Biochemical, structural, and computational analyses of two new clinically identified missense mutations of ALDH7A1.

Aldehyde dehydrogenase 7A1 (ALDH7A1) catalyzes a step of lysine catabolism. Certain missense mutations in the ALDH7A1 gene cause pyridoxine dependent epilepsy (PDE), a rare autosomal neurometabolic disorder with recessive inheritance that affects almost 1:65,000 live births and is classically characterized by recurrent seizures from the neonatal period. We report a biochemical, structural, and computational study of two novel ALDH7A1 missense mutations that were identified in a child with rare recurrent seizures from the third month of life. The mutations affect two residues in the oligomer interfaces of ALDH7A1, Arg134 and Arg441 (Arg162 and Arg469 in the HGVS nomenclature). The corresponding enzyme variants R134S and R441C (p.Arg162Ser and p.Arg469Cys in the HGVS nomenclature) were expressed in Escherichia coli and purified. R134S and R441C have 10,000- and 50-fold lower catalytic efficiency than wild-type ALDH7A1, respectively. Sedimentation velocity analytical ultracentrifugation shows that R134S is defective in tetramerization, remaining locked in a dimeric state even in the presence of the tetramer-inducing coenzyme NAD+. Because the tetramer is the active form of ALDH7A1, the defect in oligomerization explains the very low catalytic activity of R134S. In contrast, R441C exhibits wild-type oligomerization behavior, and the 2.0 Å resolution crystal structure of R441C complexed with NAD+ revealed no obvious structural perturbations when compared to the wild-type enzyme structure. Molecular dynamics simulations suggest that the mutation of Arg441 to Cys may increase intersubunit ion pairs and alter the dynamics of the active site gate. Our biochemical, structural, and computational data on two novel clinical variants of ALDH7A1 add to the complexity of the molecular determinants underlying pyridoxine dependent epilepsy.

Molecular and Phenotypic Characterization of the RORB-Related Disorder.

BACKGROUND AND OBJECTIVES: Heterozygous variants in RAR-related orphan receptor B (RORB) have recently been associated with susceptibility to idiopathic generalized epilepsy. However, few reports have been published so far describing pathogenic variants of this gene in patients with epilepsy and intellectual disability (ID). In this study, we aimed to delineate the epilepsy phenotype associated with RORB pathogenic variants and to provide arguments in favor of the pathogenicity of variants. METHODS: Through an international collaboration, we analyzed seizure characteristics, EEG data, and genotypes of a cohort of patients with heterozygous variants in RORB. To gain insight into disease mechanisms, we performed ex vivo cortical electroporation in mouse embryos of 5 selected variants, 2 truncating and 3 missense, and evaluated on expression and quantified changes in axonal morphology. RESULTS: We identified 35 patients (17 male, median age 10 years, range 2.5-23 years) carrying 32 different heterozygous variants in RORB, including 28 single-nucleotide variants or small insertions/deletions (12 missense, 12 frameshift or nonsense, 2 splice-site variants, and 2 in-frame deletions), and 4 microdeletions; de novo in 18 patients and inherited in 10. Seizures were reported in 31/35 (89%) patients, with a median age at onset of 3 years (range 4 months-12 years). Absence seizures occurred in 25 patients with epilepsy (81%). Nineteen patients experienced a single seizure type: absences, myoclonic absences, or absences with eyelid myoclonia and focal seizures. Nine patients had absence seizures combined with other generalized seizure types. One patient had presented with absences associated with photosensitive occipital seizures. Three other patients had generalized tonic-clonic seizures without absences. ID of variable degree was observed in 85% of the patients. Expression studies in cultured neurons showed shorter axons for the 5 tested variants, both truncating and missense variants, supporting an impaired protein function. DISCUSSION: In most patients, the phenotype of the RORB-related disorder associates absence seizures with mild-to-moderate ID. In silico and in vitro evaluation of the variants in our cohort, including axonal morphogenetic experiments in cultured neurons, supports their pathogenicity, showing a hypomorphic effect.

A registry for Dravet syndrome: The Italian experience.

OBJECTIVES: We describe the Residras registry, dedicated to Dravet syndrome (DS) and to other phenotypes related to SCN1A mutations, as a paradigm of registry for rare and complex epilepsies. Our primary objectives are to present the tools and framework of the integrative platform, the main characteristics emerging from the patient cohort included in the registry, with emphasis on demographic, clinical outcome, and mortality. METHODS: Standardized data of enrolled pediatric and adult patients were collected in 24 Italian expert centers and regularly updated at least on a yearly basis. Patients were prospectively enrolled, at registry starting, but historical retrospective data were also included. RESULTS: At present, 281 individuals with DS and a confirmed SCN1A mutation are included. Most patients have data available on epilepsy (n = 263) and their overall neurological condition (n = 255), based on at least one follow-up update. Median age at first clinical assessment was 2 years (IQR 0-9) while at last follow-up was 11 years (IQR 5-18.5). During the 7-year activity of the registry, five patients died resulting in a mortality rate of 1.84 per 1000-person-years. When analyzing clinical changes over the first 5-year follow-up, we observed a significant difference in cognitive function (P < 0.001), an increased prevalence of behavioral disorders including attention deficit (P < 0.001), a significant worsening of language (P = 0.001), and intellectual disability (P < 0.001). SIGNIFICANCE: The Residras registry represents a large collection of standardized national data for the DS population. The registry platform relies on a shareable and interoperable framework, which promotes multicenter high-quality data collection. In the future, such integrated platform may represent an invaluable asset for easing access to cohorts of patients that may benefit from clinical trials with emerging novel therapies, for drug safety monitoring, and for delineating natural history. Its framework makes it improvable based on growing experience with its use and easily adaptable to other rare and complex epilepsy syndromes.

Long-term effectiveness of add-on perampanel in patients with Lennox-Gastaut syndrome: A multicenter retrospective study.

This retrospective study assessed long-term effectiveness of add-on perampanel (PER) in patients with Lennox-Gastaut syndrome (LGS). Outcomes included time to PER failure and time to seizure relapse in responders. PER failure was defined as either discontinuation of PER or initiation of another treatment. Seizure relapse in responders was defined as occurrence of a seizure in seizure-free patients and increase of at least 50% in average monthly seizure frequency for those who were responders. Eighty-seven patients were included. Treatment failure occurred in 52 (59.8%) subjects at a median time of 12 months. Treatment failure was due to lack of efficacy in 27 (52.0%) patients, lack of tolerability in 14 (27.0%), and both reasons in 11 (21.0%). A slower titration was associated with a lower risk of PER failure compared to faster titration schedules, and the occurrence of adverse events increased the risk of treatment failure. Thirty-six patients (41.4%) were responders during a median follow-up of 11 months. Seizure relapse occurred in 13 of 36 (36.1%) patients after a median time of 21 months. The overall rate of seizure responders was 23 of 87 (26.4%) at the end of follow-up. This study provides real-world evidence on the effectiveness of PER as adjunctive treatment in LGS patients.

Gain of function SCN1A disease-causing variants: Expanding the phenotypic spectrum and functional studies guiding the choice of effective antiseizure medication.

OBJECTIVE: This study was undertaken to refine the spectrum of SCN1A epileptic disorders other than Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS+) and optimize antiseizure management by correlating phenotype-genotype relationship and functional consequences of SCN1A variants in a cohort of patients. METHODS: Sixteen probands carrying SCN1A pathogenic variants were ascertained via a national collaborative network. We also performed a literature review including individuals with SCN1A variants causing non-DS and non-GEFS+ phenotypes and compared the features of the two cohorts. Whole cell patch clamp experiments were performed for three representative SCN1A pathogenic variants. RESULTS: Nine of the 16 probands (56%) had de novo pathogenic variants causing developmental and epileptic encephalopathy (DEE) with seizure onset at a median age of 2 months and severe intellectual disability. Seven of the 16 probands (54%), five with inherited and two with de novo variants, manifested focal epilepsies with mild or no intellectual disability. Sodium channel blockers never worsened seizures, and 50% of patients experienced long periods of seizure freedom. We found 13 SCN1A missense variants; eight of them were novel and never reported. Functional studies of three representative variants showed a gain of channel function. The literature review led to the identification of 44 individuals with SCN1A variants and non-DS, non-GEFS+ phenotypes. The comparison with our cohort highlighted that DEE phenotypes are a common feature. SIGNIFICANCE: The boundaries of SCN1A disorders are wide and still expanding. In our cohort, >50% of patients manifested focal epilepsies, which are thus a frequent feature of SCN1A pathogenic variants beyond DS and GEFS+. SCN1A testing should therefore be included in the diagnostic workup of pediatric, familial and nonfamilial, focal epilepsies. Alternatively, non-DS/non-GEFS+ phenotypes might be associated with gain of channel function, and sodium channel blockers could control seizures by counteracting excessive channel function. Functional analysis evaluating the consequences of pathogenic SCN1A variants is thus relevant to tailor the appropriate antiseizure medication.

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.

KETASER01 protocol: What went right and what went wrong.

OBJECTIVE: To discuss the results of the KETASER01 trial and the reasons for its failure, particularly in view of future studies. METHODS: KETASER01 is a multicenter, randomized, controlled, open-label, sequentially designed, non-profit Italian study that aimed to assess the efficacy of ketamine compared with conventional anesthetics in the treatment of refractory convulsive status epilepticus (RCSE) in children. RESULTS: During the 5-year recruitment phase, a total of 76 RCSEs treated with third-line therapy were observed in five of the 10 participating Centers; only 10 individuals (five for each study arm; five females, mean age 6.5 ± 6.3 years) were enrolled in the KETASER01 study. Two of the five patients (40%) in the experimental arm were successfully treated with ketamine and two of the five (40%) children in the control arm, where successfully treated with thiopental. In the remaining six (60%) enrolled patients, RCSE was not controlled by the randomized anesthetic(s). SIGNIFICANCE: The KETASER01 study was prematurely halted due to low eligibility of patients and no successful recruitment. No conclusions can be drawn regarding the objectives of the study. Here, we discuss the KETASER01 results and critically analyze the reasons for its failure in view of future trials.

Epilepsy Course and Developmental Trajectories in STXBP1-DEE.

Background and Objectives: Clinical manifestations in STXBP1 developmental and epileptic encephalopathy (DEE) vary in severity and outcome, and the genotypic spectrum is diverse. We aim to trace the neurodevelopmental trajectories in individuals with STXBP1-DEE and dissect the relationship between neurodevelopment and epilepsy. Methods: Retrospective standardized clinical data were collected through international collaboration. A composite neurodevelopmental score system compared the developmental trajectories in STXBP1-DEE. Results: Forty-eight patients with de novo STXBP1 variants and a history of epilepsy were included (age range at the time of the study: 10 months to 35 years, mean 8.5 years). At the time of inclusion, 65% of individuals (31/48) had active epilepsy, whereas 35% (17/48) were seizure free, and 76% of those (13/17) achieved remission within the first year of life. Twenty-two individuals (46%) showed signs of developmental impairment and/or neurologic abnormalities before epilepsy onset. Age at seizure onset correlated with severity of developmental outcome and the developmental milestones achieved, with a later seizure onset associated with better developmental outcome. In contrast, age at seizure remission and epilepsy duration did not affect neurodevelopmental outcomes. Overall, we did not observe a clear genotype-phenotype correlation, but monozygotic twins with de novo STXBP1 variant showed similar phenotype and parallel disease course. Discussion: The disease course in STXBP1-DEE presents with 2 main trajectories, with either early seizure remission or drug-resistant epilepsy, and a range of neurodevelopmental outcomes from mild to profound intellectual disability. Age at seizure onset is the only epilepsy-related feature associated with neurodevelopment outcome. These findings can inform future dedicated natural history studies and trial design.

First reported case of an inherited PACS2 pathogenic variant with variable expression

Neonatal epilepsy, cerebellar dysgenesis and facial dysmorphisms may be associated with de novo PACS2 missense pathogenic variants (EIEE 66) (OMIM #618067). Here, we report a toddler boy with neonatal-onset seizures, developmental delay with hypotonia, facial dysmorphisms and prominence of the cisterna magna, mild inferior vermian and cerebellar hypoplasia. A nextgeneration epilepsy gene panel revealed a known pathogenic PACS2 missense variant, p.Glu209Lys, that was inherited from his mildly affected mother. We describe the first PACS2 pathogenic variant to be inherited, expanding the clinical spectrum, associated with a mild phenotype in the mother and a more severe phenotype in her son, in keeping with previously reported descriptions.

Pediatric Moyamoya Disease and Syndrome in Italy: A Multicenter Cohort.

Background: Moyamoya is a rare progressive cerebral arteriopathy, occurring as an isolated phenomenon (moyamoya disease, MMD) or associated with other conditions (moyamoya syndrome, MMS), responsible for 6-10% of all childhood strokes and transient ischemic attacks (TIAs). Methods: We conducted a retrospective multicenter study on pediatric-onset MMD/MMS in Italy in order to characterize disease presentation, course, management, neuroradiology, and outcome in a European country. Results: A total of 65 patients (34/65 women) with MMD (27/65) or MMS (38/65) were included. About 18% (12/65) of patients were asymptomatic and diagnosed incidentally during investigations performed for an underlying condition (incMMS), whereas 82% (53/65) of patients with MMD or MMS were diagnosed due to the presence of neurological symptoms (symptMMD/MMS). Of these latter, before diagnosis, 66% (43/65) of patients suffered from cerebrovascular events with or without other manifestations (ischemic stroke 42%, 27/65; TIA 32%, 21/65; and no hemorrhagic strokes), 18% (12/65) of them reported headache (in 4/12 headache was not associated with any other manifestation), and 26% (17/65) of them experienced multiple phenotypes (≥2 among: stroke/TIA/seizures/headache/others). Neuroradiology disclosed ≥1 ischemic lesion in 67% (39/58) of patients and posterior circulation involvement in 51% (30/58) of them. About 73% (47/64) of patients underwent surgery, and 69% (45/65) of them received aspirin, but after diagnosis, further stroke events occurred in 20% (12/61) of them, including operated patients (11%, 5/47). Between symptom onset and last follow-up, the overall patient/year incidence of stroke was 10.26% (IC 95% 7.58-13.88%). At last follow-up (median 4 years after diagnosis, range 0.5-15), 43% (26/61) of patients had motor deficits, 31% (19/61) of them had intellectual disability, 13% (8/61) of them had epilepsy, 11% (7/61) of them had behavioral problems, and 25% (13/52) of them had mRS > 2. The proportion of final mRS > 2 was significantly higher in patients with symptMMD/MMS than in patients with incMMS (p = 0.021). Onset age <4 years and stroke before diagnosis were significantly associated with increased risk of intellectual disability (p = 0.0010 and p = 0.0071, respectively) and mRS > 2 at follow-up (p = 0.0106 and p = 0.0009, respectively). Conclusions: Moyamoya is a severe condition that may affect young children and frequently cause cerebrovascular events throughout the disease course, but may also manifest with multiple and non-cerebrovascular clinical phenotypes including headache (isolated or associated with other manifestations), seizures, and movement disorder. Younger onset age and stroke before diagnosis may associate with increased risk of worse outcome (final mRS > 2).

Epilepsy, electroclinical features, and long-term outcomes in Pitt-Hopkins syndrome due to pathogenic variants in the TCF4 gene.

BACKGROUND AND PURPOSE: Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder caused by deletions/variants in the TCF4 gene. Seizures may be present in up to half of the patients, leading to a more severe disease burden. This study aims to analyse the electroclinical phenotype, treatment options, and long-term outcomes of epilepsy in PTHS. METHODS: A multicentre observational cohort study was performed, and the electroclinical data of PTHS individuals affected by epileptic seizures were retrospectively reviewed and analysed. RESULTS: The series includes 21 patients (11 female) with a median age at seizure onset of 2 years (range = 0.5-8). The median time of follow-up was 7.9 years (range = 2-27). Both generalized and focal epilepsies were present at the same prevalence (42.8%), whereas a minority of patients presented developmental and epileptic encephalopathies (14.4%). At the long-term follow-up, 42.8% achieved seizure freedom, whereas 42.8% developed drug-resistant epilepsy (DRE). The age at seizure onset was found to be an independent predictor for seizure outcome; in this regard, patients having seizure onset after the age of 2 years were more prone to achieve seizure freedom (odds ratio = 0.04, 95% confidence interval = 0.003-0.53; p = 0.01). During evolution, seizures tended to settle down, and even in patients with DRE, seizures tended to persist at a lower frequency and appeared to be more easily manageable over time. CONCLUSIONS: This study provides new insight into the natural history of epilepsy in PTHS. Better characterization of epileptic phenotype and prompt tailored treatment improve overall management and quality of life.

Epilepsy in "Sunflower syndrome": electroclinical features, therapeutic response, and long-term follow-up.

BACKGROUND: Sunflower syndrome (SFS) is a rare childhood-onset generalized epilepsy characterized by photosensitivity, heliotropism, and drug-resistant stereotyped seizures maybe self-induced by hand-waving maneuvers. Data on the long-term prognosis are scantly and evidence over best treatment strategies is lacking. METHODS: We retrospectively describe the electroclinical features, and therapeutic response in a group of 21 patients with SFS, without intellectual disability. RESULTS: 16 patients were female (67%), with a median age at onset of 7 years. In all patients, ictal episodes began with sun-staring, and hand-waving in front of the sunlight, accompanied by brief typical absence seizures. 17 patients (81%) showed interictal EEG abnormalities, mainly characterized by spike and polyspike-and-wave discharges. Ictal epileptiform activity occurred approximately less than one second after the start of hand-waving. At the last follow-up (median length 8.2 years), 12 patients (57%) were drug-resistant. Nine of them (75%) achieved seizure control with the use of tainted lenses, either alone or compared with anti-seizure medications (ASM). Disappearance of seizures was associated with EEG improvement/normalization when tinted glasses were used during EEG recordings. CONCLUSION: While the clinical and EEG characteristics of SFS are well defined, the best therapeutic approaches are still under debate. Our data confirms a high rate of drug-resistance and frequent need of polytherapy. Of note, in drug-resistant patients, lenses (but not ASM) were able to suppress PPR in our patients while wearing lenses. Regarding the role of lenses, we do not only rely on the PPR reduction but also clinically by the reduction of seizures. Although additional data are needed, lenses seem to have a powerful potential role for the management of SFS.

Results From an Italian Expanded Access Program on Cannabidiol Treatment in Highly Refractory Dravet Syndrome and Lennox-Gastaut Syndrome.

Background: Purified cannabidiol (CBD) was administered to highly refractory patients with Dravet (DS) or Lennox-Gastaut (LGS) syndromes in an ongoing expanded access program (EAP). Herein, we report interim results on CBD safety and seizure outcomes in patients treated for a 12-month period. Material and Methods: Thirty centers were enrolled from December 2018 to December 2019 within the open-label prospective EAP up to a maximum of 25 mg/kg per day. Adverse effects and liver function tests were assessed after 2 weeks; 1, 3, and 6 months of treatment; and periodically thereafter. Seizure endpoints were the percentage of patients with ≥50 and 100% reduction in seizures compared to baseline. Results: A total of 93 patients were enrolled and included in the safety analysis. Eighty-two patients [27 (32.9%) DS, 55 (67.1%) LGS] with at least 3 months of treatment have been included in the effectiveness analysis; median previously failed antiseizure medications was eight. Pediatric and adult patients were uniformly represented in the cohort. At 3-month follow-up, compared to the 28-day baseline period, the percentage of patients with at least a 50% reduction in seizure frequency was 40.2% (plus 1.2% seizure-free). Retention rate was similar according to diagnosis, while we found an increased number of patients remaining under treatment in the adult group. CBD was mostly coadministered with valproic acid (62.2%) and clobazam (41.5%). In the safety dataset, 29 (31.2%) dropped out: reasons were lack of efficacy [16 (17.2%)] and adverse events (AEs) [12 (12.9%)], and one met withdrawal criteria (1.1%). Most reported AEs were somnolence (22.6%) and diarrhea (11.9%), followed by transaminase elevation and loss of appetite. Conclusions: CBD is associated with improved seizure control also in a considerable proportion of highly refractory patients with DS and LGS independently from clobazam use. Overall, CBD safety and effectiveness are not dose-related in this cohort.

Perampanel effectiveness and tolerability in patients with epilepsy at long-term follow-up.

INTRODUCTION: The main of the present study was to assess the effectiveness and tolerability of perampanel (PER) in association with 1 or 2 concomitant antiseizure medications (ASMs) in patients with epilepsy throughout a follow-up period of 24 months or longer in a real-world setting. METHODS: This retrospective, observational, multi-center study collected data from both underage (<18 years old) and adult patients who had started PER in association with 1 or 2 ASMs. Only patients who had started PER and were followed up for at least 24 months were included. Response to treatment was analyzed at the 24-, 36-, and 48-month visits by considering the last visit undergone by patients. Subgroup analyses were performed according to age, gender, and epilepsy type and patients were categorized following PER treatment in concomitance with 1 or 2 ASMs to evaluate the factors affecting the achievement of seizure freedom (SF) at the 24-month FU. RESULTS: Ninety-four patients were included (mean age 36.89 years; 51.1% female). At the 24-month follow-up visit, 90 (95.74%) patients were still receiving PER concomitantly with 1 or 2 ASMs. The mean PER dose was 6.02 mg/day and SF was achieved by 33 (35.1%) patients. A significantly higher SF rate was found in patients who had started PER with only 1 ASM when compared to those who had started PER with 2 concomitant ASMs. Effectiveness was maintained also in the subgroups of patients with a 36- or 48-month follow-up visit. Adult patients had a higher final daily dosage of PER than underage patients. Logistic regression found that the lowest number of previously failed ASMs was associated with a higher SF rate (p = 0.036). CONCLUSION: Perampanel demonstrated a good effectiveness in association with 1 or 2 ASMs in both pediatric and adult patients, without having to use a high dose of the drug. The possibility to present SF was higher when PER was added early. Finally, the maintenance of effectiveness was observed also in the subgroups of patients with a follow-up of 36 and 48 months.

Temporal lobe epilepsy surgery in children and adults: A multicenter study.

OBJECTIVE: To assess seizure and cognitive outcomes and their predictors in children (<16 years at surgery) and adults undergoing temporal lobe epilepsy (TLE) surgery in eight Italian centers. METHODS: This is a retrospective multicenter study. We performed a descriptive analysis and subsequently carried out multivariable mixed-effect models corrected for multiple comparisons. RESULTS: We analyzed data from 511 patients (114 children) and observed significant differences in several clinical features between adults and children. The possibility of achieving Engel class IA outcome and discontinuing antiepileptic drugs (AEDs) at last follow-up (FU) was significantly higher in children (P = .006 and < .0001). However, percentages of children and adults in Engel class I at last FU (mean ± SD, 45.9 ± 17 months in children; 45.9 ± 20.6 months in adults) did not differ significantly. We identified different predictors of seizure outcome in children vs adults and at short- vs long-term FU. The only variables consistently associated with class I outcome over time were postoperative electroencephalography (EEG) in adults (abnormal, improved,odds ratio [OR] = 0.414, P = .023, Q = 0.046 vs normal, at 2-year FU and abnormal, improved, OR = 0.301, P = .001, Q = 0.002 vs normal, at last FU) and the completeness of resection of temporal magnetic resonance (MR) abnormalities other than hippocampal sclerosis in children (OR = 7.93, P = .001, Q = 0.003, at 2-year FU and OR = 45.03, P < .0001, Q < 0.0001, at last FU). Cognitive outcome was best predicted by preoperative performances in either age group. SIGNIFICANCE: Clinical differences between adult and pediatric patients undergoing TLE surgery are reflected in differences in long-term outcomes and predictors of failures. Children are more likely to achieve sustained seizure freedom and withdraw AEDs after TLE surgery. Earlier referral should be encouraged as it can improve surgical outcome.

Health Technology Assessment Report on Vagus Nerve Stimulation in Drug-Resistant Epilepsy.

Background: Vagus nerve stimulation (VNS) is a palliative treatment for medical intractable epileptic syndromes not eligible for resective surgery. Health technology assessment (HTA) represents a modern approach to the analysis of technologies used for healthcare. The purpose of this study is to assess the clinical, organizational, financial, and economic impact of VNS therapy in drug-resistant epilepsies and to establish the congruity between costs incurred and health service reimbursement. Methods: The present study used an HTA approach. It is based on an extensive detailed bibliographic search on databases (Medline, Pubmed, Embase and Cochrane, sites of scientific societies and institutional sites). The HTA study includes the following issues: (a) social impact and costs of the disease; (b) VNS eligibility and clinical results; (c) quality of life (QoL) after VNS therapy; (d) economic impact and productivity regained after VNS; and (e) costs of VNS. Results: Literature data indicate VNS as an effective treatment with a potential positive impact on social aspects and on quality of life. The diagnosis-related group (DRG) financing, both on national and regional levels, does not cover the cost of the medical device. There was an evident insufficient coverage of the DRG compared to the full cost of implanting the device. Conclusions: VNS is a palliative treatment for reducing seizure frequency and intensity. Despite its economic cost, VNS should improve patients' quality of life and reduce care needs.

d-Glycerate kinase deficiency in a neuropediatric patient.

d-Glyceric aciduria (DGA) due to d-glycerate kinase deficiency (DGKD) is a rare autosomal-recessive inborn error of metabolism that is usually linked to the metabolism of fructose and serine. We describe a Moroccan patient with DGKD whose metabolic defect has been characterized by metabolite studies, sequencing of genomic DNA and by studies on the RNA level. Since birth the index patient presented with severe muscular hypotonia, joint hypermobility and tremor. Enantioselective analysis showed elevated d-glyceric acid in the urine of the patient, but not in that of his parents. DNA analysis revealed homozygosity in the GLYCTK gene for c.517G>T [p.(Val173Leu)], the first mutation reported for exon 3 of this gene, as well as for the c.530-4A>G polymorphism. RNA studies suggest that none of these sequence variants affects splicing. The mother was heterozygous for both sequence variants, the father heterozygous for the first one and homozygous for the polymorphism, which further supports that c.517G>T is the functionally relevant nucleotide change. The conservation of GLYCTK throughout evolution suggests an important biological role of this enzyme, although it is not known yet how mutations are linked to clinical features. Future studies should investigate the molecular defect in a more general way and search for additional roles of GLYCTK beyond its established role in catabolism of serine and fructose.

Trends in pediatric epilepsy surgery in Europe between 2008 and 2015: Country-, center-, and age-specific variation.

OBJECTIVE: To profile European trends in pediatric epilepsy surgery (<16 years of age) between 2008 and 2015. METHODS: We collected information on volumes and types of surgery, pathology, and seizure outcome from 20 recognized epilepsy surgery reference centers in 10 European countries. RESULTS: We analyzed retrospective aggregate data on 1859 operations. The proportion of surgeries significantly increased over time (P < .0001). Engel class I outcome was achieved in 69.3% of children, with no significant improvement between 2008 and 2015. The proportion of histopathological findings consistent with glial scars significantly increased between the ages of 7 and 16 years (P for trend = .0033), whereas that of the remaining pathologies did not vary across ages. A significant increase in unilobar extratemporal surgeries (P for trend = .0047) and a significant decrease in unilobar temporal surgeries (P for trend = .0030) were observed between 2008 and 2015. Conversely, the proportion of multilobar surgeries and unrevealing magnetic resonance imaging cases remained unchanged. Invasive investigations significantly increased, especially stereo-electroencephalography. We found different trends comparing centers starting their activity in the 1990s to those whose programs were developed in the past decade. Multivariate analysis revealed a significant variability of the proportion of the different pathologies and surgical approaches across countries, centers, and age groups between 2008 and 2015. SIGNIFICANCE: Between 2008 and 2015, we observed a significant increase in the volume of pediatric epilepsy surgeries, stability in the proportion of Engel class I outcomes, and a modest increment in complexity of the procedures.

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.