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Aim: To identify factors that may predict and affect the risk of relapse in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Method: This was a retrospective study of an Italian cohort of patients with paediatric (≤18y) onset anti-NMDAR encephalitis. Results: Of the 62 children included (39 females; median age at onset 9y 10mo, range 1y 2mo–18y; onset between 2005 and 2018), 21 per cent relapsed (median two total events per relapsing patient, range 2–4). Time to first relapse was median 31.5months (range 7–89mo). Severity at first relapse was lower than onset (median modified Rankin Scale [mRS] 3, range 2–4, vs median mRS 5, range 3–5; admission to intensive care unit: 0/10 vs 3/10). At the survival analysis, the risk of relapsing was significantly lower in patients who received three or more different immune therapies at first disease event (hazard ratio 0.208, 95% confidence interval 0.046–0.941; p=0.042). Neurological outcome at follow-up did not differ significantly between patients with relapsing and monophasic disease (mRS 0–1 in 39/49 vs 12/13; p=0.431), although follow-up duration was significantly longer in relapsing (median 84mo, range 14–137mo) than in monophasic patients (median 32mo, range 4–108mo; p=0.002). Interpretation: Relapses may occur in about one-fifth of children with anti-NMDAR encephalitis, are generally milder than at onset, and may span over a long period, although they do not seem to be associated with severity in the acute phase or with outcome at follow-up. Aggressive immune therapy at onset may reduce risk of relapse. What this paper adds: Relapses of anti-N-methyl-D-aspartate receptor encephalitis may span over a long period. Relapses were not associated with severity in the acute phase or outcome at follow-up. Aggressive immune therapy at onset appears to decrease risk of relapse.

Summary Purpose To investigate the electroclinical features and the outcome of patients with typical absences starting before the 3 years of life. Methods We reviewed the clinical data of patients with absences started before 3 years observed over a 15-year period. Mutation analysis of SLC2A1 (GLUT-1) gene was performed when possible. Their clinical features were compared with those of subjects with a diagnosis of childhood absence epilepsy (CAE). Results Among 33 children with absence epilepsy starting before 3 years of life, there were 20 boys and 13 girls. Mean seizure onset was at 28.0±8.3 (range: 8–36) months of life. Two children displayed borderline intellectual functioning at long-term follow-up. Twenty-eight (85%) patients showed excellent response to therapy. Three subjects evolved into a different form of idiopathic generalized epilepsy (IGE). No SLC2A1 mutation was identified in 20 (60.6%) patients tested. The main clinical features of patients with early-onset absences did not differ from those of CAE except for increased prevalence of males ( p =0.002) and longer treatment duration ( p =0.001) in the former. Conclusions Strong similarities in the electroclinical features and outcome between children with early-onset absences and those with CAE support the view that these conditions are part of the wide spectrum of IGE.

ObjectivesTo describe the long-term prognosis of epilepsy and prognostic patterns in a large cohort of newly diagnosed patients and identify prognostic factors.MethodsStudy participants were 13 Italian epilepsy centres with accessible records dating back to 2005 or earlier, complete data on seizure outcome and treatments, precise epilepsy diagnosis, and follow-up of at least 10 years. Records were examined by trained neurology residents for demographics, seizure characteristics, neurological signs, psychiatric comorbidity, first electroencephalogram (EEG) and MRI/CT, epilepsy type and aetiology, antiepileptic drugs (AEDs), and 1-year, 2-year, 5-year and 10-year seizure remissions. Five predefined prognostic patterns were identified: early remission, late remission, relapsing-remitting course, worsening course and no remission. Prognostic factors were assessed using multinomial logistic regression models.Results1006 children and adults were followed for 17 892 person-years (median 16 years; range 10–57). During follow-up, 923 patients (91.7%) experienced 1-year remission. 2-year, 5-year and 10-year remissions were present in 89.5%, 77.1% and 44.4% of cases. 5-year remission was associated with one to two seizures at diagnosis, generalised epilepsy, no psychiatric comorbidity, and treatment with one or two AEDs during follow-up. 10-year remission was associated with one or two AEDs. The most common prognostic pattern was relapsing-remitting (52.2%), followed by early remission (24.5%). 8.3% of cases experienced no remission. Predictors of a relapsing-remitting course were ConclusionsFew seizures at diagnosis, generalised epilepsy and no psychiatric comorbidity predict early or late seizure freedom in epilepsy. Achieving remission at any time after the diagnosis does not exclude further relapses.

Summary Purpose Neurexins are neuronal adhesion molecules located in the presynaptic terminal, where they interact with postsynaptic neuroligins to form a transsynaptic complex required for efficient neurotransmission in the brain. Recently, deletions and point mutations of the neurexin 1 (NRXN1) gene have been associated with a broad spectrum of neuropsychiatric disorders. This study aimed to investigate if NRXN1 deletions also increase the risk of idiopathic generalized epilepsies (IGEs). Methods We screened for deletions involving the NRXN1 gene in 1,569 patients with IGE and 6,201 controls using high-density oligonucleotide microarrays. Key Findings We identified exon-disrupting deletions of NRXN1 in 5 of 1,569 patients with IGE and 2 of 6,201 control individuals (p = 0.0049; odds ratio (OR) 9.91, 95% confidence interval (CI) 1.92–51.12). A complex familial segregation pattern in the IGE families was observed, suggesting that heterozygous NRXN1 deletions are susceptibility variants. Intriguingly, we identified a second large copy number variant in three of five index patients, supporting an involvement of heterogeneous susceptibility alleles in the etiology of IGE. Significance We conclude that exon-disrupting deletions of NRXN1 represent a genetic risk factor in the genetically complex predisposition of common IGE syndromes.

PURPOSE: To assess incidence, indicators and outcome of satisfaction with antiepileptic drugs in children. METHODS: Multicenter, observational, open, prospective survey of children and adolescents with epilepsy with three-month follow-up. Included were patients aged 3-17 years with newly diagnosed ("new diagnosis") or chronic epilepsy ("old diagnosis") requiring treatment start or change. Satisfaction was assessed with the Hedonic Visual Scale or direct questions, depending on patient's age. Quality of life of adolescents (QOLIE-48) and of caregivers (SF-36) and predictors of (dis)satisfaction were also assessed. RESULTS: 293 patients completed the study. Most had generalized idiopathic epilepsy, and a disease lasting

Background and purposes: To determine the prevalence of SLC2A1 mutations inchildren with early-onset absence epilepsy (EOAE) and to investigate whether therewere differences in demographic and electroclinical data between patients whobecame seizure-free with anti-epileptic drug (AED) monotherapy (group I) andthose who needed add-on treatment of a second AED (group II).Methods: We reviewed children with EOAE attended different Italian epilepsy cen-ters. All participants had onset of absence seizures within the first 3 years of life butotherwise conformed to a strict definition of childhood absence epilepsy. Mutationanalysis of SLC2A1 was performed in each patient.Results: Eighty-four children (57 in group I, 27 in group II) fulfilled the inclusioncriteria. No mutation in SLC2A1 was found. There were no statistical differencesbetween the two groups with regard to F/M ratio, age at onset of EOAE, early his-tory of febrile seizures, first-degree family history for genetic generalized epilepsy,duration of AED therapy at 3 years after enrollment, use of AEDs at 3 years, failedwithdrawals at 3 years, terminal remission of EOAE at 3 years, and 6-month fol-low-up EEG data. Mean duration of seizures/active epilepsy was significantlyshorter in group I than in group II (P = 0.008).Conclusions: We demonstrate that in a large series of children with rigorous diag-nosis of EOAE, no mutations in SLC2A1 gene are detected. Except for duration ofseizures/active epilepsy, no significant differences in demographic and electroclinicalaspects are observed between children with EOAE who responded well to AEDmonotherapy and those who became seizure-free with add-on treatment of a secondAED.

Summary 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.

PURPOSE: Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% with heritability estimates of 80%. A considerable proportion of families with siblings affected by GGEs presumably display an oligogenic inheritance. The present genome-wide linkage meta-analysis aimed to map: (1) susceptibility loci shared by a broad spectrum of GGEs, and (2) seizure type-related genetic factors preferentially predisposing to either typical absence or myoclonic seizures, respectively. METHODS: Meta-analysis of three genome-wide linkage datasets was carried out in 379 GGE-multiplex families of European ancestry including 982 relatives with GGEs. To dissect out seizure type-related susceptibility genes, two family subgroups were stratified comprising 235 families with predominantly genetic absence epilepsies (GAEs) and 118 families with an aggregation of juvenile myoclonic epilepsy (JME). To map shared and seizure type-related susceptibility loci, both nonparametric loci (NPL) and parametric linkage analyses were performed for a broad trait model (GGEs) in the entire set of GGE-multiplex families and a narrow trait model (typical absence or myoclonic seizures) in the subgroups of JME and GAE families. KEY FINDINGS: For the entire set of 379 GGE-multiplex families, linkage analysis revealed six loci achieving suggestive evidence for linkage at 1p36.22, 3p14.2, 5q34, 13q12.12, 13q31.3, and 19q13.42. The linkage finding at 5q34 was consistently supported by both NPL and parametric linkage results across all three family groups. A genome-wide significant nonparametric logarithm of odds score of 3.43 was obtained at 2q34 in 118 JME families. Significant parametric linkage to 13q31.3 was found in 235 GAE families assuming recessive inheritance (heterogeneity logarithm of odds = 5.02). SIGNIFICANCE: Our linkage results support an oligogenic predisposition of familial GGE syndromes. The genetic risk factor at 5q34 confers risk to a broad spectrum of familial GGE syndromes, whereas susceptibility loci at 2q34 and 13q31.3 preferentially predispose to myoclonic seizures or absence seizures, respectively. Phenotype- genotype strategies applying narrow trait definitions in phenotypic homogeneous subgroups of families improve the prospects of disentangling the genetic basis of common familial GGE syndromes.

Mutations in the EFHC1 gene have been reported in six juvenile myoclonic epilepsy (JME) families from Mexico and Belize. In this study, we screened 27 unrelated JME Italian families for mutations in the EFHC1 gene.Twenty-seven families (86 affected individuals, 52 women) with at least two affected members with JME were selected. DNA was isolated from peripheral blood lymphocytes by standard methods and each exon of the EFHC1 gene was amplified and sequenced using intronic primers.Two heterozygous mutations were identified in three unrelated families. One (R353 W) was a novel missense mutation, while the F229 L mutation was previously described (say which on of the two occurred in two families). Both mutations cosegregated with the disease. In a fourth family, the variant 545G-->A (resulting in the amino acid substitution R182 H) cosegregated with JME.The results of our study extend the distribution of EFHC1 mutations to the white population and confirm the high level of genetic heterogeneity associated with JME.

Electroencephalography-functional magnetic resonance imaging (EEG-fMRI) coregistration has recently revealed that several brain structures are involved in generalized spike and wave discharges (GSWDs) in idiopathic generalized epilepsies (IGEs). In particular, deactivations and activations have been observed within the so-called brain default mode network (DMN) and thalamus, respectively. In the present study we analyzed the dynamic time course of blood oxygen level-dependent (BOLD) changes preceding and following 3 Hz GSWDs in a group of adolescent and adult patients with IGE who presented with absence seizures (AS). Our aim was to evaluate cortical BOLD changes before, during, and after GSWD onset.Twenty-one patients with IGE underwent EEG-fMRI coregistration. EEG-related analyses were run both at the single-subject and at group level (random effect). The time-course analysis was conducted for 3 s time windows before, during, and after GSWDs, and they were included until no further BOLD signal changes were observed.Fifteen patients (nine female, mean age 28 years) had GSWDs during EEG-fMRI coregistration (262 total events, mean duration 4 s). Time-course group analysis showed BOLD increments starting approximately 10 s before GSWD onset located in frontal and parietal cortical areas, and especially in the precuneus-posterior cingulate region. At GSWD onset, BOLD increments were located in thalamus, cerebellum, and anterior cingulate gyrus, whereas BOLD decrements were observed in the DMN regions persisting until 9 s after onset.Hemodynamic changes (BOLD increments) occurred in specific cortical areas, namely the precuneus/posterior cingulate, lateral parietal, and frontal cortices, several seconds before EEG onset of GSWD. A dysfunction of these brain regions, some of which belongs to the DMN, may be crucial in generating GSWDs in patients with IGE.

We investigated the electroclinical features of 12 patients with childhood absence epilepsy (CAE), presenting with typical absence seizures associated with myoclonic manifestations of the face or neck. All patients underwent repeated and prolonged split-screen video-polygraphic EEG recordings. The polygraphic recordings and clinical correlations of the absence seizures were analysed. All patients presented with multi-quotidian, typical absence seizures. During the absences, the patients could show mild, rhythmic, myoclonic jerks involving facial areas (eyebrows, nostrils, perioral region, chin) or neck muscles (sternocleidomastoideus), with the same frequency as the spike-wave complexes. Polygraphic tracings demonstrated that the myoclonias were correlated to the spike component. Clinically, all patients showed a benign course, with complete seizure control under antiepileptic treatment. In the follow-up, 7 patients withdrew from treatment without relapse. We conclude that all our patients showed an electroclinical picture consistent with CAE. The occurrence of myoclonic manifestations of the face or neck associated with the absences did not influence the benign course of their disease. The electroclinical features observed in our group of patients differentiates our cases both from epilepsy with myoclonic absences and from absences with perioral myoclonia (with Video).

Summary: Introduction: To determine the occurrence of neuroradiological abnormalities and to perform genotype–phenotype correlations in severe myoclonic epilepsy of infancy (SMEI, Dravet syndrome). Patients and Methods: Alpha-subunit type A of voltage-gated sodium channel (SCN1A) mutational screening was performed by denaturing high-performance liquid chromatography (DHPLC) and multiplex ligation probe amplification (MLPA). MRI inclusion criteria were: last examination obtained after the age of 4 years on 1.5-T systems; hippocampal cuts acquired perpendicular to the long axis of the hippocampus; qualitative assessment was performed on T1-weighted, T2-weighted, proton density, and 1–3 mm thick coronal FLAIR images. Results: We collected 58 SMEI patients in whom last MRI was performed at or later than 4 years of age. SCN1A mutations occurred in 35 (60%) cases. Thirteen (22.4%) out of 58 patients showed abnormal MRIs. Eight patients showed cortical brain atrophy of which 3 associated to ventricles abnormalities, 1 to cerebellar atrophy, 1 to white matter hyperintensity; 3 patients had ventricles enlargement only; 1 patient showed hippocampal sclerosis (HS); 1 had focal cortical dysplasia. Genotype–phenotype analysis indicated that abnormal MRIs occurred more frequently in patients without SCN1A mutations (9/23; 39.1%) compared to those carrying SCN1A mutations (4/35; 11.4%) (p = 0.02). Conclusion: Different brain abnormalities may occur in SMEI. Only one case with HS was observed; thus, our study does not support the association between prolonged febrile seizures and HS in SMEI. Abnormal MRIs were significantly more frequent in patients without SCN1A mutations. Prospective MRI studies will assess the etiological role of the changes observed in these patients.

Perampanel (PER) is a novel anti-seizure medication useful in different types of epilepsy. We intended to assess the effectiveness of PER on cortical myoclonus and seizure frequency in patients with progressive myoclonus epilepsy (PME), using quantitative validated scales. Forty-nine patients aged 36.6 ± 15.6 years with PME of various aetiology (18 EPM1, 12 EPM2, five with sialidosis, one with Kufs disease, one with EPM7, and 12 undetermined) were enrolled between January 2017 and June 2018. PER at the dose of 2–12 mg (5.3 ± 2.5) was added to existing therapy. Myoclonus severity was assessed using a minimal myoclonus scale (MMS) in all the patients before and after 4–6 months of steady PER dose, and by means of the Unified Myoclonus Rating Scale (UMRS) in 20 patients. Logistic regression analysis was used to identify the factors potentially predicting treatment efficacy. Four patients dropped out in the first two months due to psychiatric side effects. In the remaining patients, PER reduced myoclonus severity as assessed using MMS (Wilcoxon test: p < 0.001) and UMRS (p < 0.001), with the ‘Action myoclonus’ section of the UMRS showing the greatest improvement. The patients with EPM1 or EPM1-like phenotype were more likely to improve with PER (p = 0.011). Convulsive seizures which have recurred at least monthly in 17 patients were reduced by >50%. Side effects occurred in 22/49 (44.8%) patients, the most common being irritability followed by drowsiness. PER is effective in treating myoclonus and seizures in PME patients. The frequency of psychiatric side effects suggests the need for careful patient monitoring.

SummaryObjective The new epilepsy definition adopted by the International League Against Epilepsy (ILAE) includes patients with one unprovoked seizure with a probability of further seizures, similar to the general recurrence risk after two unprovoked seizures, occurring in a 10-year period. Long-term follow-up of patients diagnosed after a single seizure is needed to assess the applicability of the new epilepsy definition in clinical practice. Methods Patients with newly diagnosed epilepsy were recruited retrospectively with a minimum follow-up of 10 years. Patients were stratified in two groups depending on the occurrence of one (new definition, ND) or two or more unprovoked seizures (traditional definition, TD) at the time of epilepsy diagnosis and compared for disease characteristics and factors predicting seizure recurrence. The primary outcome was the occurrence of a new unprovoked seizure during follow-up in the ND group. The secondary outcome was the achievement of an early remission in both groups. Results Among 1,006 patients with newly diagnosed epilepsy, 152 (15.1%) were diagnosed after a single seizure. Compared to patients diagnosed using the TD, patients diagnosed according to the ND showed a higher proportion of subjects with an abnormal neurologic examination (19.9% vs. 13.7%, p = 0.0504) and with focal seizures (69.3% vs. 60.4%, p = 0.0021). The two samples differed in the presence of at least one of the factors predicting seizure recurrence (focal seizures or abnormal findings in at least one among the following: neurologic examination, electroencephalography [EEG], and neuroimaging) (94.6% vs. 89.1%, p = 0.0376). Long-term recurrence in patients diagnosed with the new definition was 83.6% at 10 years and 89.1% at 15 years. The probability of early remission did not differ between the two groups. Significance Our results support the applicability of the new epilepsy definition in clinical practice. Individual patient characteristics and a personalized diagnostic approach can justify treatment after a single unprovoked seizure.

Summary Purpose To dissect the genetics of benign familial epilepsies of the first year of life and to assess the extent of the genetic overlap between benign familial neonatal seizures (BFNS), benign familial neonatal-infantile seizures (BFNIS), and benign familial infantile seizures (BFIS). Methods Families with at least two first-degree relatives affected by focal seizures starting within the first year of life and normal development before seizure onset were included. Families were classified as BFNS when all family members experienced neonatal seizures, BFNIS when the onset of seizures in family members was between 1 and 4 months of age or showed both neonatal and infantile seizures, and BFIS when the onset of seizures was after 4 months of age in all family members. SCN2A, KCNQ2, KCNQ3, PPRT2 point mutations were analyzed by direct sequencing of amplified genomic DNA. Genomic deletions involving KCNQ2 and KCNQ3 were analyzed by multiple-dependent probe amplification method. Key Findings A total of 46 families including 165 affected members were collected. Eight families were classified as BFNS, 9 as BFNIS, and 29 as BFIS. Genetic analysis led to the identification of 41 mutations, 14 affecting KCNQ2, 1 affecting KCNQ3, 5 affecting SCN2A, and 21 affecting PRRT2. The detection rate of mutations in the entire cohort was 89%. In BFNS, mutations specifically involve KCNQ2. In BFNIS two genes are involved (KCNQ2, six families; SCN2A, two families). BFIS families are the most genetically heterogeneous, with all four genes involved, although about 70% of them carry a PRRT2 mutation. Significance Our data highlight the important role of KCNQ2 in the entire spectrum of disorders, although progressively decreasing as the age of onset advances. The occurrence of afebrile seizures during follow-up is associated with KCNQ2 mutations and may represent a predictive factor. In addition, we showed that KCNQ3 mutations might be also involved in families with infantile seizures. Taken together our data indicate an important role of K-channel genes beyond the typical neonatal epilepsies. The identification of a novel SCN2A mutation in a family with infantile seizures with onset between 6 and 8 months provides further confirmation that this gene is not specifically associated with BFNIS and is also involved in families with a delayed age of onset. Our data indicate that PRRT2 mutations are clustered in families with BFIS. Paroxysmal kinesigenic dyskinesia emerges as a distinctive feature of PRRT2 families, although uncommon in our series. We showed that the age of onset of seizures is significantly correlated with underlying genetics, as about 90% of the typical BFNS families are linked to KCNQ2 compared to only 3% of the BFIS families, for which PRRT2 represents the major gene.

Summary Purpose To assess the clinical characteristics and the outcome of benign convulsions associated with mild gastroenteritis (CwG) in Italian children. Methods We studied clinical and EEG features of 128 children with CwG who were hospitalized between January 2004 and February 2008 and then followed for at least 12 months in 14 Italian centers. Results Age at onset ranged from 6 to 60 months. The seizures were generalized in 73 cases (57%), only focal in 16 (12.5%), and secondarily generalized in 39 (30.5%). The duration of the seizures was under 5 min in 97 patients (75.8%), between 5 and 30 min in 26 (20.3%), and longer than 30 min in 5 (3.9%). Seventy-three participants (57%) had 2 or more seizures, which recurred within 24–48 h. In the acute phase, antiepileptic drugs were used in 72 patients (56.3%). Although interictal abnormalities were present in EEG of 28 children (21.9%), these reverted to normal. During the follow up period, only 6 patients (4.7%) suffered from recurrence of CwG, 7 (5.5%) suffered from simple febrile seizures, and 3 (2.3%) developed epilepsy. Conclusions Recognition of CwG in children allows pediatricians to avoid extensive evaluations and continuous antiepileptic therapy and to reassure parents regarding the lack of long-term complications.

Summary Purpose: This retrospective study aims to review the electroclinical features of patients presenting with eyelid myoclonia (EM) with and without absences. Methods: The Italian chapter of the International League Against Epilepsy (ILAE) has been conducting an electroclinical study of patients with EM. Among these, we searched for and selected the patients presenting with both impairment of intellectual functions and a peculiar ictal electroencephalography (EEG) pattern, that is, a discharge of fast generalized polyspikes/polyspikes and waves. Results: We found 18 patients matching this electroclinical picture. All the patients were photosensitive. All of them had associated generalized, mostly nocturnal, tonic–clonic seizures. During the evolution, 13 patients presented episodes of EM status. Despite adequate antiepileptic treatment, the patients remained drug resistant for many years or throughout the evolution. The degree of impairment of intellectual functions varied from borderline level to moderate mental retardation. Discussion: The patients we described herein can be considered a homogeneous group in the more heterogeneous group of patients presenting with EM. Further clinical and, more probably, genetic studies will clarify whether this condition could be considered a specific and homogeneous condition in the more heterogeneous group of patients presenting with EM.