Electroclinical Features in Two Novel STRADA Patients and a Functional Yeast Assay for the Validation of Missense STRADA Mutations.

Loss of function of the STRADA gene, an upstream mTOR inhibitor, causes a rare neurodevelopmental disorder characterized by polyhydramnios, megalencephaly, and symptomatic epilepsy (PMSE syndrome). Patients display a homogeneous phenotype including early-onset drug-resistant epilepsy, severe psychomotor delay, multisystemic comorbidities, and increased risk of premature death. The administration of sirolimus, an mTOR inhibitor, is helpful in controlling seizures in this syndrome. We report the electroclinical phenotype of two novel patients and the development of a yeast model to validate the pathogenicity of missense variants. Patient 1 harbored a missense STRADA variant and had a peculiar electroclinical phenotype with a relatively mild epilepsy course. Patient 2 harbored a truncating STRADA variant and showed a typical PMSE phenotype and a favorable response to early treatment with sirolimus. When we modeled the p.(Ser264Arg) STRADA change in its yeast homolog SPS1, it impaired SPS1 function. The results underlie the importance of a timely molecular diagnosis in these patients and show that yeast is a simple yet effective model to validate the pathogenicity of missense variants.

Myoclonic super-refractory status epilepticus with favourable evolution in a teenager with FIRES: Is the association of vagus nerve stimulation and cannabidiol effective?

BACKGROUND: Febrile infection-related epilepsy syndrome (FIRES) is a rare and catastrophic clinical syndrome occurring in previously healthy patients. Aetiology is still unknown and outcome usually poor. We describe a case of myoclonic prolonged super refractory status epilepticus (P-SRSE) in FIRES in a patient admitted to the paediatric intensive care unit of Padova, Italy. CASE REPORT: A previously healthy 14-year-old girl with onset of myoclonic status epilepticus after a mild febrile illness was admitted to our hospital with a diagnosis of FIRES. Extensive diagnostic work-up was inconclusive. Status epilepticus and electroclinical seizures recurred every time weaning from anaesthetic agents was attempted. Eventually, a vagal nerve stimulator (VNS) was implanted and cannabidiol (CBD) administered, 43 days and 70 days after P-SRSE onset, respectively. Two days after CBD introduction, status epilepticus weaned and the girl rapidly regained complete consciousness showing a brilliant and unexpected recovery. At last follow-up, 12 months later, she is 8-months seizure free on multiple antiseizure medications, has only mild neuropsychological impairment with no neurological and intellective deficit. CONCLUSIONS: To our knowledge, this represents a unique case with an extremely favourable evolution with a possible effect of the association of VNS and CBD to traditional antiseizure medications.

Clinical and Neurophysiologic Phenotypes in Neonates With BRAT1 Encephalopathy.

BACKGROUND AND OBJECTIVES: BRAT1 encephalopathy is an ultra-rare autosomal recessive neonatal encephalopathy. We delineate the neonatal electroclinical phenotype at presentation and provide insights for early diagnosis. METHODS: Through a multinational collaborative, we studied a cohort of neonates with encephalopathy associated with biallelic pathogenic variants in BRAT1 for whom detailed clinical, neurophysiologic, and neuroimaging information was available from the onset of symptoms. Neuropathologic changes were also analyzed. RESULTS: We included 19 neonates. Most neonates were born at term (16/19) from nonconsanguineous parents. 15/19 (79%) were admitted soon after birth to a neonatal intensive care unit, exhibiting multifocal myoclonus, both spontaneous and exacerbated by stimulation. 7/19 (37%) had arthrogryposis at birth, and all except 1 progressively developed hypertonia in the first week of life. Multifocal myoclonus, which was present in all but 1 infant, was the most prominent manifestation and did not show any EEG correlate in 16/19 (84%). Video-EEG at onset was unremarkable in 14/19 (74%) infants, and 6 (33%) had initially been misdiagnosed with hyperekplexia. Multifocal seizures were observed at a median age of 14 days (range: 1-29). During the first months of life, all infants developed progressive encephalopathy, acquired microcephaly, prolonged bouts of apnea, and bradycardia, leading to cardiac arrest and death at a median age of 3.5 months (range: 20 days to 30 months). Only 7 infants (37%) received a definite diagnosis before death, at a median age of 34 days (range: 25-126), and almost two-thirds (12/19, 63%) were diagnosed 8 days to 12 years postmortem (median: 6.5 years). Neuropathology examination, performed in 3 patients, revealed severely delayed myelination and diffuse astrogliosis, sparing the upper cortical layers. DISCUSSION: BRAT1 encephalopathy is a neonatal-onset, rapidly progressive neurologic disorder. Neonates are often misdiagnosed as having hyperekplexia, and many die undiagnosed. The key phenotypic features are multifocal myoclonus, an organized EEG, progressive, persistent, and diffuse hypertonia, and an evolution into refractory multifocal seizures, prolonged bouts of apnea, bradycardia, and early death. Early recognition of BRAT1 encephalopathy allows for prompt workup, appropriate management, and genetic counseling.

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.

Executive Functions and Attention in Childhood Epilepsies: A Neuropsychological Hallmark of Dysfunction?

OBJECTIVE: Patients with epilepsy are at risk for several lifetime problems, in which neuropsychological impairments may represent an impacting factor. We evaluated the neuropsychological functions in children suffering from three main epilepsy categories. Further, we analyzed the longitudinal evolution of the neuropsychological profile over time. METHODS: Patients undergoing neuropsychological evaluation at our Department from 2012 to 2018 were identified retrospectively. We selected patients aged 6-16 years and with at least two evaluations. Three epilepsy categories were considered: focal/structural, focal self-limited, and idiopathic generalized. Each evaluation included the same structured assessment of main neuropsychological domains. The effect of the epilepsy category, illness duration, seizure status, and medication was computed in multilevel models. RESULTS: We identified 103 patients (focal self-limited = 27; focal/structural = 51; and idiopathic generalized = 25), for 233 evaluations. The majority of deficits were reported in attention and executive functions (>30% of patients); the results were dichotomized to obtain global indexes. Multilevel models showed a trend toward statistical significance of category of epilepsy on the global executive index and of illness duration on global attention index. Illness duration predicted the scores of executive and attention tasks, while category and medication predicted executive task performance. Focal/structural epilepsies mostly affected the executive domain, with deficits persisting over time. By contrast, an ameliorative effect of illness duration for attention was documented in all epilepsies. CONCLUSIONS: This study offers lacking information about the evolution of deficits in time, the role of epilepsy category, and possible psychological implications for high-order cognitive skills, central in several social and academic problems.

Dexmedetomidine for EEG sedation in children with behavioral disorders.

OBJECTIVE: To evaluate the efficacy and safety of sedation with dexmedetomidine, a highly selective α2-agonist with sedative effect, for EEG recording in children with behavioral disorders. MATERIAL AND METHODS: Prospective observational study on children with behavioral disorders undergoing EEG at the Pediatric Hospital in Padova, Italy. A 2 mcg/kg intravenous bolus of dexmedetomidine was administered, followed by a 1-2 mcg/kg/h infusion. If necessary, bolus was repeated up to 3 times to reach the target level of sedation, assessed by Pediatric Sedation State Scale. Patients were fully monitored before, during and after the procedure until complete recovery. EEG recording quality, and caregivers' satisfaction were collected. Any adverse effect was registered using SIVA score. RESULTS: For this preliminary study, 19 patients were enrolled. EEG was successfully completed in all of them. Mean total dose of dexmedetomidine was 3.7 ± 1.7 mcg/kg. Adequate sedation was achieved within 11.9 ± 8 minutes. Mean time to first awakening was 30.9 ± 36.9 minutes and time to complete recovery 113.3 ± 92.7 minutes. Adverse effects (hypotension, bradycardia) were reported in 10 patients, all classified as "minor." EEG recording quality was good or excellent. Parents' satisfaction was high in all the interviewed families. CONCLUSIONS: Intravenous dexmedetomidine as a single drug showed an excellent efficacy and good safety profile for EEG recording in children with behavioral disorders.

Cardiac Myxoma as a Rare Cause of Pediatric Arterial Ischemic Stroke: Case Report and Literature Review.

BACKGROUND: Cardiac disorders are the second leading cause of pediatric arterial ischemic stroke (AIS). Limited literature is available on pediatric AIS caused by cardiac myxoma, a rare tumor in childhood. METHODS: We describe a new case of pediatric AIS due to a previously unknown atrial myxoma and we conduct a literature review on children with AIS due to cardiac myxoma. RESULTS: We identified 41 published pediatric cases of AIS and cardiac myxoma, including ours (56% males, median age at AIS was 11 years [range: 3-18]). AIS presentation was most frequently with hemiparesis/hemiplegia (89%). Multiple brain ischemic lesions were detected in 69% of patients, and arteriopathy in 91%. Seven patients underwent mechanical thrombectomy. At AIS presentation, 73% of children had one or more of the following clinical symptoms/signs suggesting a possible underlying cardiac myxoma: Carney's complex, cardiac auscultation abnormalities, extraneurological symptoms/signs, such as skin signs (12, 38, and 65%, respectively). Cardiac myxoma was diagnosed within 72 hours in 68% of cases. Death occurred in 11%, and 40% had persistent neurological deficits. CONCLUSION: Neurological presentation of AIS due to cardiac myxoma is similar to that of AIS with other etiologies, although clues suggesting a possible underlying cardiac myxoma can be detected in most cases. A timely diagnosis of cardiac myxoma in patients with AIS may favor prompt identification of candidates for endovascular therapy. Therefore, we suggest that in otherwise-healthy children presenting with AIS, transthoracic echocardiography should be performed early after stroke presentation.

A Novel WAC Loss of Function Mutation in an Individual Presenting with Encephalopathy Related to Status Epilepticus during Sleep (ESES).

WAC (WW Domain Containing Adaptor With Coiled-Coil) mutations have been reported in only 20 individuals presenting a neurodevelopmental disorder characterized by intellectual disability, neonatal hypotonia, behavioral problems, and mildly dysmorphic features. Using targeted deep sequencing, we screened a cohort of 630 individuals with variable degrees of intellectual disability and identified five WAC rare variants: two variants were inherited from healthy parents; two previously reported de novo mutations, c.1661_1664del (p.Ser554*) and c.374C>A (p.Ser125*); and a novel c.381+2T>C variant causing the skipping of exon 4 of the gene, inherited from a reportedly asymptomatic father with somatic mosaicism. A phenotypic evaluation of this individual evidenced areas of cognitive and behavioral deficits. The patient carrying the novel splicing mutation had a clinical history of encephalopathy related to status epilepticus during slow sleep (ESES), recently reported in another WAC individual. This first report of a WAC somatic mosaic remarks the contribution of mosaicism in the etiology of neurodevelopmental and neuropsychiatric disorders. We summarized the clinical data of reported individuals with WAC pathogenic mutations, which together with our findings, allowed for the expansion of the phenotypic spectrum of WAC-related disorders.

Identification of SETBP1 Mutations by Gene Panel Sequencing in Individuals With Intellectual Disability or With "Developmental and Epileptic Encephalopathy".

SETBP1 mutations are associated with the Schinzel-Giedion syndrome (SGS), characterized by profound neurodevelopmental delay, typical facial features, and multiple congenital malformations (OMIM 269150). Refractory epilepsy is a common feature of SGS. Loss of function mutations have been typically associated with a distinct and milder phenotype characterized by intellectual disability and expressive speech impairment. Here we report three variants of SETBP1, two novel de novo truncating mutations, identified by NGS analysis of an Intellectual Disability gene panel in 600 subjects with non-specific neurodevelopmental disorders, and one missense identified by a developmental epilepsy gene panel tested in 56 pediatric epileptic cases. The three individuals carrying the identified SETBP1 variants presented mild to severe developmental delay and lacked the cardinal features of classical SGS. One of these subjects, carrying the c.1765C>T (p.Arg589*) mutation, had mild Intellectual Disability with speech delay; the second one carrying the c.2199_2203del (p.Glu734Alafs19*) mutation had generalized epilepsy, responsive to treatment, and moderate Intellectual Disability; the third patient showed a severe cognitive defects and had a history of drug resistant epilepsy with West syndrome evolved into a Lennox-Gastaut syndrome. This latter subject carries the missense c.2572G>A (p.Glu858Lys) variant, which is absent from the control population, reported as de novo in a subject with ASD, and located close to the SETBP1 hot spot for SGS-associated mutations. Our findings contribute to further characterizing the associated phenotypes and suggest inclusion of SETBP1 in the list of prioritized genes for the genetic diagnosis of overlapping phenotypes ranging from non-specific neurodevelopmental disorders to "developmental and epileptic encephalopathy" (DEE).

Prognostic role of Mini-Mental State Pediatric Examination (MMSPE) on neuropsychological functioning.

OBJECTIVE: The aim of this study was to evaluate the ability of the Mini-Mental State Pediatric Examinations (MMSPE) in the individuation of neuropsychological impairments. METHOD: MMSPE was administered to 60 children attending a primary or lower secondary school suffering from neurological diseases, admitted to our neuropsychology services. All children performed both a MMSPE examination and a neuropsychological evaluation. Results of neuropsychological evaluation and MMSPE were dichotomized. Positive predictive value (PPV), negative predictive value (NPV), and accuracy were also calculated. RESULTS: The diagnostic performance of MMSPE showed a good overall accuracy (0.83, CI 95% 0.64-0.91), NPV (0.81, CI 95% 0.73-1.00), PPV (0.87, CI 95% 0.68-0.94), specificity (0.91, CI 95% 0.81-1.00), sensitivity (0.74, CI 95% 0.57-0.90), and odds ratio of 28.5 (CI 95% 6.6-123), p < 0.001. CONCLUSIONS: MMSPE has a good prognostic ability in predicting neuropsychological problems in the context of different neurological pediatric diseases. We suggest that this instrument could greatly improve pediatric clinical practice in identifying high-risk children.

Time perception in childhood absence epilepsy: Findings from a pilot study.

OBJECTIVES: With this explorative study, we aimed to examine time perception in children with childhood absence epilepsy (CAE) and to compare those children with a matched control group. The study also investigated the association between the neuropsychological performance of the group with CAE and time judgment. We hypothesize that children with CAE could fail in time perception and that this may be because of a common underlying substrate with executive impairments. METHODS: Thirteen children with CAE, aged 6-13 years, and 17 healthy children were recruited. All children performed the time bisection task; the children with CAE also performed a cognitive and neuropsychological assessment. We performed a univariate analysis using each parameter of the bisection task (bisection point [BP]) and Weber ratio (WR) as dependent variables, the group (patients vs. controls) as fixed factors and age at evaluation and vocabulary scores as covariates. In the subgroup of patients, we correlated bisection task parameters with neuropsychological tests using a nonparametric partial correlation; the analysis has corrected for age at evaluation. RESULTS: The BP and WR measures differed between controls and patients with CAE. In the subgroup of patients also performing a neuropsychological assessment, we found a correlation between the WR measure and performance on the inhibition test (r = -0.641, p = .025), coding test (r = -0.815, p = .014), and Trail Making Test B (TMT B) (r = 0.72, p = .042). CONCLUSIONS: We found an altered time perception in a pilot study of a small group of children with CAE. A neurophysiological mechanism underlying CAE seems to influence cognitive and behavioral deficits and time sensibility.

First-ever convulsive seizures in children presenting to the emergency department: risk factors for seizure recurrence and diagnosis of epilepsy.

AIM: Aetiologies of first-ever convulsive seizures may be diverse, not all leading to recurrence or epilepsy diagnosis. We aimed to describe the epidemiology of first-ever convulsive seizures in children, investigating risk factors for recurrence and epilepsy diagnosis. METHOD: This was a retrospective study of children presenting with a first-ever convulsive seizure to a tertiary-care paediatric emergency department (PED) in Italy, in a 12-month period (2011-2012). RESULTS: One hundred and eight children (57 males, 51 females) presented to the PED for a first-ever convulsive seizure; 90.7% were 6 months to 6 years old (median age 1y 10mo, mean 2y 7mo, range 0mo-14y 4mo). Seizure duration was less than 5 minutes in 76.8%. Seizures were 'unprovoked' in 19.4% and 'provoked' in 80.6%. At 4-year follow-up, 37.9% of patients experienced recurrence and 13.6% received a diagnosis of epilepsy. Factors significantly associated with recurrence were the 'unprovoked' nature of the first seizure, multiple seizures in the first 24 hours, positive family history of febrile seizures or epilepsy, and pre-existing neurological conditions/problems. Factors significantly associated with a diagnosis of epilepsy were the 'unprovoked' nature of the first seizure, age older than 6 years, pre-existing neurological conditions/problems, and focal onset of first seizure. INTERPRETATION: Children presenting to the PED with first-ever convulsive seizures represent a heterogeneous group. The identification of prognostic factors for recurrence and epilepsy diagnosis may help provide tailored counselling and follow-up. WHAT THIS PAPER ADDS: Seizures were 'unprovoked' in 19.4% and 'provoked' in 80.6% of children presenting to the emergency department. At 4-year follow-up, 37.9% relapsed, and 13.6% received a diagnosis of epilepsy. 'Unprovoked' first seizure, family history of febrile seizures, and pre-existing neurological conditions were associated with recurrence. 'Unprovoked' first seizure, age younger than 6 years, and pre-existing neurological conditions were associated with epilepsy diagnosis.

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.

Mutations in MICAL-1cause autosomal-dominant lateral temporal epilepsy.

OBJECTIVE: Autosomal-dominant lateral temporal epilepsy (ADLTE) is a genetic focal epilepsy characterized by auditory symptoms. Two genes, LGI1 and RELN, encoding secreted proteins, are implicated in the etiology of ADLTE, but half of the affected families remain genetically unsolved, and the underlying molecular mechanisms are yet to be clarified. We aimed to identify additional genes causing ADLTE to better understand the genetic basis and molecular pathway underlying this epileptic disorder. METHODS: A cohort of Italian ADLTE families was examined by whole exome sequencing combined with genome-wide single-nucleotide polymorphism-array linkage analysis. RESULTS: We identified two ADLTE-causing variants in the MICAL-1 gene: a p.Gly150Ser substitution occurring in the enzymatically active monooxygenase (MO) domain and a p.Ala1065fs frameshift indel in the C-terminal domain, which inhibits the oxidoreductase activity of the MO domain. Each variant segregated with ADLTE in a single family. Examination of candidate variants in additional genes excluded their implication in ADLTE. In cell-based assays, both variants significantly increased MICAL-1 oxidoreductase activity and induced cell contraction in COS7 cells, which likely resulted from deregulation of F-actin dynamics. INTERPRETATION: MICAL-1 oxidoreductase activity induces disassembly of actin filaments, thereby regulating the organization of the actin cytoskeleton in developing and adult neurons and in other cell types. This suggests that dysregulation of the actin cytoskeleton dynamics is a likely mechanism by which MICAL-1 pathogenic variants lead to ADLTE. Ann Neurol 2018;83:483-493.

Pediatric epilepsy and psychiatric comorbidity: preliminary observational data from a prospective study.

BACKGROUND: Several studies have confirmed psychiatric comorbidity and a worse quality of life in children with epilepsy, but the clinical assessment and monitoring of these patients often pays insufficient attention to their psychological aspects alongside their neurological issues. The present study aims to describe the distribution of psychopathologies and their clinical evolution over 18 months in a sample of children followed up since the onset of their epilepsy. METHODS: After being diagnosed with epilepsy, 49 subjects (age 4-18 y) were followed up with psychiatric and psychological assessments based on the use of dimensional and categorical psychometric tools. RESULTS: Baseline data (T0) showed a high psychiatric comorbidity in epileptic children, with a prevalence of anxious-depressive disorders and attention deficit hyperactivity disorder (ADHD). Specifically, generalized epilepsy, antiepileptic drug intake and more frequent seizures were associated with externalizing problems, while focal epilepsy was linked with anxiety disorders. The follow-up at 18 months revealed that about 90% of patients had achieved a reduction in the frequency and duration of their seizures, but their psychopathological assessment remained virtually unchanged. The patients' psychological issues had warranted psychotherapy in 43% of cases. CONCLUSIONS: When children or adolescents are diagnosed with epilepsy, their psychopathological profile should be investigated and monitored over time. Psychotherapy and/or psychopharmacological treatments should be offered to pediatric patients with epilepsy who suffer from emotional-behavioral disorders.

Psychopathology, quality of life and risk factors in children and adolescents with recent-onset epilepsy.

BACKGROUND: The aim of this study was to describe the distribution, timing, and risk factors for psychopathology and to further examine the quality of life (QoL) in an Italian sample of children with recent onset epilepsy. Sociodemographic and psychosocial variables, family factors, as well as illness-related factors themselves were examined in order to clarify the relationship among these variables, psychopathology and QoL. METHODS: For this purpose, 49 children and adolescents (4-18 years), consecutively referred to a Neurophysiology Service, were evaluated by a multidisciplinary team using dimensional as well as categorical instruments both self-administered (self-report and proxy-report) and interviewer administered. RESULTS: Forty-five percent of the patients exhibited one or more Axis I disorders (DSM-IV) when evaluated with K-SADS-PL interview. It's worth noting that preadolescent and adolescent patients tend to underestimate their problems compared to their parents'opinion, when answering self-administer questionnaires. Self-reported QoL appeared to be generally satisfactory. Social and family factor, as well as epilepsy related factors appeared to be linked both to the presence of psychopathology and to the QoL. Patients affected by psychiatric disorders exhibited the poorest QoL. CONCLUSIONS: Also after many years from the onset, childhood epilepsy frequently fosters negative consequences in terms of social life, work, psychopathology and life expectancy. The ability of health services and public health measures to prevent and treat psychiatric comorbidity may have a pivotal role in enhancing patients' QoL.

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.

Supraventricular Tachycardia During Status Epilepticus in Dravet Syndrome: A Link Between Brain and Heart?

BACKGROUND: The possibility that epileptic seizures and arrhythmias are different clinical manifestations of a common channelopathy is an interesting but unproved hypothesis. Patients with Dravet syndrome show heart rate variability and affected individuals with arrhythmias have also been documented. The possibility that a genetic mutation affecting sodium channel functions may predispose to both Dravet syndrome and arrhythmogenic disorders is an interesting hypothesis. PATIENT PRESENTATION: We describe a 5-month-old girl with Dravet syndrome who presented with paroxysmal supraventricular tachycardia during status epilepticus. She presented to the hospital the first time with afebrile tonic-clonic seizures and then several subsequent times with status epilepticus confirmed with electroencephalography. During two of these episodes she also exhibited paroxysmal supraventricular tachycardia. She received propofol for status epilepticus and adenosine for the arrhythmia. A clinical and genetic (denovo mutation of a sodium channel, SCN1A) diagnosis of Dravet syndrome was made. CONCLUSIONS: Our patient supports the hypothesis that SCN1A mutation might have a role as a common substrate to both epilepsy and cardiac arrhythmia. More studies are needed to better assess genetic, cardiac, respiratory, and autonomic dysfunction in patients with Dravet syndrome.

Paediatric anti-N-methyl-D-aspartate receptor encephalitis: The first Italian multicenter case series.

BACKGROUND: Given the rarity of this condition, especially in children, there is a paucity of large reported paediatric case series of anti-N-methyl-d-aspartate receptor encephalitis. METHODS: To contribute to define the features of this condition, we describe retrospectively a new nationwide case series of 20 children (50% females), referred by 13 Italian centres. RESULTS: Mean age at onset was 8 years (range 3-17). Prodromal symptoms were reported in 31.6%; onset was with neurological symptoms in 70%, and with behavioural/psychiatric disturbances in 30%. Most patients developed a severe clinical picture (90%), and 41% experienced medical complications; children 12-18 years old seemed to be more severe and symptomatic than younger patients. All children received first-line immune therapy; second-line treatment was administered to 45%. Relapses occurred in 15%. At last follow-up (mean 23.9 months, range 5-82), 85% patients had mRS 0-1; this rate was higher among older patients, and in those receiving first immune therapy within 1 month. CONCLUSIONS: Our case series confirms a symptomatologic core of paediatric anti-N-methyl-d-aspartate receptor encephalitis, even though displaying some distinctive features that may be explained by a specific genetic background or by the limited number of patients. The growing incidence of this condition, the relative age-dependent variability of its manifestations, the availability of immunotherapy and the possible better outcome with early treatment impose a high index of clinical suspicion be maintained. In the absence of data suggesting other specific etiologies, paediatricians should consider this diagnosis for children presenting with neurological and/or behavioural or psychiatric disturbances, regardless of age and gender.

Ring 17 syndrome: first clinical report without intellectual disability.

Ring chromosomes are rare abnormalities caused by the fusion of the telomeric regions. Three-ring chromosome syndromes (Cr 20, Cr 17 and Cr 14) cause epilepsy with variable phenotypes. In ring 17 patients with mild phenotype, some authors have shown an epilepsy syndrome similar to that of ring 20. We report the first case of a girl with ring chromosome 17 and a normal neurological and general cognitive profile. She had had, from 9 years old, focal pharmacoresistant epilepsy associated with episodes of non-convulsive status epilepticus with mainly autonomic features. Cytogenetic analysis revealed an abnormal karyotype characterised by the presence of de novo ring chromosome 17 in 19% of metaphases. The array CGH (100 KB) did not show any genetic deletion. The clinical and epilepsy phenotype was, to a certain degree, similar to that of ring 20 syndrome.