a concentration on experienced centers and multicenter data acquisition and sharing are needed.Invasive electroencephalographic (EEG) monitoring with subdural electrodes and especially with stereotactically implanted depth electrodes have been used increasingly more often for presurgical evaluation in recent years. They are applied when non-invasive diagnostics show insufficient results to exactly identify the location and extent of the epileptogenic zone or cannot be adequately distinguished from eloquent cortex areas. Complications include intracranial hemorrhage, infections and increased intracranial pressure but lasting deficits or even death are rare (≤2 %). The outcome of invasive monitoring is inferior to non-invasive monitoring because of the higher degree of complexity of the cases; however, it is far superior to the seizure-free rates achieved by anticonvulsant drug treatment alone.

Neurocysticercosis: An uncommon cause of drug-refractory epilepsy in North Indian population.

OBJECTIVE: Being a common cause of epilepsy in endemic areas, neurocysticercosis (NCC) is expected to account for a sizable proportion of patients with drug-refractory epilepsy (DRE) as well. However, data regarding prevalence of DRE in NCC are sparse. This study aimed to determine the prevalence of DRE as well as identification of clinical and radiologic factors that lead to DRE in patients with NCC. METHODS: This study was conducted in a tertiary-care postgraduate teaching institute in Northern India from July 2011 to July 2013. Two hundred patients with epilepsy due to NCC (definite [n = 59, 29.5%] or probable [n = 141, 70.5%]) based on diagnostic criteria by Del Brutto et al. were enrolled in the study in both a prospective (n = 51 [25.5%]) and a retrospective manner (n = 149 [74.5%]), and were followed for a minimum period of 1 year. RESULTS: Thirteen patients with NCC were found to be refractory to drug therapy. Prevalence of DRE was found to be 65 of 1,000 NCC patients with epilepsy in the present study. The risk factors associated with high risk of DRE were male sex (p = 0.035), older age (p = 0.016), pig-raising practices (p = 0.003), pork eating (p = 0.04), and presence of multiple (>2) (p = 0.0001) or mixed stage lesions (p = 0.007) on neuroimaging. On multivariate analysis, it was found that residing in an area where pig raising is prevalent (p = 0.01) and presence of multiple (>2) (p = 0.004) lesions on neuroimaging are associated with increased risk of DRE. SIGNIFICANCE: NCC is only rarely associated with the development of DRE. The common risk factors associated with increased chance of DRE include pig-rearing practices and presence of multiple (>2) lesions on neuroimaging.

Mozart's music in children with drug-refractory epileptic encephalopathies.

Mozart's sonata for two pianos in D major, K448, has been shown to decrease interictal EEG discharges and recurrence of clinical seizures in both adults and young patients. In this prospective, open-label study, we evaluated the effect of listening to a set of Mozart's compositions, according to the Tomatis method, on sleep quality and behavioral disorders, including auto-/hetero-aggression, irritability, and hyperactivity, in a group of children and adolescents with drug-resistant epilepsy. The study group was composed of 11 outpatients (7 males and 4 females), between 1.5years and 21years of age (mean age: 11.9years), all suffering from drug-resistant epileptic encephalopathy (n=11). All of them had a severe/profound intellectual disability associated with cerebral palsy. During the study period, each patient had to listen to a set of Mozart's compositions 2h per day for fifteen days for a total of 30h, which could be distributed over the day depending on the habits and compliance of each patient. The music was filtered by a device preferably delivering higher sound frequencies (>3000Hz) according to the Tomatis principles. The antiepileptic drug therapy remained unchanged throughout the study period. During the 15-day music therapy, 2 out of 11 patients had a reduction of 50-75% in seizure recurrence, and 3 out of 12 patients had a reduction of 75-89%. Overall, 5 (45.4%) out of 11 patients had a ≥50% reduction in the total number of seizures, while the percentage decrease of the total seizure number (11/11) compared with baseline was -51.5% during the 15-day music therapy and -20.7% in the two weeks after the end of treatment. All responders also had an improvement in nighttime sleep and daytime behavior.

Long-term outcome after limited cortical resections in two cases of adult-onset Rasmussen encephalitis.

Rasmussen encephalitis (RE) is a progressive inflammatory disorder characterized by brain hemiatrophy, unilateral focal deficits, and drug-refractory focal epilepsy. Epilepsia partialis continua (EPC) is a hallmark of the disease. Several immunomodulatory treatments may slow but not halt the disease progression. The treatment of choice still relies on surgical hemispheric disconnection, which is burdened by heavy neurologic morbidity. More limited cortical resections, although more tolerable, are usually considered to be, at best, only transiently effective in RE. Hemispheric disconnections may be not feasible when neurologic functions are preserved and the dominant hemisphere is affected. Adult patients with a milder RE course that preserves neurologic function for a long period are particularly at risk of developing severe deficits after surgery. In this study we present the histories of two patients with adult-onset RE who have undergone selective cortical resections to control EPC, avoiding, at the same time, the severe postsurgical deficits that may be induced by hemispheric disconnective surgery. The good result obtained on EPC has been stable over a prolonged period; however, this result was not paralleled by the stop of neurologic progression in one of the two cases. A PowerPoint slide summarizing this article is available for download in the Supporting Information section http://dx.doi.org/10.1111/epi.12596/supinfo.

Analysis of clinical characteristics and histopathological transcription in 40 patients afflicted by epilepsy stemming from focal cortical dysplasia.

OBJECTIVE: This study aims to comprehensively analyze the clinical characteristics and identify the differentially expressed genes associated with drug-resistant epilepsy (DRE) in patients with focal cortical dysplasia (FCD). METHODS: A retrospective investigation was conducted from July 2019 to June 2022, involving 40 pediatric cases of DRE linked to FCD. Subsequent follow-ups were done to assess post-surgical outcomes. Transcriptomic sequencing and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used to examine differential gene expression between the FCD and control groups. RESULTS: Among the 40 patients included in the study, focal to bilateral tonic-clonic seizures (13/40, 32.50%) and epileptic spasms (9/40, 22.50%) were the predominant seizure types. Magnetic resonance imaging (MRI) showed frequent involvement of the frontal (22/40, 55%) and temporal lobes (12/40, 30%). In cases with negative MRI results (13/13, 100%), positron emission tomography/computed tomography (PET-CT) scans revealed hypometabolic lesions. Fused MRI/PET-CT images demonstrated lesion reduction in 40.74% (11/27) of cases compared with PET-CT alone, while 59.26% (16/27) yielded results consistent with PET-CT findings. FCD type II was identified in 26 cases, and FCD type I in 13 cases. At the last follow-up, 38 patients were prescribed an average of 1.27 ± 1.05 anti-seizure medications (ASMs), with two patients discontinuing treatment. After a postoperative follow-up period of 23.50 months, 75% (30/40) of patients achieved Engel class I outcome. Transcriptomic sequencing and qRT-PCR analysis identified several genes primarily associated with cilia, including CFAP47, CFAP126, JHY, RSPH4A, and SPAG1. SIGNIFICANCE: This study highlights focal to bilateral tonic-clonic seizures as the most common seizure type in patients with DRE due to FCD. Surgical intervention primarily targeted lesions in the frontal and temporal lobes. Patients with FCD-related DRE showed a promising prognosis for seizure control post-surgery. The identified genes, including CFAP47, CFAP126, JHY, RSPH4A, and SPAG1, could serve as potential biomarkers for FCD. PLAIN LANGUAGE SUMMARY: This study aimed to comprehensively evaluate the clinical data of individuals affected by focal cortical dysplasia and analyze transcriptomic data from brain tissues. We found that focal to bilateral tonic-clonic seizures were the most prevalent seizure type in patients with drug-resistant epilepsy. In cases treated surgically, the frontal and temporal lobes were the primary sites of the lesions. Moreover, patients with focal cortical dysplasia-induced drug-resistant epilepsy exhibited a favorable prognosis for seizure control after surgery. CFAP47, CFAP126, JHY, RSPH4A, and SPAG1 have emerged as potential pathogenic genes for the development of focal cortical dysplasia.