Ictal Electroencephalographic Characteristics of Nodding Syndrome: A Comparative Case-Series from South Sudan, Tanzania, and Uganda.

Nodding syndrome (NS) is a poorly understood form of childhood-onset epilepsy that is characterized by the pathognomonic ictal phenomenon of repetitive vertical head drops. To evaluate the underlying ictal neurophysiology, ictal EEG features were evaluated in nine participants with confirmed NS from South Sudan, Tanzania, and Uganda and ictal presence of high frequency gamma oscillations on scalp EEG were assessed. Ictal EEG during the head nodding episode predominantly showed generalized slow waves or sharp-and-slow wave complexes followed by electrodecrement. Augmentation of gamma activity (30-70 Hz) was seen during the head nodding episode in all the participants. We confirm that head nodding episodes in persons with NS from the three geographically distinct regions in sub-Saharan Africa share the common features of slow waves with electrodecrement and superimposed gamma activity. ANN NEUROL 2022;92:75-80.

Adaptive behaviour in adolescents and adults with Dravet syndrome.

AIM: To explore the feasibility of using an adaptive behaviour profile (ABP) assessment generated from a well-known measure-the Vineland Adaptive Behavior Scales, Second Edition (VABS-II)-as an instrument for outcome measures in adolescents and adults with Dravet syndrome. METHOD: We administered the VABS-II to 35 adolescents and adults with Dravet syndrome (15 males; mean age 24 years, SD 8 years, range: 12-46 years) and collected epilepsy history and neurological features at the time of assessment. We conducted a cross-sectional analysis of VABS-II raw scores and performed cluster analysis to identify different subgroups. We then explored possible relationships between clinical and epilepsy features, ABPs, and age. RESULTS: Most participants obtained the minimum standard scores in the various VABS-II subdomains, while the raw score analysis outlined interindividual and intraindividual differences among skills. We found two subpopulations: one with a 'lower' ABP and one with a 'higher' ABP, corresponding respectively to individuals in whom myoclonic seizures or generalized spike-and-wave activity were present ('complete phenotype') or absent ('incomplete phenotype') on electroencephalography. INTERPRETATION: This study further delineates the natural history of Dravet syndrome. The assessment of an ABP through the VABS-II raw score analysis provides a means by which to illustrate profiles of adaptive behaviour in adolescents and adults with Dravet syndrome but shows limitations related to poor sensitivity in measuring fine clinical details. There is a need for new and more specific tools to monitor patients with developmental and epileptic encephalopathies. WHAT THIS PAPER ADDS: Most adults with Dravet syndrome obtained the minimum standard scores in the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) subdomains. The VABS-II raw score analysis showed interindividual and intraindividual variability. Individuals with myoclonic seizures and/or generalized spike-and-wave activity on electroencephalography showed a worse adaptive behaviour profile.

PRRT2 benign familial infantile seizures (BFIS) with atypical evolution to encephalopathy related to status epilepticus during sleep (ESES).

PURPOSE: Heterozygous variants in PRRT2 are mostly associated with benign phenotypes, being the major genetic cause of benign familial infantile seizures (BFIS), as well as in paroxysmal disorders. We report two children from unrelated families with BFIS that evolved to encephalopathy related to status epilepticus during sleep (ESES). METHODS AND RESULTS: Two probands presented with focal motor seizures at 3 months of age, with a limited course. Both children presented, at around 5 years of age, with centro-temporal interictal epileptiform discharges with a source in the frontal operculum, markedly activated by sleep, and associated with stagnation on neuropsychological development. Whole-exome sequencing and co-segregation analysis revealed a frameshift mutation c.649dupC in the proline-rich transmembrane protein 2 (PRRT2) in both probands and all affected family members. CONCLUSION: The mechanism leading to epilepsy and the phenotypic variability of PRRT2 variants remain poorly understood. However, its wide cortical and subcortical expression, in particular in the thalamus, could partially explain both the focal EEG pattern and the evolution to ESES. No variants in the PRRT2 gene have been previously reported in patients with ESES. Due to the rarity of this phenotype, other possible causative cofactors are likely contributing to the more severe course of BFIS in our probands.

Epilepsy and movement disorders in CDG: Report on the oldest-known MOGS-CDG patient.

Congenital glycosylation disorders (CDG) are inherited metabolic diseases due to defective glycoprotein and glycolipid glycan assembly and attachment. MOGS-CDG is a rare disorder with seven patients from five families reported worldwide. We report on a 19-year-old girl with MOGS-CDG. At birth she presented facial dysmorphism, marked hypotonia, and drug-resistant tonic seizures. In the following months, her motility was strongly limited by dystonia, with forced posture of the head and of both hands. She showed a peculiar hyperkinetic movement disorder with a rhythmic and repetitive pattern repeatedly documented on EEG-polygraphy recordings. Brain MRI showed progressive cortical and subcortical atrophy. Epileptic spasms appeared in first months and ceased by the age of 7 years, while tonic seizures were still present at last assessment (19 years). We report the oldest-known MOGS-CDG patient and broaden the neurological phenotype of this CDG.

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.

Dravet syndrome: Early electroclinical findings and long-term outcome in adolescents and adults.

To describe the outcome of Dravet syndrome (DS) in adolescents and adults we conducted a longitudinal retrospective study of two independent cohorts of 34 adolescents (group 1) and 50 adults (group 2). In both cohorts, we collected information about genetic mutation, and semiology of seizures at onset and during disease course. At the last evaluation, we considered the following features: epilepsy (distinguishing myoclonic/complete and nonmyoclonic/incomplete phenotype), neurologic signs, intellectual disability (ID), and behavioral disorders. Moreover, in both cohorts, we performed a correlation analysis between early characteristics of the disease and the outcome of DS with regard to seizure persistence, ID, behavioral disorder, and neurologic impairment at last evaluation. Group 1 includes 22 adolescents with complete form of DS and 12 with incomplete form; group 2 includes 35 adults with complete form and 15 with incomplete form. The seizures persisted in 73.6% of adolescents and in 80% of adults, but epilepsy severity progressively decreased through age. Seizure persistence correlated with the complete phenotype and with the occurrence of reflex seizures. At last evaluation, ID was moderate or severe in 70.5% of adolescents and in 80% of adults. The most severe cognitive and motor impairment was observed in patients with persisting seizures. The severity of cognition, language, and neurologic impairment at last evaluation correlated statistically with the complete phenotype. The study confirms that the global outcome of DS is poor in most cases, albeit epilepsy severity decreases throughout adulthood. The improvement of epilepsy throughout ages is not associated with improvement in intellectual abilities and motor skills; this confirms that the unfavorable outcome is not a pure consequence of epilepsy.

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.

Symptomatic and presumed symptomatic focal epilepsies in childhood: An observational, prospective multicentre study.

OBJECTIVE: To describe the clinical, neuropsychological, and psychopathologic features of a cohort of children with a new diagnosis of symptomatic or presumed symptomatic focal epilepsy at time of recruitment and through the first month. The selected population will be followed for 2-5 years after enrollment to investigate the epilepsy course and identify early predictors of drug resistance. METHODS: In this observational, multicenter, nationwide study, children (age 1 month-12.9 years) with a new diagnosis of symptomatic or presumed symptomatic focal epilepsy were consecutively enrolled in 15 Italian tertiary childhood epilepsy centers. Inclusion criteria were as follows: (1) diagnosis of symptomatic focal epilepsy due to acquired and developmental etiologies, and presumed symptomatic focal epilepsy; (2) age at diagnosis older than 1 month and <13 years; and (3) written informed consent. Children were subdivided into three groups: ≤3 years, >3 to 6 years, and >6 years. Clinical, electroencephalography (EEG), neuroimaging, and neuropsychological variables were identified for statistical analyses. RESULTS: Two hundred fifty-nine children were enrolled (116 female and 143 male). Median age: 4.4 years (range 1 month-12.9 years); 46.0% (n = 119) of children were younger than 3 years, 24% (61) from 3 to 6 years of age, and 30% (79) older than 6 years. Neurologic examination findings were normal in 71.8%. Brain magnetic resonance imaging (MRI) was abnormal in 59.9%. Children age ≤3 years experienced the highest seizure frequency in the first month after recruitment (p < 0.0001). Monotherapy in the first month was used in 67.2%. Cognitive tests at baseline revealed abnormal scores in 30%; behavioral problems were present in 21%. At multivariate analysis, higher chances to exhibit more than five seizures in the first month after epilepsy onset was confirmed for younger children and those with temporal lobe epilepsy. SIGNIFICANCE: In this prospective cohort study, an extensive characterization of epilepsy onset in children with symptomatic or presumed symptomatic focal epilepsies is reported in relation to the age group and the localization of the epileptogenic zone.

Optimizing the molecular diagnosis of CDKL5 gene-related epileptic encephalopathy in boys.

OBJECTIVE: Mutations involving the cyclin-dependent kinase-like 5 (CDKL5) gene cause an early onset epileptic encephalopathy (EE) with severe neurologic impairment and a skewed 12:1 female-to-male ratio. To date, 18 mutations have been described in boys. We analyzed our cohort of boys with early onset EE to assess the diagnostic yield of our molecular approach. METHODS: We studied 74 boys who presented early onset severe seizures, including infantile spasms and developmental delay, in the setting of EE, using Sanger sequencing, next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA). RESULTS: We identified alterations involving CDKL5 in four boys (5.4%) using NGS in one and MLPA in three. Three of four mutations were indicative of somatic mosaicism. SIGNIFICANCE: CDKL5 gene mutations accounted for 5.4% of boys with early onset EE. Somatic mosaic mutations might be even more represented than germline mutations, probably because their less deleterious effect enhances viability of the male embryo. The molecular approach used for CDKL5 screening remarkably influences the diagnostic yield in boys. Diagnosis is optimized by Sanger sequencing combined with array-based methods or MLPA; alternatively, NGS targeted resequencing designed to also detect copy number alterations, may be performed.

Epilepsy-related brain networks in ring chromosome 20 syndrome: an EEG-fMRI study.

OBJECTIVE: To identify the brain networks that are involved in the different electroencephalography (EEG) abnormalities in patients with ring chromosome 20 [r(20)] syndrome. We hypothesize the existence of both distinctive and common brain circuits for the paroxysmal high voltage sharp waves (hSWs), the seizures, and the slow-wave 3-7 Hz rhythm that characterize this condition. METHODS: Thirteen patients with [r(20)] syndrome were studied by means of EEG simultaneously recorded with functional magnetic resonance imaging (EEG-fMRI). EEG traces were reviewed in order to detect the pathologic interictal (hSWs) and ictal activities; the 3-7 Hz theta-delta power was derived using a fast Fourier transform. A group-level analysis was performed for each type of EEG abnormality separately using a fixed-effect model and a conjunction analysis. Finally, a second-level random-effect model was applied considering together the different EEG abnormalities, without distinction between hSW, seizures, or theta-delta rhythms. RESULTS: Subcontinuous theta-delta rhythm was recorded in seven patients, seizures in two, and hSWs in three patients. The main results are the following: (1) the slow-wave rhythm was related to blood oxygen level-dependent (BOLD) increases in the premotor, sensory-motor, and temporoparietal cortex, and to BOLD decrements involving the default mode (DMN) and the dorsal attention networks (DANs); (2) the ictal-related BOLD changes showed an early involvement of the prefrontal lobe; (3) increases in BOLD signal over the basal ganglia, either for interictal and ictal activities, were observed; (4) a common pattern of positive BOLD changes in the bilateral perisylvian regions was found across the different EEG abnormalities. SIGNIFICANCE: The BOLD increment in the perisylvian network and the decrease of the DMN and DAN could be the expression of the [r(20)] syndrome-related cognitive and behavioral deficits. The observed BOLD patterns are similar to the ones detected in other epileptic encephalopathies, suggesting that different epileptic disorders characterized by neurobehavioral regression are associated with dysfunction in similar brain networks. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Molecular mechanisms generating and stabilizing terminal 22q13 deletions in 44 subjects with Phelan/McDermid syndrome.

In this study, we used deletions at 22q13, which represent a substantial source of human pathology (Phelan/McDermid syndrome), as a model for investigating the molecular mechanisms of terminal deletions that are currently poorly understood. We characterized at the molecular level the genomic rearrangement in 44 unrelated patients with 22q13 monosomy resulting from simple terminal deletions (72%), ring chromosomes (14%), and unbalanced translocations (7%). We also discovered interstitial deletions between 17-74 kb in 9% of the patients. Haploinsufficiency of the SHANK3 gene, confirmed in all rearrangements, is very likely the cause of the major neurological features associated with PMS. SHANK3 mutations can also result in language and/or social interaction disabilities. We determined the breakpoint junctions in 29 cases, providing a realistic snapshot of the variety of mechanisms driving non-recurrent deletion and repair at chromosome ends. De novo telomere synthesis and telomere capture are used to repair terminal deletions; non-homologous end-joining or microhomology-mediated break-induced replication is probably involved in ring 22 formation and translocations; non-homologous end-joining and fork stalling and template switching prevail in cases with interstitial 22q13.3. For the first time, we also demonstrated that distinct stabilizing events of the same terminal deletion can occur in different early embryonic cells, proving that terminal deletions can be repaired by multistep healing events and supporting the recent hypothesis that rare pathogenic germline rearrangements may have mitotic origin. Finally, the progressive clinical deterioration observed throughout the longitudinal medical history of three subjects over forty years supports the hypothesis of a role for SHANK3 haploinsufficiency in neurological deterioration, in addition to its involvement in the neurobehavioral phenotype of PMS.

Clinical dissection of early onset absence epilepsy in children and prognostic implications.

PURPOSE: To investigate whether patients with typical absence seizures (TAS) starting in the first 3 years of life, conformed to Panayiotopoulos's definition of childhood absence epilepsy (CAE), show different electroclinical course than those not fulfilling CAE criteria. METHODS: In this multicenter retrospective study, we choose a fixed duration follow-up of 36 months to examine the electroclinical course of epilepsy in all children with TAS starting before 3 years of age. The probands who fulfilled Panayiotopoulos's criteria for CAE were classified as having pure early onset absence epilepsy (P-EOAE), whereas those who did not as nonpure EOAE (NP-EOAE). In addition, these two groups of patients were further stratified according to the number of antiepileptic drugs taken to obtain initial seizure control (mono-, bi-, and tritherapy). KEY FINDINGS: Patients with P-EOAE (n = 111) showed earlier initial seizure control (p = 0.030) and better seizure-free survival curve (p = 0.004) than those with NP-EOAE (n = 77). No mutation in SLC2A1 gene or abnormal neuroimaging was observed in P-EOAE. Among patients with NP-EOAE, those receiving tritherapy showed increased risk of structural brain abnormalities (p = 0.001) or SLC2A1 mutations (p = 0.001) but fewer myoclonic features (p = 0.031) and worse seizure-free survival curve (p = 0.047) than those treated with mono- and bitherapy. Children with NP-EOAE had 2.134 the odds of having relapse during the follow-up compare to those with P-EOAE. SIGNIFICANCE: Children with early onset TAS who did meet Panayiotopoulos's criteria showed a favorable course of epilepsy, whereas patients not fulfilling Panayiotopoulos's criteria showed increased risk of relapse at long-term follow-up.

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.

PRRT2 mutations are the major cause of benign familial infantile seizures.

Mutations in PRRT2 have been described in paroxysmal kinesigenic dyskinesia (PKD) and infantile convulsions with choreoathetosis (PKD with infantile seizures), and recently also in some families with benign familial infantile seizures (BFIS) alone. We analyzed PRRT2 in 49 families and three sporadic cases with BFIS only of Italian, German, Turkish, and Japanese origin and identified the previously described mutation c.649dupC in an unstable series of nine cytosines to occur in 39 of our families and one sporadic case (77% of index cases). Furthermore, three novel mutations were found in three other families, whereas 17% of our index cases did not show PRRT2 mutations, including a large family with late-onset BFIS and febrile seizures. Our study further establishes PRRT2 as the major gene for BFIS alone.

Complex segmental duplications mediate a recurrent dup(X)(p11.22-p11.23) associated with mental retardation, speech delay, and EEG anomalies in males and females.

Submicroscopic copy-number variations make a considerable contribution to the genetic etiology of human disease. We have analyzed subjects with idiopathic mental retardation (MR) by using whole-genome oligonucleotide-based array comparative genomic hybridization (aCGH) and identified familial and de novo recurrent Xp11.22-p11.23 duplications in males and females with MR, speech delay, and a peculiar electroencephalographic (EEG) pattern in childhood. The size of the duplications ranges from 0.8-9.2 Mb. Most affected females show preferential activation of the duplicated X chromosome. Carriers of the smallest duplication show X-linked recessive inheritance. All other affected individuals present dominant expression and comparable clinical phenotypes irrespective of sex, duplication size, and X-inactivation pattern. The majority of the rearrangements are mediated by recombination between flanking complex segmental duplications. The identification of common clinical features, including the typical EEG pattern, predisposing genomic structure, and peculiar X-inactivation pattern, suggests that duplication of Xp11.22-p11.23 constitutes a previously undescribed syndrome.

Focal seizures with affective symptoms are a major feature of PCDH19 gene-related epilepsy.

PURPOSE: Mutations of the protocadherin19 gene (PCDH19) cause a female-related epilepsy of variable severity, with or without mental retardation and autistic features. Despite the increasing number of patients and mutations reported, the epilepsy phenotype associated with PCDH19 mutations is still unclear. We analyzed seizure semiology through ictal video-electroencephalography (EEG) recordings in a large series of patients. METHODS: We studied 35 patients with PCDH19 gene-related epilepsy and analyzed clinical history and ictal video-EEG recordings obtained in 34 of them. KEY FINDINGS: Clusters of focal febrile and afebrile seizures had occurred in 34 patients, at a mean age of 10 months. The predominant and more consistent ictal sign was fearful screaming, occurring in 24 patients (70.5%); it was present since epilepsy onset in 12 and appeared later on, during the course in the remaining 12 patients. In infancy, fearful screaming mainly appeared within the context of seizures with prominent hypomotor semiology, whereas during follow-up it was associated with prominent early motor manifestations. In 16 patients, seizures were video-EEG recorded both at onset and during follow-up: in five patients (31%) seizure semiology remained identical, in 7 (44%) semiology varied and in four patients it was unclear whether ictal semiology changed with age. Three patients (9%) had both focal and generalized seizures, the latter consisting of absences and myoclonus. Ictal EEG during focal seizures showed a prominent involvement of the frontotemporal regions (22 patients). About 45% of patients had an alternating EEG pattern, with the ictal discharge migrating from one hemisphere to the contralateral during the same ictal event. Status epilepticus occurred in 30% of patients. Cognitive impairment occurred in 70%, ranging from mild (42%) to moderate (54%) and severe (4%); autistic features occurred in 28.5%. Direct sequencing detected 33 different heterozygous candidate mutations, 8 of which were novel. Mutations were missense substitutions (48.5%), premature termination (10 frameshift, 4 nonsense, and 2 splice-site mutations; 48.5%), and one in-frame deletion. Thirty candidate mutations (91%) were de novo. No specific genotype-phenotype correlation could be established, as missense and truncating mutations were associated with phenotypes of comparable severity. SIGNIFICANCE: Most patients with PCDH19 mutations exhibit a distinctive electroclinical pattern of focal seizures with affective symptoms, suggesting an epileptogenic dysfunction involving the frontotemporal limbic system. Awareness of this distinctive phenotype will likely enhance recognition of this disorder.

Individually tailored extratemporal epilepsy surgery in children: anatomo-electro-clinical features and outcome predictors in a population of 53 cases.

Surgery for refractory extratemporal lobe epilepsy (ETLE) in the pediatric age group has been reported to be associated with a high percentage of failure and relapse. We performed a retrospective study of 53 consecutive patients with epilepsy onset before 12 years of age, who underwent, mostly at a pediatric age, an individually tailored ETLE surgery (32 in frontal and 21 in posterior cerebral areas) for pharmacoresistant seizures; these patients were selected and followed by a single national tertiary care pediatric center. Mean age at seizure onset was 3.14 years, and mean age at surgery was 11.23 years. Complete seizure freedom was achieved in 75% of the subjects. Short duration of illness before surgery, MRI features, no invasive pre-surgical evaluation, a localized interictal and ictal pattern as well as the presence of ictal fast activity on scalp EEG, localized interictal fast rhythms and absence of a diffuse initial ictal modification during SEEG, a complete resection of the epileptogenic zone, a type II FCD, and the absence of acute postoperative seizures correlated in a statistically significant way with a seizure-free outcome. We conclude that the seizure outcome of ETLE surgery in a carefully selected pediatric population can be excellent.

Natural History Study of STXBP1-Developmental and Epileptic Encephalopathy Into Adulthood.

BACKGROUND AND OBJECTIVES: Pathogenic STXBP1 variants cause a severe early-onset developmental and epileptic encephalopathy (STXBP1-DEE). We aimed to investigate the natural history of STXBP1-DEE in adults focusing on seizure evolution, the presence of movement disorders, and the level of functional (in)dependence. METHODS: In this observational study, patients with a minimum age of 18 years carrying a (likely) pathogenic STXBP1 variant were recruited through medical genetics departments and epilepsy centers. Treating clinicians completed clinical questionnaires and performed semistructured video examinations while performing tasks from the (modified) Unified Parkinson Disease Rating Scale when possible. RESULTS: Thirty adult patients were included for summary statistics, with video recordings available for 19 patients. The median age at last follow-up was 24 years (range 18-58 years). All patients had epilepsy, with a median onset age of 3.5 months. At last follow-up, 80% of adults had treatment-resistant seizures despite long periods of seizure freedom in 37%. Tonic-clonic, focal, and tonic seizures were most frequent in adults. Epileptic spasms, an unusual feature beyond infancy, were present in 3 adults. All individuals had developmental impairment. Periods of regression were present in 59% and did not always correlate with flare-ups in seizure activity. Eighty-seven percent had severe or profound intellectual disability, 42% had autistic features, and 65% had significant behavioral problems. Video examinations showed gait disorders in all 12 patients able to walk, including postural abnormalities with external rotation of the feet, broad-based gait, and asymmetric posture/dystonia. Tremor, present in 56%, was predominantly of the intention/action type. Stereotypies were seen in 63%. Functional outcome concerning mobility was variable ranging from independent walking (50%) to wheelchair dependence (39%). Seventy-one percent of adults were nonverbal, and all were dependent on caregivers for most activities of daily living. DISCUSSION: STXBP1-DEE warrants continuous monitoring for seizures in adult life. Periods of regression are more frequent than previously established and can occur into adulthood. Movement disorders are often present and involve multiple systems. Although functional mobility is variable in adulthood, STXBP1-DEE frequently leads to severe cognitive impairments and a high level of functional dependence. Understanding the natural history of STXBP1-DEE is important for prognostication and will inform future therapeutic trials.

Electroencephalographic characteristics of Dravet syndrome.

In Dravet syndrome, interictal and ictal electroencephalography (EEG) recording may remain misleading, and are not specifically altered. Moreover, there is a great polymorphism of clinical and EEG seizure types. Some can be observed in other epileptic syndromes, but others are more specific--particularly the peculiar unilateral seizures, the falsely generalized seizures, probably with a focal onset, and the unstable seizures. In some cases, the ictal manifestations are characterized by the persistent predominant recurrence of convulsive seizures, often induced by body temperature increase, eventually associated with partial complex seizures. The myoclonic events, absences with myoclonic component, obtundation status, and photosensitivity and/or pattern sensitivity are absent or appear relatively late and recur transiently for short periods. In these cases interictal EEG is characterized by the persistent paucity of paroxysmal discharges. In other cases, on a background of convulsive seizures and body temperature sensitivity, one may find a variable association of (1) myoclonic seizures of different types, (2) a strong sensitivity to light and pattern stimulations, with early onset and persistent in time. In these cases, interictal paroxysms and spontaneous and induced (intermittent photic stimulation, patterns, and eye closure) stimulation tend to appear early and to be frequent and persistent during the evolution. According to these electroclinical patterns it is possible to divide the population into two subsets, both sharing common genetic mechanisms but with a different clinical outcome.