Severe Drug-resistant Epilepsy Research Articles

Role of vagus nerve stimulation in epilepsy

ABSTRACT Introduction and purpose: Epilepsy affects 1% globally, with 2.6 to 6 million cases in Europe. 30-40% of the 50 million epilepsy patients globally don't respond to drugs. For those ineligible for surgery, Vagus Nerve Stimulation (VNS) therapy offers an alternative for drug-resistant epilepsy and major depression. A brief description of the state of knowledge: Vagus Nerve Stimulation (VNS) is a modern therapy using implanted or non-invasive devices to regulate nerve activity with controlled electrical impulses. Vagus Nerve Stimulation (VNS) is effective for focal seizures, including simple partial seizures and auras. It also shows promise in reducing seizures in generalized tonic-clonic seizures and benefits patients with epileptic encephalopathies like Lennox-Gastaut syndrome. VNS effectively decreases both the frequency and duration of seizures in individuals contending with intractable epilepsy. The use of vagus nerve stimulation is generally a safe and well-tolerated form of treatment. VNS therapy improves psychomotor functions in patients with severe drug-resistant epilepsy, showing positive effects on cognitive aspects. The precise mechanism through which VNS affects the body is not fully understood, but it has demonstrated effectiveness, especially in cases of drug-resistant epilepsy. Conclusions: Extensive research backs Vagus Nerve Stimulation (VNS) as an effective palliative for intractable epilepsy, reducing seizures. Yet, identifying specific patients who would benefit most from VNS treatment lacks clear criteria. Neuromodulation remains crucial for healthcare professionals handling drug-resistant epilepsy.

Cenobamate: real-world data from a retrospective multicenter study

BackgroundClinical trials have shown that cenobamate (CNB) is an efficacious and safe anti-seizure medication (ASM) for drug-resistant focal epilepsy. Here, we analyzed one of the largest real-world cohorts, covering the entire spectrum of epilepsy syndromes, the efficacy and safety of CNB, and resulting changes in concomitant ASMs.MethodsWe conducted a retrospective observational study investigating CNB usage in two German tertiary referral centers between October 2020 and June 2023 with follow-up data up to 27 months of treatment. Our primary outcome was treatment response. Secondary outcomes comprised drug response after 12 and 18 months, seizure freedom rates, CNB dosage and retention, adverse drug reactions (ADRs), and changes in concomitant ASMs.Results116 patients received CNB for at least two weeks. At 6 months, 98 patients were eligible for evaluation. Thereof 50% (49/98) were responders with no relevant change at 12 and 18 months. Seizure freedom was achieved in 18.4% (18/98) at 6 months, 16.7% (11/66), and 3.0% (1/33) at 12 and 18 months. The number of previous ASMs did not affect the seizure response rate. Overall, CNB was well-tolerated, however, in 7.7% (9/116), ADRs led to treatment discontinuation. The most frequent changes of concomitant ASMs included the discontinuation or reduction of sodium channel inhibitors, clobazam reduction, and perampanel discontinuation, while brivaracetam doses were usually left unchanged.ConclusionsCNB proved to be a highly effective and generally well-tolerated ASM in patients with severe drug-resistant epilepsy, comprising a broad array of epilepsy syndromes beyond focal epilepsy.

P.014 Intravenous immunoglobulin use for central nervous system disorders in British Columbia: implementation of a provincial screening program

Background: Intravenous Immunoglobulin (IVIg) use for Central Nervous System (CNS) conditions has increased over the last decade. In many CNS disorders, robust evidence for IVIg efficacy is still lacking. Building on the success of the British Columbia (BC) Neuromuscular IVIg utilization initiative, Guidelines for IVIg use in CNS conditions were developed. A provincial screening program was launched in 2023. Methods: For CNS IVIg, requests, diagnosis, dosing, consultation letters and treatment questionnaires were reviewed. Patient management was compared to provincial guidelines. A letter was sent to the ordering physician with the results of the review and treatment recommendations when management differed significantly from guidelines. Review of the first year’s cases was conducted. Results: Over the first 11 months of the program, 79 IVIg renewal requests were reviewed. The most common diagnoses were antibody mediated autoimmune encephalitis, severe drug resistant non-surgical epilepsy and Susac’s syndrome. Recommendations included dose reduction, discontinuation of IVIg, or initiation of alternative therapies for many of the requests. Conclusions: IVIg may be effective in the management of some CNS inflammatory conditions. A physician-led utilization program in BC with targeted education to ordering physicians promotes best practice. Review of year one data will inform a quality improvement cycle to optimize the guidelines.

Phenotypic Variability in Novel Doublecortin Gene Variants Associated with Subcortical Band Heterotopia.

Doublecortin, encoded by the DCX gene, plays a crucial role in the neuronal migration process during brain development. Pathogenic variants of the DCX gene are the major causes of the "lissencephaly (LIS) spectrum", which comprehends a milder phenotype like Subcortical Band Heterotopia (SBH) in heterozygous female subjects. We performed targeted sequencing in three unrelated female cases with SBH. We identified three DCX-related variants: a novel missense (c.601A>G: p.Lys201Glu), a novel nonsense (c.210C>G: p.Tyr70*), and a previously identified nonsense (c.907C>T: p.Arg303*) variant. The novel c.601A>G: p.Lys201Glu variant shows a mother-daughter transmission pattern across four generations. The proband exhibits focal epilepsy and achieved seizure freedom with a combination of oxcarbazepine and levetiracetam. All other affected members have no history of epileptic seizures. Brain MRIs of the affected members shows predominant fronto-central SBH with mixed pachygyria on the overlying cortex. The two nonsense variants were identified in two unrelated probands with SBH, severe drug-resistant epilepsy and intellectual disability. These novel DCX variants further expand the genotypic-phenotypic correlations of lissencephaly spectrum disorders. Our documented phenotypic descriptions of three unrelated families provide valuable insights and stimulate further discussions on DCX-SBH cases.

Benefits of vagus nerve stimulation on psychomotor functions in patients with severe drug-resistant epilepsy

PurposePatients with severe drug-resistant epilepsy (DRE) experience psychomotor disorders. Our study aimed to assess the psychomotor outcomes after vagus nerve stimulation (VNS) in this population. MethodsWe prospectively evaluated psychomotor function in 17 adult patients with severe DRE who were referred for VNS. Psychomotor functions were examined, in the preoperative period and at 18 months post-surgery, by a psychomotor therapist using a full set of the following specific tests: the Rey–Osterrieth complex figure (ROCF) test, the Zazzo's cancelation task (ZCT), the Piaget-Head test and the paired images test. ResultsAt 18 months post-VNS surgery, the Piaget-head scores increased by 3 points (p = 0.008) compared to baseline. Performances were also improved for ROCF test both in copy (+2.4 points, p = 0.001) and recall (+2.0 points, p = 0.008) tasks and for the paired images test (accuracy index: +28.6 %, p = 0.03). Regarding the ZCT findings, the efficiency index increased in both single (+16 %, p = 0.005) and dual (+17.1 %, p < 0.001) tasks. QoL improved in 88.2 % of patients. ConclusionsPatients with severe DRE treated with VNS experienced improved performance in terms of global psychomotor functions. Perceptual organization, visuospatial memory, laterality awareness, sustained attention, concentration, visual scanning, and inhibition were significantly improved.

Rasmussen's Encephalitis of the Adult: A Case Report

Rasmussen syndrome (RS) is a chronic inflammatory disease of unknown etiology.it characterized by severe drug-resistant epilepsy, hemicorporeal neurologic deficit and progressive onset cerebral hemi-atrophy. Although it has long been considered a childhood disease, this pathology can appear in adolescence or adulthood. We report the observation of a patient with Rasmussen syndrome in adulthood, through which and the data of the literature we have discussed clinical, electro-radiological and therapeutic aspect of this serious pathology.

Adjunctive cenobamate in highly active and ultra-refractory focal epilepsy: A "real-world" retrospective study.

Recent clinical trials have shown that cenobamate substantially improves seizure control in focal-onset drug-resistant epilepsy (DRE). However, little is known about cenobamate's performance in highly active (≥20 seizures/month) and ultra-refractory focal epilepsy (≥6 failed epilepsy treatments, including antiseizure medications [ASMs], epilepsy surgery, and vagus nerve stimulation). Here, we studied cenobamate's efficacy and tolerability in a "real-world" severe DRE cohort. We conducted a single-center retrospective analysis of consecutive adults treated with cenobamate between October 2020 and September 2022. All patients received cenobamate through an Early Access Program. Cenobamate retention, seizure outcomes, treatment-emergent adverse events, and adjustments to concomitant ASMs were analyzed. Fifty-seven patients received cenobamate for at least 3 months (median duration, 11 months). The median cenobamate dose was 250 mg/day (range 75-350 mg). Baseline demographics were consistent with highly active (median seizure frequency, 60/month) and ultra-refractory epilepsy (median previously failed ASMs, nine). Most (87.8%) had prior epilepsy surgery and/or vagus nerve stimulation. Six patients stopped cenobamate due to lack of efficacy and/or adverse events. One patient died from factors unrelated to cenobamate. Among patients who continued cenobamate, three achieved seizure freedom (5.3% of cohort), 24 had a 75%-99% reduction in seizures (42.1% of cohort), and 16 had a 50%-74% reduction (28.1% of cohort). Cenobamate led to abolition of focal to bilateral tonic-clonic seizures in 55.6% (20/36) of patients. Among treatment responders, 67.4% (29/43) were treated with cenobamate doses of ≥250 mg/day. Three-fourths of patients reported at least one side-effect, most commonly fatigue and somnolence. Adverse events most commonly emerged at cenobamate doses of ≥250 mg/day. Side-effects were partially manageable by reducing the overall ASM burden, most often clobazam, eslicarbazepine, and perampanel. Patients with highly active and ultra-refractory focal epilepsy experienced meaningful seizure outcomes on cenobamate. Emergence of adverse events at doses above 250 mg/day may limit the potential for further improvements in seizure control at higher cenobamate doses.

FIRES Syndrome in a Preschool Child

Severe epileptic syndromes of childhood are an urgent problem for pediatric neurologists and neuroresuscitators. The article presents a clinical observation of FIRES syndrome in a pediatric patient, which is a form of severe drug-resistant epilepsy in children of preschool and school age, the development of which is caused by hyperthermia, probably associated with herpesvirus (human herpesvirus type 6) infection. The features of the progressive course and the difficulties of diagnostic search are reflected. An empirical approach to etiotropic therapy is described, since the disease manifested itself with respiratory manifestations and fever. The tactic of pathogenetic treatment is described, in which drugs of polyfunctional action, such as Cytoflavin, have a priority, many years of experience in the use of which allows the authors to recommend it as a starting intensive therapy.

Brivaracetam add-on treatment in pediatric patients with severe drug-resistant epilepsy: Italian real-world evidence

Purpose: To report the efficacy and tolerability of brivaracetam (BRV) in add-on therapy in pediatric patients with severe drug-resistant epilepsy. Prognostic factors of clinical outcome were also analyzed. Methods: This Italian multicenter retrospective observational study was conducted on 45 pediatric patients with severe drug-resistant epilepsy, treated with BRV for at least 1 month and with a follow-up >6 months. Demographic, clinical, and treatment variables were assessed at T0 (baseline, BRV introduction) and T1 (6 months after BRV introduction). The response was defined as ≥50% seizure frequency reduction; responders and non-responders were then compared to assess potential prognostic factors. Results: Forty-five patients (M = 28, mean age 12.4+/-4.4 years) were enrolled (focal epilepsy=14; generalized epilepsy=2; epileptic encephalopathy=29). At T1, 19/45 patients (42.2%) were responders (≥50% seizure frequency reduction), with 4 patients (8.9%) achieving a ≥ 75% seizure reduction and 2 patients (4.4%) becoming seizure free. Epilepsy onset at >12 months of age (p = 0.001), disease duration ≤6 years (p = 0.036), and lower seizure frequency at baseline (p = 0.008) were the prognostic factors significantly associated with a better prognosis. No significant difference emerged for demographics, epilepsy types/etiology, intellectual disability, or therapy variables. At T1, 21 patients (46.6%) discontinued BRV, mainly due to lack of efficacy (13 subjects; 28.9%) and adverse events in 8 patients (17.8%). Conclusion: Brivaracetam was an effective and tolerated treatment in pediatric patients with severe drug-resistant epilepsy, especially when the seizure onset was at >12 months of age, the epilepsy duration ≤6 years, and the seizure frequency before BRV treatment was low. Further and controlled studies are needed.

Psychobehavioural and Cognitive Adverse Events of Anti-Seizure Medications for the Treatment of Developmental and Epileptic Encephalopathies.

The developmental and epileptic encephalopathies encompass a group of rare syndromes characterised by severe drug-resistant epilepsy with onset in childhood and significant neurodevelopmental comorbidities. The latter include intellectual disability, developmental delay, behavioural problems including attention-deficit hyperactivity disorder and autism spectrum disorder, psychiatric problems including anxiety and depression, speech impairment and sleep problems. Classical examples of developmental and epileptic encephalopathies include Dravet syndrome, Lennox–Gastaut syndrome and tuberous sclerosis complex. The mainstay of treatment is with multiple anti-seizure medications (ASMs); however, the ASMs themselves can be associated with psychobehavioural adverse events, and effects (negative or positive) on cognition and sleep. We have performed a targeted literature review of ASMs commonly used in the treatment of developmental and epileptic encephalopathies to discuss the latest evidence on their effects on behaviour, mood, cognition, sedation and sleep. The ASMs include valproate (VPA), clobazam, topiramate (TPM), cannabidiol (CBD), fenfluramine (FFA), levetiracetam (LEV), brivaracetam (BRV), zonisamide (ZNS), perampanel (PER), ethosuximide, stiripentol, lamotrigine (LTG), rufinamide, vigabatrin, lacosamide (LCM) and everolimus. Bromide, felbamate and other sodium channel ASMs are discussed briefly. Overall, the current evidence suggest that LEV, PER and to a lesser extent BRV are associated with psychobehavioural adverse events including aggressiveness and irritability; TPM and to a lesser extent ZNS are associated with language impairment and cognitive dulling/memory problems. Patients with a history of behavioural and psychiatric comorbidities may be more at risk of developing psychobehavioural adverse events. Topiramate and ZNS may be associated with negative effects in some aspects of cognition; CBD, FFA, LEV, BRV and LTG may have some positive effects, while the remaining ASMs do not appear to have a detrimental effect. All the ASMs are associated with sedation to a certain extent, which is pronounced during uptitration. Cannabidiol, PER and pregabalin may be associated with improvements in sleep, LTG is associated with insomnia, while VPA, TPM, LEV, ZNS and LCM do not appear to have detrimental effects. There was variability in the extent of evidence for each ASM: for many first-generation and some second-generation ASMs, there is scant documented evidence; however, their extensive use suggests favourable tolerability and safety (e.g. VPA); second-generation and some third-generation ASMs tend to have the most robust evidence documented over several years of use (TPM, LEV, PER, ZNS, BRV), while evidence is still being generated for newer ASMs such as CBD and FFA. Finally, we discuss how a variety of factors can affect mood, behaviour and cognition, and untangling the associations between the effects of the underlying syndrome and those of the ASMs can be challenging. In particular, there is enormous heterogeneity in cognitive, behavioural and developmental impairments that is complex and can change naturally over time; there is a lack of standardised instruments for evaluating these outcomes in developmental and epileptic encephalopathies, with a reliance on subjective evaluations by proxy (caregivers); and treatment regimes are complex involving multiple ASMs as well as other drugs.Graphical Supplementary InformationThe online version contains supplementary material available at 10.1007/s40263-022-00955-9.

Modeling PCDH19-CE: From 2D Stem Cell Model to 3D Brain Organoids.

PCDH19 clustering epilepsy (PCDH19-CE) is a genetic disease characterized by a heterogeneous phenotypic spectrum ranging from focal epilepsy with rare seizures and normal cognitive development to severe drug-resistant epilepsy associated with intellectual disability and autism. Unfortunately, little is known about the pathogenic mechanism underlying this disease and an effective treatment is lacking. Studies with zebrafish and murine models have provided insights on the function of PCDH19 during brain development and how its altered function causes the disease, but these models fail to reproduce the human phenotype. Induced pluripotent stem cell (iPSC) technology has provided a complementary experimental approach for investigating the pathogenic mechanisms implicated in PCDH19-CE during neurogenesis and studying the pathology in a more physiological three-dimensional (3D) environment through the development of brain organoids. We report on recent progress in the development of human brain organoids with a particular focus on how this 3D model may shed light on the pathomechanisms implicated in PCDH19-CE.

Efficacy, tolerability, and retention of fenfluramine for the treatment of seizures in patients with Dravet syndrome: Compassionate use program in Germany.

Dravet syndrome (DS) is a rare but severe drug-resistant epilepsy. Before the approval of fenfluramine (FFA) for the treatment of seizures in DS, patients in Germany could receive treatment under a compassionate use program (CUP). We conducted a multicenter, retrospective, observational study to describe the efficacy, tolerability, and retention of FFA within the CUP. Patients received add-on therapy with oral FFA gradually titrated to a target dose between .13 and .7mg/kg/day. Overall, 78 patients with DS (median age = 8.0 years, range = 2.1-46.0; 53% female, median concomitant antiseizure medications [ASMs] = 3) were treated with FFA for a median duration of 255.5days (range = 31-572). Responder rates (a ≥50% reduction; n=78) and seizure-freedom rates at 3months were 68% and 14% for total seizures, respectively, and 67% and 23% for generalized tonic-clonic seizures. Responder rates were consistent at 6 and 12months (n=66 and n=43, respectively). Median seizure days per month significantly decreased from 10.0 (range = .5-30) to 3.0 (range = 0-30) in the 3-month period before and after FFA treatment (p<.001). Significantly fewer patients reported at least one episode of status epilepticus (28% vs. 14% patients before and after FFA initiation, p=.005). During FFA treatment, 35 (45%) patients were able to discontinue a concomitant ASM. At the last follow-up date, 66 (85%) patients remained on treatment with FFA. The most common adverse events were somnolence (36%), decreased appetite (22%), and ataxia (8%). Forty-eight (62%) patients were reported as having a meaningful global clinical improvement. In a large cohort of patients, FFA demonstrated efficacy across a range of outcomes including clinically significant reductions in convulsive seizures, and was well tolerated, providing valuable information for real-world practice.

The efficacy and tolerability of auto-stimulation-VNS in children with Lennox-Gastaut syndrome

ObjectiveLennox-Gastaut syndrome (LGS) is a severe drug-resistant epilepsy (DRE) of childhood. The Vagus Nerve Stimulator (VNS) is established as a safe and effective treatment for DRE. This study assesses efficacy and tolerability of the auto-stimulation VNS models in pediatric patients with LGS. MethodsThis is a retrospective chart review of a cohort of pediatric patients (Age 1–18 years old) with LGS implanted with an auto-stimulation VNS model at a single level four pediatric epilepsy center. Patient responder’s rate was measured as seizure reduction over baseline and improvements in five quality-of-life measures as reported by the patients and families. Efficacy and tolerability were assessed at 1, 3, 6, 12, 18 and 24 months compared to baseline. ResultsThis cohort includes 71 consecutive children with Lennox-Gastaut syndrome who underwent implantation with one of two models of the auto-stimulation VNS. The average age of the children at implantation was 20.82 months. Of those patients, 55 % of patients achieved greater than 50 % seizure reduction at six months, 67.7 % at 12 months, and 65 % at 24 months. At 12 months 11 % of the patients were completely seizure free and at 24 months 17 % were seizure free. By 24 months post implantation most of the patient families reported at least a 50 % improvement rate in one or more of the quality-of-life measures. The most commonly reported adverse events were dysphonia, paresthesia, and shortness of breath, all of which were tolerated and subsided by 24 months. SignificanceThis study provides evidence that VNS models with the auto-stimulation paradigm based on detection of tachycardia are well tolerated and effective in a pediatric population with LGS. Furthermore, this study shows that for this population, the auto-stimulation models of the VNS may provide additional benefits over the earlier VNS versions.

Electrographic pattern recognition: A simple tool to predict clinical outcome in children with lissencephaly

PurposeTo describe and correlate the clinical, radiological and EEG findings in children with lissencephaly. MethodRetrospective record analysis of children with lissencephaly presenting to tertiary health centre in Northern India was performed. Radiological classification and severity scoring were done. EEG findings were categorized into three patterns and its association with clinical severity was studied. ResultsTwenty-eight children (males = 17) with lissencephaly were enrolled. Median age at diagnosis was 6.5months (range 3days-3years). Global developmental delay (median social quotient (SQ) = 25 (range15−68) was seen in all; motor deficits in 23 (82 %); epilepsy in 21 (75 %); behavioural problems in 18 (64 %); ophthalmic problems in 17 (61 %); microcephaly in 13 (46 %); feeding difficulty in 12 (43 %). Radiologically, classical Type I lissencephaly was seen in 18(64 %), cobblestone variant (Type II) in 5 (18 %) and microlissencephaly in 5 (18 %). Grade 4 (diffuse pachygyria) radiologic severity was most common (severity grade 1–6); no cases with severity score 5 or 6 were seen. The clinical profile did not correspond with radiological severity grading. EEG pattern recognition revealed pattern I in 14 (50 %); pattern II in 6 (21 %); pattern III in 8 (29 %). Children with pattern III EEG had drug resistant epilepsy and severe developmental delay. No relationship between EEG patterns and radiological severity grading was evident. ConclusionEEG is better predictor of clinical status and outcome rather than radiological severity grading. EEG pattern III is associated with severe developmental delay and drug resistant epilepsy.

Hemispherotomy in the surgical treatment of severe symptomatic epilepsy

Purpose. To evaluate the efficacy of peri-insular functional hemispherotomy (FH) for patients with severe drug-resistant epilepsy. Materials and Methods. Nine patients underwent peri-insular functional hemispherotomy. The patients included 1 adult (11.1 %) and 8 (88.8 %) children. Patients’ age ranged from 4 to 23 years (mean 9.9 ± 4.2 years). Epilepsy duration ranged from 1.5 to 16 years (mean 7.1 ± 3.1 years), mean seizures frequency was 12.9 ± 6.8 per day; before treatment patients used on average 5.1 ± 2.6 antiepileptic drugs. Diffuse injury of one hemisphere and contralateral hemiparesis were observed in all cases. Follow-up lasted from 1 to 17 months (mean 9.6 ± 1.4 months). Three (33.3 %) patients experienced Rasmussen’s encephalitis, 2 (22.2 %) had multi-lobar cortical malformation, 2 (22.2 %) had complications associated with intracerebral hemorrhage, 1 (11.1 %) patient represented with hypoxic-ischemic encephalopathy and 1 (11.1 %) patient experienced epilepsy associated with PNET resection, chemotherapy and local radiation. Results. After FH, 7 (77.7 %) children became seizure-free (Engel Class I A), seizure recurrence was observed in one (11.1 %) case in 6 months after surgery. Perioperative complications with following death occurred in one case (11.1 %). Hydrocephalus, which required shunting developed in one (11.1 %) child. Conclusion. Functional peri-insular hemispherotomy is an effective and safe method for surgical treatment of severe symptomatic epilepsy. Seizure cessation improves psychomotor development and diminishes neurocognitive disorders.

BOLD mapping of human epileptic spikes recorded during simultaneous intracranial EEG-fMRI: The impact of automated spike classification

ObjectivesSimultaneous intracranial EEG and functional MRI (icEEG-fMRI) can be used to map the haemodynamic (BOLD) changes associated with the generation of IEDs. Unlike scalp EEG-fMRI, in most patients who undergo icEEG-fMRI, IEDs recorded intracranially are numerous and show variability in terms of field amplitude and morphology. Therefore, visual marking can be highly subjective and time consuming. In this study, we applied an automated spike classification algorithm, Wave_clus (WC), to IEDs marked visually on icEEG data acquired during simultaneous fMRI acquisition. The motivation of this work is to determine whether using a potentially more consistent and unbiased automated approach can produce more biologically meaningful BOLD patterns compared to the BOLD patterns obtained based on the conventional, visual classification. MethodsWe analysed simultaneous icEEG-fMRI data from eight patients with severe drug resistant epilepsy, and who subsequently underwent resective surgery that resulted in a good outcome: confirmed epileptogenic zone (EZ). For each patient two fMRI analyses were performed: one based on the conventional visual IED classification and the other based on the automated classification. We used the concordance of the IED-related BOLD maps with the confirmed EZ as an indication of their biological meaning, which we compared for the automated and visual classifications for all IED originating in the EZ. ResultsAcross the group, the visual and automated classifications resulted in 32 and 24 EZ IED classes respectively, for which 75% vs 83% of the corresponding BOLD maps were concordant. At the single-subject level, the BOLD maps for the automated approach had greater concordance in four patients, and less concordance in one patient, compared to those obtained using the conventional visual classification, and equal concordance for three remaining patients. These differences did not reach statistical significance. ConclusionWe found automated IED classification on icEEG data recorded during fMRI to be feasible and to result in IED-related BOLD maps that may contain similar or greater biological meaning compared to the conventional approach in the majority of the cases studied. We anticipate that this approach will help to gain significant new insights into the brain networks associated with IEDs and in relation to postsurgical outcome.

Risk Assessment for Sudden Death in Epilepsy: The SUDEP-7 Inventory.

Sudden unexpected death in epilepsy (SUDEP) is a major cause of death in those with drug-resistant epilepsy (DRE). There is a need for inventories and biomarkers associated with the risk for SUDEP. To explore the revised SUDEP Risk Inventory (SUDEP-7) in a cohort with DRE and determine the association with Heart Rate and other covariates. Twenty-five subjects with severe DRE were enrolled in a clinical trial for epilepsy. Baseline demographics, duration of epilepsy, seizure types, seizure frequency, seizure severity, AEDs, and vital signs were collected. Heart rate variability (HRV) was calculated from 1-h recordings of ECG. A SUDEP Risk Inventory (SUDEP-7) was administered, which included seven validated and weighted risk factors initially identified by Walczak et al. as factors associated with SUDEP risk. The total score on the revised SUDEP-7 ranged from 1 to 7, mean = 3.4 (SD 1.8). The SUDEP Risk Inventory score was inversely correlated with RMSSD (Pearson r = -0.45, p = 0.027). The following variables were significantly associated with RMSSD: epilepsy duration (p = 0.02), age (p = 0.03), and developmental intellectual disability (p < 0.001). The correlation between RMSSD and SUDEP-7 tended to persist also after the adjustment for patient age (r = -0.40, p = 0.05). Two subjects died of SUDEP: their SUDEP-7 scores were above average and in the upper twenty-fifth and fiftieth percentiles, respectively (6 and 4, mean = 3.4). RMSSD, a measure of low frequency HRV, was significantly associated with SUDEP Risk Inventory (SUDEP-7) scores. Using a multivariate model, the covariates of developmental intellectual disability, age, and duration of epilepsy were also significantly associated with decreased HRV. The correlation between decreased HRV and a higher SUDEP-7 score remained unchanged even after the adjustment for patient age. The results suggest that older age, greater duration of epilepsy, and the presence of developmental intellectual disability may increase the risk of SUDEP through their direct influence on decreasing the vagus nerve-mediated HRV. Further validation of the SUDEP-7 inventory is indicated. ClinicalTrials.gov, NCT00871377.

P31 – 2682: Improved seizure control by lacosamide in a patient with MECP2 duplication syndrome

Objective MECP2 duplication syndrome, caused by the duplication of the Xq28 region, is a severe neurodevelopmental disorder involving multiple organ systems including drug-resistant epilepsy. Patients have polymorphic seizures, predominantly tonic-clonic and atonic seizures. EEG show slowing of the background activity, multifocal spike discharges and polyspike-waves with frontotemporal predominance. Frequent seizures are only poorly controlled by anti-epileptic therapy. Methods and results We present a Caucasian boy with hypotonia, severe developmental delay and drug-resistant epilepsy. Genetic testing (aCGH) confirmed the duplication of the MECP2 gene. He presented with feeding difficulties in the first days after birth, in the first months general hypotonia developed. Then regression of the social skills was observed, followed by regression of the motor skills. At the age of 3 years he developed epilepsy. EEG showed slow and chaotic background activity with multifocal slow spikewaves. They observed epileptic spasms, but several other types of seizures were subsequently documented. In the last 2 years 14 different anti-epileptic drugs were introduced in different combinations, with little or no electro-clinical improvement. He was hospitalized for several times because of status epilepticus. He had myoclonic seizures almost all the time during wakefulness in addition to 10–20 epileptic spasms and tonic seizures per day. Improvement in seizure control more than 50% reduction was noticed when lacosamide was introduced in combination with levetiracetam in clobazam. Myoclonic seizures were completely controlled. Conclusion In a boy with MECP2 duplication syndrome add-on therapy with lacosamide proved to be the most efficient anti-epileptic drug due to more than 50% reduction in number of tonic seizures and epileptic spasms and complete control of myoclonic seizures.

Reappraisal of corpus callosotomy.

Corpus callosotomy is a palliative surgical treatment modality that has gone in and out of favor. The purpose of this review is to summarize the studies of callosotomy in the past years as a treatment for severe drug-resistant epilepsy with traumatizing drop attacks, mostly in children and also in some adults. The aim is also to discuss knowledge gaps and suggest how these could be addressed. Lately, a number of callosotomy series, mostly retrospective and single center, have included 289 operated patients. A few series have included nonoperated controls; one prospective long-term series is national and population based. Seizure outcome is shown to be comparable to that earlier reported, with best effect against drop attacks. There is no consensus on whether anterior or complete callosotomy is to be preferred. In a meta-analysis of callosotomy versus vagal nerve stimulation, callosotomy led to better seizure outcome. Diffusion tensor imaging may be a promising tool to analyze the completeness of the procedure. Callosotomy remains an effective palliative procedure. Many unresolved issues, such as prognostic indicators, nonseizure-related outcomes, whether to choose anterior or complete callosotomy, and outcomes and adverse effects in adults, need to be studied in prospective, preferably multicenter studies.

The specific features and pattern of febrile infection-related epilepsy syndrome (FIRES) in children

The paper considers the etiology, pathogenesis, clinical presentations, diagnosis and treatment in children with febrile infection-related epilepsy syndrome (FIRES) and the aspects of identifying this disease as an individual nosological entity. It details a study of the possible etiological factors of FIRES, such as metabolic, genetic, and immunological disorders, aseptic inflammatory processes, as well as a search for a certain infectious agent by inoculations of different biological environments of the body and by polymerase chain reaction; the diagnostic characteristics of FIRES at the present stage, including the use of electroencephalography, positron emission tomography, and magnetic resonance imaging; different approaches to drug therapy for FIRES at the onset stages of its clinical manifestations, protracted status epilepticus, and drugresistant epilepsy. The issues of the predictable outcome of this disease, including survival and the probability of further development of epilepsy and maintenance of cognitive functions, are also viewed. Diagnostic criteria for the syndrome, such as age at its onset 3 to 15 years in previously healthy children; acute onset as fever to develop high-frequency focal seizures several days later; the absence of the identified disease pathogen detected by the examinations of cerebrospinal fluid, serum, and other environments of the body; the development of drug-resistant epilepsy and severe permanent cognitive and motor deficits after the completion of an acute period in most cases are presented. The paper is clinically exemplified by the authors’ observation of an 11-year-old boy who meets the above criteria for the syndrome, but has a relatively favorable course, without developing severe drug-resistant epilepsy.