Fenfluramine below the age of 2 years in Dravet syndrome: What about safety and efficacy?

Dravet syndrome (DS) is a rare developmental and epileptic encephalopathy. Infants with DS are especially vulnerable to the detrimental effects of prolonged and frequent seizures on development. Fenfluramine (FFA) is approved for the treatment of DS in patients aged 2 years and older. This study aims to evaluate the safety and efficacy of FFA in patients with DS younger than 2 years. We analyzed safety, tolerability, seizure, and neuropsychological outcome in a real-world setting. Developmental profile was investigated using Griffiths Mental Development Scales (GMDS). Five patients received FFA at a mean age of 14.9 months (9.6-18.6). Median follow-up was 13 months (interquartile range [IQR] = 12.9-24.4). All patients showed good tolerance to FFA. No significant variation of body mass index or echocardiographic issue was observed. Monthly median convulsive seizure frequency (MCSF) was 1.71 (IQR = 1.56-3.27) at the 6-month baseline period and .92 (IQR = .43-1.28) at last follow-up, with a median 54.43 (IQR = 40.91-60.83) percentage reduction in MCSF. Two of five patients had a performance improvement on GMDS subscales. Overall, the use of FFA below the age of 2 years in our small sample of patients was safe and represents a promising opportunity for seizure control and for protection of the neurodevelopmental outcome.

Hypothalamic Hamartoma related epilepsy: A systematic review exploring clinical, neuropsychological, and psychiatric outcome after surgery.

The post-surgical outcome for Hypothalamic Hamartoma (HH) related epilepsy in terms of seizure freedom (SF) has been extensively studied, while cognitive and psychiatric outcome has been less frequently reported and defined. This is a systematic review of English language papers, analyzing the post-surgical outcome in series of patients with HH-related epilepsy (≥5 patients, at least 6 months follow-up), published within January 2002-December 2022. SF was measured using Engel scale/equivalent scales. We looked at the outcome related to different surgical techniques, and HH types according to Delalande classification. We evaluated the neuropsychological and neuropsychiatric status after surgery, and the occurrence of post-surgical complications. Forty-six articles reporting 1318 patients were included, of which ten pediatric series. SF was reported in 686/1222 patients (56,1%). Delalande classification was reported in 663 patients from 24 studies, of which 70 were type I HH (10%), 320 were type II HH (48%), 189 were type III HH (29%) and 84 were type IV HH (13%). The outcome in term of SF was reported in 243 out of 663 patients. SF was reported in 12 of 24 type I HH (50%), 80 of 132 type II HH (60,6%), 32 of 59 type III HH (54,2%) and 12 of 28 type IV HH (42,9%). SF was reached in 129/262 (49,2%) after microsurgery, 102/199 (51,3%) after endoscopic surgery, 46/114 (40,6%) after gamma knife surgery, 245/353 (69,4%) after radiofrequency thermocoagulation, and 107/152 (70,4%) after MRI-guided laser interstitial thermal therapy. Hyperphagia/weight gain were the most reported surgical complications. Others were electrolyte alterations, diabetes insipidus, hypotiroidism, transient hyperthermia/poikilothermia. The highest percentage of memory deficits was reported after microsurgery, while hemiparesis and cranial nerves palsy were reported after microsurgery or endoscopic surgery. Thirty studies reported developmental delay/intellectual disability in 424/819 (51,7%) patients. 248/346 patients obtained a global improvement (72%), 70/346 were stable (20%), 28/346 got worse (8%). 22 studies reported psychiatric disorders in 257/465 patients (55,3%). 78/98 patients improved (80%), 13/98 remained stable (13%), 7/98 got worse (7%). Most of the patients had non-structured cognitive/psychiatric assessments. Based on the available data, the surgical management in patients with HH related epilepsy should be individualized, aiming to reach not only the best epilepsy result, but also the optimal cognitive and psychiatric outcome.

New paradigms for the treatment of pediatric monogenic epilepsies: Progressing toward precision medicine.

Despite the availability of 28 antiseizure medications (ASMs), one-third of people with epilepsy fail to achieve sustained freedom from seizures. Clinical outcome is even poorer for children with developmental and epileptic encephalopathies (DEEs), many of which are due to single-gene mutations. Discovery of causative genes, however, has paved the way to understanding the molecular mechanism underlying these epilepsies, and to the rational application, or development, of precision treatments aimed at correcting the specific functional defects or their consequences. This article provides an overview of current progress toward precision medicine (PM) in the management of monogenic pediatric epilepsies, by focusing on four different scenarios, namely (a) rational selection of ASMs targeting specifically the underlying pathogenetic mechanisms; (b) development of targeted therapies based on novel molecules; (c) use of dietary treatments or food constituents aimed at correcting specific metabolic defects; and (d) repurposing of medications originally approved for other indications. This article is part of the Special Issue "Severe Infantile Epilepsies".

Is Cenobamate the Breakthrough We Have Been Wishing for?

Close to one-third of patients with epilepsies are refractory to current anti-seizure medications; however, trials with cenobamate suggest effectiveness in such patients with focal onset seizures. We searched for data published or otherwise reported on cenobamate and outlined these here. Despite being marketed in the USA, few studies are yet published in full, and trials are ongoing. Nevertheless, cenobamate showed potential for a high degree of efficacy in reducing seizures with an unprecedented seizure-free rate of up to 28%. Rare cases of hypersensitivity reactions seen in early trials seem to be avoided by the current recommended titration schedule. Other adverse events were rated mild-to-moderate and most commonly included dizziness, drowsiness, and headache. If data are confirmed in further published trials, cenobamate will be a welcome new treatment and further analyses may identify those that will benefit the most.

Efficacy and safety of Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: A real-world study.

OBJECTIVE: Dravet syndrome (DS) is a drug-resistant, infantile onset epilepsy syndrome with multiple seizure types and developmental delay. In recently published randomized controlled trials, fenfluramine (FFA) proved to be safe and effective in DS. METHODS: DS patients were treated with FFA in the Zogenix Early Access Program at four Italian pediatric epilepsy centers. FFA was administered as add-on, twice daily at an initial dose of 0.2 mg/kg/d up to 0.7 mg/kg/d. Seizures were recorded in a diary. Adverse events and cardiac safety (with Doppler echocardiography) were investigated every 3 to 6 months. RESULTS: Fifty-two patients were enrolled, with a median age of 8.6 years (interquartile range [IQR] = 4.1-13.9). Forty-five (86.5%) patients completed the efficacy analysis. The median follow-up was 9.0 months (IQR = 3.2-9.5). At last follow-up visit, there was a 77.4% median reduction in convulsive seizures. Thirty-two patients (71.1%) had a ≥50% reduction of convulsive seizures, 24 (53.3%) had a ≥75% reduction, and five (11.1%) were seizure-free. The most common adverse event was decreased appetite (n = 7, 13.4%). No echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed. There was no correlation between type of genetic variants and response to FFA. SIGNIFICANCE: In this real-world study, FFA provided a clinically meaningful reduction in convulsive seizure frequency in the majority of patients with DS and was well tolerated.

Defining the phenotype of FHF1 developmental and epileptic encephalopathy.

Fibroblast growth-factor homologous factor (FHF1) gene variants have recently been associated with developmental and epileptic encephalopathy (DEE). FHF1 encodes a cytosolic protein that modulates neuronal sodium channel gating. We aim to refine the electroclinical phenotypic spectrum of patients with pathogenic FHF1 variants. We retrospectively collected clinical, genetic, neurophysiologic, and neuroimaging data of 17 patients with FHF1-DEE. Sixteen patients had recurrent heterozygous FHF1 missense variants: 14 had the recurrent p.Arg114His variant and two had a novel likely pathogenic variant p.Gly112Ser. The p.Arg114His variant is associated with an earlier onset and more severe phenotype. One patient carried a chromosomal microduplication involving FHF1. Twelve patients carried a de novo variant, five (29.5%) inherited from parents with gonadic or somatic mosaicism. Seizure onset was between 1 day and 41 months; in 76.5% it was within 30 days. Tonic seizures were the most frequent seizure type. Twelve patients (70.6%) had drug-resistant epilepsy, 14 (82.3%) intellectual disability, and 11 (64.7%) behavioral disturbances. Brain magnetic resonance imaging (MRI) showed mild cerebral and/or cerebellar atrophy in nine patients (52.9%). Overall, our findings expand and refine the clinical, EEG, and imaging phenotype of patients with FHF1-DEE, which is characterized by early onset epilepsy with tonic seizures, associated with moderate to severe ID and psychiatric features.

Management of epileptic seizures in school-age children: Educational project dedicated to school staff.

OBJECTIVE: The objective of this study was to educate the school staff for a correct management of epileptic seizures in order to increase the safety of young people at school and promoting the administration of rescue drugs and in order to improve care and reduce improper calls to the health emergency number. METHODS: This project started in January 2016, and it is still ongoing at the Department of Neuroscience of Bambino Gesù Children's Hospital in Rome, Italy. There has been a data cut-off evaluation in November 2018. Two-hour training meetings with the school staff have been organized. The major topics of the training activities were as follows: report what epilepsy is, how to manage students with epileptic seizures, and how to administer rescue medications. During the meetings, the following two questionnaires were administered: one pretest in order to collect personal information and information on awareness of epilepsy, willingness to administer rescue medications, and anxiety in facing a seizure; and one posttest in order to check the knowledge acquired after the training sessions. Statistical analysis was performed using R version 3.2.3 (R Foundation for Statistical Computing, http://www.R-project.org/). Demographics (sex and age) and teaching experience were summarized with descriptive statistics for each variable. Demographics, teaching experience, awareness of disability, and knowledge of epilepsy were correlated to the management of seizures occurring in the classroom before the course; results are reported as odds ratios [OR] and 95% confidence interval (95 CI). RESULTS: Nine hundred school staff members (95% school staff and 5% social workers) entered in the project between January 2016 and November 2018. Seven hundred and forty (82%) returned the questionnaires fulfilled, and not all of them were completely filled. Ninety-eight percent of school staff (676/691) were aware about epilepsy; however, only in 16% (110) the awareness of epilepsy came from medical staff, scientific brochures, or participation in conventions. Thirty-five percent of school staff (248/707) believed that epilepsy reduces learning abilities, and 58% (409/703) believed that children with epilepsy need school support. After the training, 68% of school staff (496/734) correctly filled in the questionnaire related to the management of acute seizures versus 8% of them (57/718) in the prequestionnaire. After the training, 89% of school staff (601/675) were ready to administer rescue medications versus 54% (384/712) before the training. The majority of participants reported that the level of anxiety related to the management of seizures after the training significantly reduced. CONCLUSIONS: Results of this project documented an increase in knowledge of epilepsy, a better knowledge on management of acute seizures in the school settings, a reduction in anxiety, and an increase in willingness to administer rescue medications. Further studies should be planned in order to document the changes in the real-world management of seizures, to evaluate if a reduction in hospital admittances might be reached, and to extend the project by assessing, through a questionnaire, the stigma and prejudices against the children affected by epilepsy by their classmates.

Impact of COVID-19 pandemic on pediatric patients with epilepsy - The caregiver perspective.

The recent COVID-19 pandemic has disrupted care systems around the world. We assessed how the COVID-19 pandemic affected children with epilepsy in Italy, where lockdown measures were applied from March 8 to May 4, 2020. We compiled an Italian-language online survey on changes to healthcare and views on telehealth. Invitations were sent to 6631 contacts of all patients diagnosed with epilepsy within the last 5 years at the BambinoGesù Children's Hospital in Rome. Of the 3321 responses received, 55.6% of patients were seizure-free for at least 1 year before the COVID-19-related lockdown, 74.4% used anti-seizure medications (ASMs), and 59.7% had intellectual disability. Only 10 patients (0.4%) became infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Seizure frequency remained stable for most patients during the lockdown period (increased in 13.2%; decreased in 20.3%), and seizure duration, use of rescue medications, and adherence to treatment were unchanged. Comorbidities were more affected (behavioral problems worsened in 35.8%; sleep disorder worsened in 17.0%). Visits were canceled/postponed for 41.0%, but 25.1% had remote consultation during the lockdown period (93.9% were satisfied). Most responders (67.2%) considered continued remote consultations advantageous. Our responses support that patients/caregivers are willing to embrace telemedicine for some scenarios.

New-onset refractory status epilepticus and febrile infection-related epilepsy syndrome.

New-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES) are relatively rare clinical presentations. They are characterized by de novo onset of refractory status epilepticus (RSE) without clearly identifiable acute or active cause (structural, toxic, or metabolic). We reviewed the literature using PubMed reports published between 2003 and 2019 and summarized the clinical, neurophysiological, imaging, and treatment findings. Focal motor seizures, which tend to evolve into status epilepticus, characterize the typical presentation. Disease course is biphasic: acute phase followed by chronic phase with refractory epilepsy and neurological impairment. Aetiology is unknown, but immune-inflammatory-mediated epileptic encephalopathy is suspected. Electroencephalograms show variety in discharges (sporadic or periodic, focal, generalized, or more frequently bilateral), sometimes with a multifocal pattern. About 70% of adult NORSE have abnormal magnetic resonance imaging (MRI); in paediatric series of FIRES, 61.2% of patients have a normal brain MRI at the beginning and only 18.5% during the chronic phase. No specific therapy for FIRES and NORSE currently exists; high doses of barbiturates and ketogenic diet can be used with some effectiveness. Recently, anakinra and tocilizumab, targeting interleukin pathways, have emerged as potential specific therapies. Mortality rate is around 12% in children and even higher in adults (16-27%).

Pediatric status epilepticus: Identification of prognostic factors using the new ILAE classification after 5 years of follow-up.

OBJECTIVE: Status epilepticus (SE) is the most common neurologic emergency in childhood. This study aimed to report on a large cohort of pediatric patients with SE, applying the International League Against Epilepsy (ILAE) Classification for SE to identify prognostic factors. METHODS: We included 173 children treated at "Bambino Gesù" Children's Hospital in Rome for SE exceeding 30 minutes (mean age 4.43 ± 4.93 years old, median 2.28, interquartile range [IQR] 0.41-7.32; follow-up for a mean of 4.9 ± 3.4 years, median 8.75, IQR 4,58-12.63). A multivariate model was constructed to predict neurocognitive outcome, recurrence of SE, development of epilepsy, and mortality. Adjusted odds ratios [ORs] were calculated with 95% confidence interval (OR, 95% CIs). RESULTS: We observed a different prevalence of etiologies for the different semiologies (P < .05) and for each age group (P < .05), overlapping only in part with the recent ILAE classification. After SE, patients showed 69.9% epilepsy (drug-resistant in half of them), 23.1% worsening of neurologic findings on examination, 28.9% cognitive deficit, and 28.3% recurrent SE. At multivariate analysis: superrefractory SE was correlated to an increased risk of developing cognitive (OR 6.00, 95% CI 2.09, 17.31) or neurologic sequelae (OR 4.9, 95% CI 1.75, 19.77). A similar finding was observed for patients with onset in the neonatal period for cognitive (OR 4.84, 95% CI 1.13, 17.3) and neurologic sequelae (OR 9.03, 95% CI 2.40, 34.04). Recurrence of SE was associated with unknown etiology (OR 6.15, 95% CI 1.43, 26.76), and myoclonic semiology (OR 6.1, 95% CI 1.23, 29.3). Patients with acute symptomatic etiology (OR 0.12, 95% CI 0.04, 0.40) had a lower risk for developing epilepsy. SIGNIFICANCE: Age at onset and duration of SE were critical independent variables associated with worse neurocognitive outcome. The risk of developing epilepsy was lower after acute symptomatic and febrile SE. Semiology and age at onset correlate with etiology of SE. For this reason, ILAE classification with respect to four axes seems an appropriate advancement.

Outcome after hemispherotomy in patients with intractable epilepsy: Comparison of techniques in the Italian experience.

OBJECTIVE: The objective of the study was to evaluate clinical characteristics and outcome of hemispherotomy in children and adolescents with hemispheric refractory epilepsy in an Italian cohort of patients. METHODS: We retrospectively evaluated the clinical course and outcome of 92 patients with refractory epilepsy who underwent hemispherotomy in three Italian epilepsy centers between 2006 and 2016. Three different approaches for hemispherotomy were used: parasagittal, modified parasagittal, and lateral. RESULTS: Mean age at epilepsy onset was 1.8 ±â€¯2.51 years, and mean duration of epilepsy prior to surgery was 7.4 ±â€¯5.6 years. Mean age at surgery was 9.2 ±â€¯8.0 years. After a mean follow-up of 2.81 ±â€¯2.4 years, 66 of 90 patients (two lost from follow-up, 73.3%) were seizure-free (Engel class I). The etiology of epilepsy was related to acquired lesions (encephalomalacia or gliosis) in 44 patients (47.8%), congenital malformations (cortical dysplasia, hemimegalencephaly, other cortical malformations) in 38 (41.3%), and progressive conditions (Rasmussen or Sturge-Weber syndrome) in 10 patients (10.9%). Regarding seizure outcome, we could not identify statistically significant differences between vertical and lateral approaches (p = 0.154). Seizure outcome was not statistically different in patients with congenital vs acquired or progressive etiologies (p = 0.43). Acute postoperative seizures (APOS) correlated with poor outcome (p < 0.05). On multivariate analysis, presurgical focal to bilateral tonic-clonic seizures (Odds Ratio (OR) = 3.63, 95% Confidence Interval (CI): 1.86-15.20, p = 0.048) independently predicted seizure recurrence. Twenty-one patients (22.8%) exhibited postoperative complications, with no unexpected and persistent neurological deficit. More than 50% of the patients completely tapered drugs. SIGNIFICANCE: Our data confirm hemispherotomy to be a safe and effective procedure in patients with drug resistant epilepsies due to hemispheric lesions. Presurgical focal to bilateral tonic-clonic seizures are the strongest predictor of seizure recurrence after surgery, independently from the type of hemispherotomy.

Defining the electroclinical phenotype and outcome of PCDH19-related epilepsy: A multicenter study.

OBJECTIVE: PCDH19-related epilepsy is an epileptic syndrome with infantile onset, characterized by clustered and fever-induced seizures, often associated with intellectual disability (ID) and autistic features. The aim of this study was to analyze a large cohort of patients with PCDH19-related epilepsy and better define the epileptic phenotype, genotype-phenotype correlations, and related outcome-predicting factors. METHODS: We retrospectively collected genetic, clinical, and electroencephalogram (EEG) data of 61 patients with PCDH19-related epilepsy followed at 15 epilepsy centers. All consecutively performed EEGs were analyzed, totaling 551. We considered as outcome measures the development of ID, autistic spectrum disorder (ASD), and seizure persistence. The analyzed variables were the following: gender, age at onset, age at study, genetic variant, fever sensitivity, seizure type, cluster occurrence, status epilepticus, EEG abnormalities, and cognitive and behavioral disorders. Receiver operating characteristic curve analysis was performed to evaluate the age at which seizures might decrease in frequency. RESULTS: At last follow-up (median = 12 years, range = 1.9-42.1 years), 48 patients (78.7%) had annual seizures/clusters, 13 patients (21.3%) had monthly to weekly seizures, and 12 patients (19.7%) were seizure-free for ≥2 years. Receiver operating characteristic analysis showed a significant decrease of seizure frequency after the age of 10.5 years (sensitivity = 81.0%, specificity = 70.0%). Thirty-six patients (59.0%) had ID and behavioral disturbances. ASD was present in 31 patients. An earlier age at epilepsy onset emerged as the only predictive factor for ID (P = 0.047) and ASD (P = 0.014). Conversely, age at onset was not a predictive factor for seizure outcome (P = 0.124). SIGNIFICANCE: We found that earlier age at epilepsy onset is related to a significant risk for ID and ASD. Furthermore, long-term follow-up showed that after the age of 10 years, seizures decrease in frequency and cognitive and behavioral disturbances remain the primary clinical problems.

Italian Wikipedia and epilepsy: An infodemiological study of online information-seeking behavior.

Wikipedia is the most commonly accessed source of health information by both healthcare professionals and the lay public worldwide. We aimed to evaluate information-seeking behavior of Internet users searching the Italian Wikipedia for articles related to epilepsy and its treatment. Using Pageviews Analysis, we assessed the total and mean monthly views of articles from the Italian Wikipedia devoted to epilepsy, epileptic syndromes, seizure type, and antiepileptic drugs (AEDs) from January 1, 2015 to October 31, 2017. We compared the views of the article on epilepsy with those of articles focusing on Alzheimer's disease, migraine, multiple sclerosis, syncope, and stroke and adjusted all results for crude disease prevalence. With the only exception of the article on multiple sclerosis, the adjusted views for the Italian Wikipedia article on epilepsy were higher than those for the other neurological disorders. The most viewed articles on seizure type were devoted to tonic-clonic seizure, typical absence seizure, tonic convulsive seizures, and clonic convulsive seizures. The most frequently accessed articles on epilepsy syndromes were about temporal lobe epilepsy and Lennox-Gastaut syndrome. The most frequently viewed articles on AEDs were devoted to valproic acid, carbamazepine, and levetiracetam. Wikipedia searches seem to mirror patients' fears and worries about epilepsy more than its actual epidemiology. The ultimate reasons for searching online remain unknown. Epileptologists and epilepsy scientific societies should make greater efforts to work jointly with Wikipedia to convey more accurate and up-to-date information about epilepsy.

Photosensitivity is an early marker of neuronal ceroid lipofuscinosis type 2 disease.

OBJECTIVE: This study aimed to identify early clinical, magnetic resonance imaging (MRI), and electroencephalographic (EEG) characteristics of neuronal ceroid lipofuscinosis type 2 (CLN2) disease to enable early diagnosis, thus providing the key to early treatment, and optimized care and outcomes. METHODS: Retrospective clinical chart review of a series of patients diagnosed with CLN2 disease from 2005 to 2015 at a single center in Italy. Clinical, MRI, and EEG findings were reviewed. RESULTS: A total of 14 patients were included. For the whole group, median (range) age at disease onset was 3.0 (2.0-3.8) years. Epilepsy was the most commonly reported presenting symptom (in 50% [seven of 14] of patients), occurring at the age of 3.2 (2.6-3.8) years. First seizure was myoclonic in 36% (five of 14) of patients, followed by generalized tonic-clonic in 29% (4 of 14), atonic in 22% (three of 14), and focal with motor signs in 14% (two of 14). All patients walked independently at the age of 12.0 (11.0-18.0) months, but delayed speech or regression of acquired verbal skills was present in 100% of patients at 3 years. EEGs revealed a photoparoxysmal response (PPR) on intermittent photic stimulation in 93% (13 of 14) of patients. PPR was present from the first EEG, which was performed at 3.6 (3.1-4.0) years, in 43% (six of 14) of patients; it was documented at low (1-3 Hz) stimulation frequencies in 69% (nine of 13) and took the form of a flash-per-flash response in 69% (nine of 13). First brain MRI at the age of 3.8 (3.0-5.1) years revealed cerebellar atrophy in 100% (14 of 14) of patients and alteration of the periventricular white matter signal in the posterior hemispheric region in 79% (11 of 14). SIGNIFICANCE: Early photosensitivity (typically PPR at low stimulation frequencies of 1-3 Hz) is a hallmark of CLN2 disease. This diagnosis should be considered in a child presenting with any type of seizure, and particularly if it is accompanied by delayed speech and/or ataxia or MRI abnormalities (posterior white matter signal alteration or cerebellar atrophy).

Characterisation of CASPR2 deficiency disorder--a syndrome involving autism, epilepsy and language impairment.

BACKGROUND: Heterozygous mutations in CNTNAP2 have been identified in patients with a range of complex phenotypes including intellectual disability, autism and schizophrenia. However heterozygous CNTNAP2 mutations are also found in the normal population. Conversely, homozygous mutations are rare in patient populations and have not been found in any unaffected individuals. CASE PRESENTATION: We describe a consanguineous family carrying a deletion in CNTNAP2 predicted to abolish function of its protein product, CASPR2. Homozygous family members display epilepsy, facial dysmorphisms, severe intellectual disability and impaired language. We compared these patients with previously reported individuals carrying homozygous mutations in CNTNAP2 and identified a highly recognisable phenotype. CONCLUSIONS: We propose that CASPR2 loss produces a syndrome involving early-onset refractory epilepsy, intellectual disability, language impairment and autistic features that can be recognized as CASPR2 deficiency disorder. Further screening for homozygous patients meeting these criteria, together with detailed phenotypic and molecular investigations will be crucial for understanding the contribution of CNTNAP2 to normal and disrupted development.

Mutation of CHRNA2 in a family with benign familial infantile seizures: Potential role of nicotinic acetylcholine receptor in various phenotypes of epilepsy.

Nicotinic acetylcholine receptor genes are involved mainly in nocturnal frontal epilepsy. Despite extensive studies, to date, the α2 subunit did not show a strong association with this peculiar epileptic phenotype. We report CHRNA2 missense mutation in a family with benign familial infantile seizures (BFIS). TrueSeq Custom Amplicon (TSCA) sequencing approach was used to screen 10 ion channel genes in patients with idiopathic epilepsies. TSCA revealed a heterozygous single-nucleotide substitution in CHRNA2 gene (c.1126 C>T; p. Arg376Trp) that segregated in a family with BFIS; based on bio-informatics inspection, the change was predicted to be pathogenic. The investigated family includes parents and their three daughters. In affected individuals, seizures started between 6 and 24 months of age. Seizures were mainly in cluster and well-controlled. Outcome was good in all subjects. Even if nicotinic acetylcholine receptor genes are traditionally associated with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), this single-family description can open new possibilities in the genetic diagnosis, molecular characterization, and management of CHRNA2-related epilepsy. The pathogenic conversion of arginine 376 to tryptophan alters all of these interactions in the cytoplasmic domain, never reported to be involved in epileptogenic mechanism. Further functional tests will be necessary to strongly relate CHRNA2 mutation with BFIS phenotype.

Genetic and forensic implications in epilepsy and cardiac arrhythmias: a case series.

Epilepsy affects approximately 3% of the world's population, and sudden death is a significant cause of death in this population. Sudden unexpected death in epilepsy (SUDEP) accounts for up to 17% of all these cases, which increases the rate of sudden death by 24-fold as compared to the general population. The underlying mechanisms are still not elucidated, but recent studies suggest the possibility that a common genetic channelopathy might contribute to both epilepsy and cardiac disease to increase the incidence of death via a lethal cardiac arrhythmia. We performed genetic testing in a large cohort of individuals with epilepsy and cardiac conduction disorders in order to identify genetic mutations that could play a role in the mechanism of sudden death. Putative pathogenic disease-causing mutations in genes encoding cardiac ion channel were detected in 24% of unrelated individuals with epilepsy. Segregation analysis through genetic screening of the available family members and functional studies are crucial tasks to understand and to prove the possible pathogenicity of the variant, but in our cohort, only two families were available. Despite further research should be performed to clarify the mechanism of coexistence of both clinical conditions, genetic analysis, applied also in post-mortem setting, could be very useful to identify genetic factors that predispose epileptic patients to sudden death, helping to prevent sudden death in patients with epilepsy.

Ictal vomiting as a sign of temporal lobe epilepsy confirmed by stereo-EEG and surgical outcome.

Vomiting is uncommon in patients with epilepsy and has been reported in both idiopathic and symptomatic epilepsies. It is presumed to originate in the anterior part of the temporal lobe or insula. To date, 44 cases of nonidiopathic focal epilepsy and seizures associated with ictal vomiting have been reported. Of the 44 cases, eight were studied using invasive exploration (3 stereo-EEG/5 subdural grids). Here, we report a 4-year-and-7-month-old patient with a history of febrile convulsion in the second year of life and who developed episodes of vomiting and complex partial seizures at 3 years of age. Scalp EEG showed no electrical modification during vomiting while the complex partial seizure displayed a clear right temporal origin. Brain MR showed hippocampal volume reduction with mild diffuse blurring of the temporal lobe. Stereoelectroencephalography study confirmed the mesiotemporal origin of the seizures and showed that the episodes of vomiting were strictly related to an ictal discharge originating in the mesial temporal structures without insular diffusion. The patient is now seizure-free (18 months) after removal of the right anterior and mesial temporal structures. In all the reported patients, seizures seemed to start in mesial temporal structures. The grid subgroup is more homogeneous, and the most prominent characteristic (4/5) is the involvement of both mesial and lateral temporal structures at the time of vomiting. In the S-EEG group, there is evidence of involvement of either the anterior temporal structures alone (2/3) or both insular cortices (1/3). Our case confirms that vomiting could occur when the ictal discharge is limited to the anterior temporal structure without insular involvement. Regarding the pathophysiology of vomiting, the role of subcortical structures such as the dorsal vagal complex and the central pattern generators (CPG) located in the reticular area is well established. Vomiting as an epileptic phenomenon seems to be related to the involvement of temporal structures, mainly mesial structures (amygdala) and with an uncertain role of the insula. An intriguing hypothesis is that the ictal discharge in mesial structures determines seizure manifestation that could be explained not only by tonic activation of the cortex, but also by 'release' (reduction of inhibition?) of the CPG responsible for involuntary motor behaviors.