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Lysine-specific demethylase 5C (KDM5C) has been identified as an important chromatin remodeling gene, contributing to X-linked neurodevelopmental disorders (NDDs). The KDM5C gene, located in the Xp22 chromosomal region, encodes the H3K4me3-me2 eraser involved in neuronal plasticity and dendritic growth. Here we report 30 individuals carrying 13 novel and one previously identified KDM5C variants. Our cohort includes the first reported case of somatic mosaicism in a male carrying a KDM5C nucleotide substitution, and a dual molecular finding in a female carrying a homozygous truncating FUCA1 alteration together with a de novo KDM5C variant. With the use of next generation sequencing strategies, we detected 1 frameshift, 1 stop codon, 2 splice-site and 10 missense variants, which pathogenic role was carefully investigated by a thorough bioinformatic analysis. The pattern of X-chromosome inactivation was found to have an impact on KDM5C phenotypic expression in females of our cohort. The affected individuals of our case series manifested a neurodevelopmental condition characterized by psychomotor delay, intellectual disability with speech disorders, and behavioral features with particular disturbed sleep pattern; other observed clinical manifestations were short stature, obesity and hypertrichosis. Collectively, these findings expand the current knowledge about the pathogenic mechanisms leading to dysfunction of this important chromatin remodeling gene and contribute to a refinement of the KDM5C phenotypic spectrum.

Background and ObjectivesKCNH5encodes the voltage-gated potassium channel EAG2/Kv10.2. We aimed to delineate the neurodevelopmental and epilepsy phenotypic spectrum associated with de novoKCNH5variants.MethodsWe screened 893 individuals with developmental and epileptic encephalopathies forKCNH5variants using targeted or exome sequencing. Additional individuals withKCNH5variants were identified through an international collaboration. Clinical history, EEG, and imaging data were analyzed; seizure types and epilepsy syndromes were classified. We included 3 previously published individuals including additional phenotypic details.ResultsWe report a cohort of 17 patients, including 9 with a recurrent de novo missense variant p.Arg327His, 4 with a recurrent missense variant p.Arg333His, and 4 additional novel missense variants. All variants were located in or near the functionally critical voltage-sensing or pore domains, absent in the general population, and classified as pathogenic or likely pathogenic using the American College of Medical Genetics and Genomics criteria. All individuals presented with epilepsy with a median seizure onset at 6 months. They had a wide range of seizure types, including focal and generalized seizures. Cognitive outcomes ranged from normal intellect to profound impairment. Individuals with the recurrent p.Arg333His variant had a self-limited drug-responsive focal or generalized epilepsy and normal intellect, whereas the recurrent p.Arg327His variant was associated with infantile-onset DEE. Two individuals with variants in the pore domain were more severely affected, with a neonatal-onset movement disorder, early-infantile DEE, profound disability, and childhood death.DiscussionWe describe a cohort of 17 individuals with pathogenic or likely pathogenic missense variants in the voltage-sensing and pore domains of Kv10.2, including 14 previously unreported individuals. We present evidence for a putative emerging genotype-phenotype correlation with a spectrum of epilepsy and cognitive outcomes. Overall, we expand the role of EAG proteins in human disease and establishKCNH5as implicated in a spectrum of neurodevelopmental disorders and epilepsy.

Objective: Data on COVID-19 outcomes in persons with epilepsy (PWE) are scarce and inconclusive. We aimed to study the risk of hospitalization and death for COVID-19 in a large cohort of PWE from March 1, 2020 to October 31, 2021. Methods: The historical cohort design (EpiLink Bologna) compared adult PWE grouped into people with focal epilepsy (PFE), idiopathic generalized epilepsy (PIGE), and developmental and/or epileptic encephalopathy (PDEE), and a population cohort matched (ratio 1:10) for age, sex, residence, and comorbidity (assessed with the multisource comorbidity score), living in the local health trust of Bologna (approximately 800 000 residents). Clinical data were linked to health administrative data. Results: In both cohorts (EpiLink: n=1575 subjects, 1128 PFE, 267 PIGE, 148 PDEE, 32 other; controls: n=15 326 subjects), 52% were females, and the mean age was 50 years (SD=18). Hospital admissions for COVID-19 in the whole period were 49 (3.1%) in PWE and 225 (1.5%) in controls. The adjusted hazard ratio (aHR) in PWE was 1.9 (95% confidence interval [CI] = 1.4–2.7). The subgroups at higher risk were PFE (aHR=1.9, 95% CI=1.3–2.8) and PDEE (aHR=3.9, 95% CI=1.7–8.7), whereas PIGE had a risk comparable to the controls (aHR=1.1, 95% CI =.3–3.5). Stratified analyses of the two main epidemic waves (March–May 2020, October 2020–May 2021) disclosed a higher risk of COVID-19-related hospitalization during the first epidemic wave (March–May 2020; aHR=3.8, 95% CI=2.2–6.7). Polytherapy with antiseizure medications contributed to a higher risk of hospital admission. Thirty-day risk of death after hospitalization was 14% in both PWE and controls. Significance: During the first 20 months since the outbreak of COVID-19 in Bologna, PWE had a doubled risk of COVID-19 hospital admission compared to a matched control population. Conversely, epilepsy did not represent a risk factor for COVID-19-related death.

BackgroundLafora disease (LD) is a rare fatal autosomal recessive form of progressive myoclonus epilepsy. It affects previously healthy children or adolescents, causing pharmacoresistant epilepsy, myoclonus and severe psychomotor deterioration. This work aims to describe the clinical course of LD and identify predictors of outcome by means of a prognostic systematic review with individual participant data meta-analysis.MethodsA search was conducted on MEDLINE and Embase with no restrictions on publication date. Only studies reporting genetically confirmed LD cases were included. Kaplan–Meier estimate was used to assess probability of death and loss of autonomy. Univariable and multivariable Cox regression models with mixed effects (clustered survival data) were performed to evaluate prognostic factors.ResultsSeventy-three papers describing 298 genetically confirmed LD cases were selected. Mean age at disease onset was 13.4 years (SD 3.7), with 9.1% aged ≥ 18 years. Overall survival rates in 272 cases were 93% [95% CI 89–96] at 5 years, 62% [95% CI 54–69] at 10 years and 57% [95% CI 49–65] at 15 years. Median survival time was 11 years. The probability of loss of autonomy in 110 cases was 45% [95% CI 36–55] at 5 years, 75% [95% CI 66–84] at 10 years, and 83% [95% CI 74–90] at 15 years. Median loss of autonomy time was 6 years. Asian origin and age at onset ConclusionsThis study documented that half of patients survived at least 11 years. The notion of actual survival rate and prognostic factors is crucial to design studies on the effectiveness of upcoming new disease-modifying therapies.

Epilepsy is one of the most frequent neurological diseases, with focal epilepsy accounting for the largest number of cases. The genetic alterations involved in focal epilepsy are far from being fully elucidated.Here, we show that defective lipid signalling caused by heterozygous ultra-rare variants in PIK3C2B, encoding for the class II phosphatidylinositol 3-kinase PI3K-C2β, underlie focal epilepsy in humans. We demonstrate that patients’ variants act as loss-of-function alleles, leading to impaired synthesis of the rare signalling lipid phosphatidylinositol 3,4-bisphosphate, resulting in mTORC1 hyperactivation. In vivo, mutant Pik3c2b alleles caused dose-dependent neuronal hyperexcitability and increased seizure susceptibility, indicating haploinsufficiency as a key driver of disease. Moreover, acute mTORC1 inhibition in mutant mice prevented experimentally induced seizures, providing a potential therapeutic option for a selective group of patients with focal epilepsy.Our findings reveal an unexpected role for class II PI3K-mediated lipid signalling in regulating mTORC1-dependent neuronal excitability in mice and humans.

The study aims to characterize the epilepsy phenotype of maternally inherited Leigh's syndrome (MILS) and neuropathy, ataxia, retinitis pigmentosa (NARP) due to mutations in the mitochondrial ATP6 gene and to correlate electroclinical features with mutant heteroplasmy load (HL). We investigated 17 individuals with different phenotype, from asymptomatic carriers to MILS: 11 carried the m.8993T>G mutation, 5 the m.8993T>C and one the novel, de novo m.8858G>A mutation. Seizures occurred in 37.5% of patients, EEG abnormalities in 73%. We ranked clinical and EEG abnormalities severity and performed quantitative EEG to estimate Abnormality Ratio (AR) and Spectral Relative Power (SRP). Spearman’s rho and Kruskal–Wallis test were used for correlation with heteroplasmy load (HL). HL correlated with disease severity (Rho=0.63, P=0.012) and was significantly higher in patients with seizures or EEG abnormalities (P=0.014). HL correlated with EEG severity score only for the m.8993T>G (Rho=0.73, P=0.040), showing a trend toward a positive correlation with AR and delta SPR, irrespective of the mutation.

Background Lafora disease (LD) is a rare, lethal, progressive myoclonus epilepsy for which no targeted therapy is currently available. Studies on a mouse model of LD showed a good response to metformin, a drug with a well known neuroprotective effect. For this reason, in 2016, the European Medicines Agency granted orphan designation to metformin for the treatment of LD. However, no clinical data is available thus far. Methods We retrospectively collected data on LD patients treated with metformin referred to three Italian epilepsy centres. Results Twelve patients with genetically confirmed LD (6 EPM2A, 6 NHLRC1) at middle/late stages of disease were treated with add-on metformin for a mean period of 18 months (range: 6–36). Metformin was titrated to a mean maintenance dose of 1167 mg/day (range: 500–2000 mg). In four patients dosing was limited by gastrointestinal side-effects. No serious adverse events occurred. Three patients had a clinical response, which was temporary in two, characterized by a reduction of seizure frequency and global clinical improvement. Conclusions Metformin was overall safe in our small cohort of LD patients. Even though the clinical outcome was poor, this may be related to the advanced stage of disease in our cases and we cannot exclude a role of metformin in slowing down LD progression. Therefore, on the grounds of the preclinical data, we believe that treatment with metformin may be attempted as early as possible in the course of LD.

A 27-year-old woman presented with acute onset of double vision, right-sided orbital pain exacerbated by ocular movements, and ipsilateral conjunctival hyperemia. Her personal medical history was negative and she denied any recent illness, journey, or sick contact. Family history was positive for Hashimoto thyroiditis in her mother. Neurologic evaluation revealed complete lateral and partial upward gaze palsy in her right eye, with binocular horizontal diplopia. The remaining clinical examination was unremarkable; in particular, pupillary reflex was preserved and there was no evidence of ptosis, conjunctival chemosis, proptosis, eye discharge, or visual defects.

Ictal piloerection (IP) is a rare manifestation of focal epilepsy. Autoimmune limbic encephalitis (LE) and malignant brain tumours are the most frequent recognized aetiologies.We selected all patients diagnosed with LE in our Institute from 2004 to 2020 and manifesting with IP. We performed a literature review on LE patients presenting IP.Of 15 patients diagnosed with LE (13.3%), two manifested IP as prominent ictal feature. One of them also had stiff-limb syndrome. Video-EEG documented ictal discharges from the right temporal regions with concomitant sympathetic skin response (SSR) recording. Antibody testing showed elevated serum and CSF titres of GAD65 antibodies (Ab), in both cases. Despite a combination of several anti-seizure medications and first- and second-line immunotherapy, they showed a poor clinical outcome after 2 and 9 years of follow-up, respectively. The literature review yielded 13 papers reporting 26 LE cases with IP. LGI1 Ab were the most frequently associated (73.1%) followed by VGKC-complex (7.7%), GAD65 (7.7%), NMDAr (3.8%), Ma2 (3.8%) and Hu (3.8%) Ab. Cases with LGI1 Ab showed a good response to immunotherapy.The prevalence of IP in our LE cohort was of 13.3%, higher than expected. According to the literature review, most cases were associated with LGI1 Ab and showed a good response to immunotherapy. With the contribution of our cases, GAD65 emerged as the second most frequently detected Ab, showing a poor outcome. Our findings widen the spectrum of IP-associated Ab, with the respective prognostic implications.

Background:KCNC2 encodes Kv3.2, a member of the Shaw-related (Kv3) voltage-gated potassium channel subfamily, which is important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. The objective of this study was to analyse the clinical phenotype, genetic background, and biophysical function of disease-associated Kv3.2 variants.Methods:Individuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic, and functional analysis. Cases were referred through clinical and research collaborations. Selected de novo variants were examined electrophysiologically in Xenopus laevis oocytes.Results:We identified novel KCNC2 variants in 18 patients with various forms of epilepsy including genetic generalized epilepsy (GGE), developmental and epileptic encephalopathy (DEE) including early-onset absence epilepsy (EOAE), focal epilepsy (FE), and myoclonic-atonic epilepsy (MAE). 10/18 variants were de novo and 8/18 variants were classified as modifying variants. 8 drug responsive cases became seizure-free using valproic acid as monotherapy or in combination including severe DEE cases. Functional analysis of four variants demonstrated gain-of-function in three severely affected DEE cases and loss-of-function in one case with a milder phenotype (GGE) as the underlying pathomechanisms.Conclusion:These findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical role of KV3.2 in the regulation of brain excitability.

Hearing loss (HL) is the most common sensory impairment, and it is characterized by a high clinical/genetic heterogeneity. Here we report the identification of dual molecular diagnoses (i.e., mutations at two loci that lead to the expression of two Mendelian conditions) in a series of families affected by non-syndromic and syndromic HL. Eighty-two patients who displayed HL as a major clinical feature have been recruited during the last year. After an accurate clinical evaluation, individuals have been analyzed through whole-exome sequencing (WES). This protocol led to the identification of seven families characterized by the presence of a dual diagnosis. In particular, based on the clinical and genetic findings, patients have been classified into two groups: (a) patients with HL and distinct phenotypes not fitting in a known syndrome due to mutations at two loci (e.g., HL in association with Marfan syndrome) and (b) patients with two genes involved in HL phenotype (e.g., TMPRSS3 and MYH14). These data highlight for the first time the high prevalence of dual molecular diagnoses in HL patients and suggest that they should be considered especially for those cases that depart from the expected clinical manifestation or those characterized by a significant intra-familiar variability.

Epilepsy with auditory features (EAF) is a focal epilepsy belonging to the focal epileptic syndromes with onset at variable age according to the new ILAE Classification. It is characterized by seizures with auditory aura or receptive aphasia suggesting a lateral temporal lobe involvement of the epileptic discharge. Etiological factors underlying EAF are largely unknown. In the familial cases with an autosomal dominant pattern of inheritance several genes have been involved, among which the first discovered, LGI1, was thought to be predominant. However, increasing evidence now points to a multifactorial etiology, as familial and sporadic EAF share a virtually identical electro-clinical characterization and only a few have a documented genetic etiology. Patients with EAF usually have an unremarkable neurological examination and a good response to antiseizure medications. However, it must be underscored that total remission might be lower than expected and that treatment withdrawal might lead to relapses. Thus, a proper understanding of this condition is in order for better patient treatment and counseling. Further studies are still required to further characterize the many facets of EAF.

Background and ObjectivesTo assess the current diagnostic yield of genetic testing for the progressive myoclonus epilepsies (PMEs) of an Italian series described in 2014 where Unverricht-Lundborg and Lafora diseases accounted for ∼50% of the cohort.MethodsOf 47/165 unrelated patients with PME of indeterminate genetic origin, 38 underwent new molecular evaluations. Various next-generation sequencing (NGS) techniques were applied including gene panel analysis (n = 7) and/or whole-exome sequencing (WES) (WES singleton n = 29, WES trio n = 7, and WES sibling n = 4). In 1 family, homozygosity mapping was followed by targeted NGS. Clinically, the patients were grouped in 4 phenotypic categories: “Unverricht-Lundborg disease-like PME,” “late-onset PME,” “PME plus developmental delay,” and “PME plus dementia.”ResultsSixteen of 38 (42%) unrelated patients reached a positive diagnosis, increasing the overall proportion of solved families in the total series from 72% to 82%. Likely pathogenic variants were identified in NEU1 (2 families), CERS1 (1 family), and in 13 nonfamilial patients in KCNC1 (3), DHDDS (3), SACS, CACNA2D2, STUB1, AFG3L2, CLN6, NAXE, and CHD2. Across the different phenotypic categories, the diagnostic rate was similar, and the same gene could be found in different phenotypic categories.DiscussionThe application of NGS technology to unsolved patients with PME has revealed a collection of very rare genetic causes. Pathogenic variants were detected in both established PME genes and in genes not previously associated with PME, but with progressive ataxia or with developmental encephalopathies. With a diagnostic yield >80%, PME is one of the best genetically defined epilepsy syndromes.

GRIN2A encodes for the 2A subunit of N-methyl-D-aspartate receptors. Pathogenic variants in GRIN2A have been associated with a wide spectrum of neurodevelopmental disorders ranging from speech disorders and/or self-limiting epilepsy (childhood epilepsy with centrotemporal spikes) to severe and disabling phenotypes (atypical childhood epilepsy with centrotemporal spikes, epileptic encephalopathy with continuous spike-wave during sleep, Landau-Kleffner syndrome and infantile-onset epileptic encephalopathy). Here we describe a family with two affected sisters with atypical childhood epilepsy with centrotemporal spikes and their mildly affected mother carrying a novel N-terminal null variant in GRIN2A gene. These familial cases corroborate previous studies showing that loss-of-function GRIN2A variants are associated with milder phenotypes, possibly due to haploinsufficiency.

KCNQ2-associated brain abnormalities include thinning of the corpus callosum but complete ACC has never been reported.

Sleep-related hypermotor epilepsy (SHE), formerly known as Nocturnal Frontal Lobe Epilepsy is a focal epilepsy characterized by seizures with complex hyperkinetic automatisms and/or asymmetric tonic/dystonic posturing occurring mostly during sleep. SHE is a rare disease with an estimated minimum prevalence of 1.8/100,000 individuals and represent about 10% of drug-resistant surgical cases. This disorder, though uncommon, is of considerable interest to a broad spectrum of specialists, from child neurologists to neurosurgeons. Distinguishing this condition from non-epileptic paroxysmal behaviour occurring physiologically or pathologically during sleep is often difficult and sometimes impossible on clinical grounds alone, even for experienced epileptologists and sleep physicians. Recognized aetiologies of SHE are heterogeneous and include acquired injuries, genetic causes and structural anomalies such as focal cortical dysplasia. Multiple aetiologies (structural-genetic) are also possible. Non-specific clinical features distinguished different aetiologies even if SHE due to structural lesions usually manifests with early-onset drug-resistant seizures and showed a worse long-term prognosis. The causative genes for SHE are multiple and encode for proteins involved in different molecular pathways. The cholinergic system and the mTOR pathway are the most relevant. This review will provide an exhaustive overview of the genetic background of SHE.

BackgroundKCNC2 encodes a member of the shaw-related voltage-gated potassium channel family (KV3.2), which are important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain.MethodsIndividuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic and functional analysis. The cases were referred through clinical and research collaborations in our study. Four de novo variants were examined electrophysiologically in Xenopus laevis oocytes.ResultsWe identified novel KCNC2 variants in 27 patients with various forms of epilepsy. Functional analysis demonstrated gain-of-function in severe and loss-of-function in milder phenotypes as the underlying pathomechanisms with specific response to valproic acid.ConclusionThese findings implicate KCNC2 as a novel causative gene for epilepsy emphasizing the critical role of KV3.2 in the regulation of brain excitability with an interesting genotype-phenotype correlation and a potential concept for precision medicine.

IntroductionEpilepsy is a chronic condition requiring consistent follow-up aimed at seizure control, and monitoring of anti-seizure medication (ASM) levels and side effects. Telemedicine (TM) offers invaluable support to patient follow-up, guaranteeing the prompt availability of a team of experts for persons with epilepsy (PWE) widely distributed across the country. Although many health institutions have endorsed the use of TM, robust data on effectiveness, safety and costs of TM applied to epilepsy are lacking. TELEmedicine for EPIlepsy Care (TELE-EPIC) will evaluate the effectiveness of video consultation (VC) via TM compared with usual care (UC) for the monitoring of PWE (TELE-EPIC_RCT). Moreover, TELE-EPIC will apply an innovative Volumetric Absorptive Microsampling (VAMS) device for quantitation of ASM through finger prick blood sampling as an alternative to venipuncture sampling (TELE-EPIC_VAMS).Methods and analysisTELE-EPIC_RCT is a multicentre, open, pragmatic two-arm randomised controlled trial prospectively including adult and paediatric outpatients with established diagnosis of epilepsy consecutively attending the Epilepsy Centres of Bologna and Rome, respectively. The primary outcome is the non-inferiority of VC on seizure control compared with UC after an 18-month follow-up. Secondary outcomes are adherence to treatment, ASM-related adverse events, quality of life, mood disorders, patient and caregiver satisfaction, safety and costs. TELE-EPIC_VAMS is a cross-validation study for blood ASM quantitation through a novel, VAMS-based device, comparing (1) VAMS versus plasma samples (reference standard method); and (2) nurse-collected versus self-collected blood by VAMS device.Ethics and disseminationThe study has been approved by the local ethics committee (349-2019-SPER-AUSLBO). Complete information about the state of project, relevant events and results will be regularly updated on the project’s webpage on ClinicalTrials.gov. The project’s results and data on the potential impact of TM in epilepsy will be disseminated on social media. A closeout meeting will be convened for the communication and dissemination of the project, highlighting its main achievements and impacts.Trial registration numberNCT04496310

Epilepsy with Auditory Features (EAF) is a focal epilepsy syndrome mainly of unknown aetiology. LGI1 and RELN have been identified as the main cause of Autosomal Dominant EAF and anecdotally reported in non-familial cases. Pathogenic variants in SCN1A and DEPDC5 have also been described in a few EAF probands belonging to families with heterogeneous phenotypes and incomplete penetrance. We aimed to estimate the contribution of these genes to the disorder by evaluating the largest cohort of EAF. We included 112 unrelated EAF cases (male/female: 52/60) who underwent genetic analysis by next-generation sequencing (NGS) techniques. Thirty-three (29.5%) were familial cases. We identified a genetic diagnosis for 8% of our cohort, including pathogenic/likely pathogenic variants (4/8 novel) in LGI1 (2.7%, CI: 0.6-7.6); RELN (1.8%; CI: 0.2-6.3); SCN1A (2.7%; CI: 0.6-7.6) and DEPDC5 (0.9%; CI 0-4.9).This study shows that the contribution of each of the known genes to the overall disorder is limited and that the genetic background of EAF is still largely unknown. Our data emphasize the genetic heterogeneity of EAF and will inform the diagnosis and management of individuals with this disorder.

EBioMedicine 72, 103588 (2021). doi:10.1016/j.ebiom.2021.103588, Published by Elsevier, Amsterdam [u.a.]

Summary Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.

Introduction We aimed to create standardized protocol for language examination in patients who underwent video-EEG recording and assessed its efficacy in the characterization of ictal language impairment, its ability to differentiate this from impaired awareness, and interobserver reliability in clinical practice. Methods From our database of video-EEG recordings, we selected a representative sample of 63 focal seizures with presumed language impairment. A multidisciplinary team of epileptologists, EEG technicians, and speech therapists analyzed the selected videos to highlight the critical issues of ordinary ictal language evaluation. We subsequently followed a multi-step process to develop the protocol and assess its interobserver reliability. Results A protocol based on seven tests in hierarchical succession was created, summed up in the acronym CA-P-S C-A-R-E (Closed Answers, Pro-speak question, Simple orders, Common object denomination, Audio repetition, Reading, Evoke). Following its preliminary administration for 5 months, we assessed the inter-observer reliability of 16 healthcare professionals in distinguishing between language impairment and impaired awareness among a sample of 10 seizures, finding a substantial agreement (kappa 0.61). Conclusion The proposed protocol, made of simple and easy to memorize tests, is an effective tool that evaluates multiple domains beyond language. Its use could help to recognize ictal aphasia effectively and differentiate it from impaired awareness, minimizing inter-examiner variability.

Special considerations are required for women with epilepsy. These include issues such as catamenial exacerbation, concerns for contraception, teratogenesis (including both anatomical and neurodevelopmental effects), and other concerns for pregnancy complications such as increased seizures or adverse obstetric outcomes. In this manuscript, several cases are presented and discussed addressing some of the important issues in the management of women with epilepsy.

Objective: Sleep-related hypermotor epilepsy (SHE) is a focal epilepsy characterized by seizures occurring mostly during sleep, ranging from brief seizures with paroxysmal arousals (SPAs) to hyperkinetic seizures and ambulatory behaviors. SPAs are brief and stereotypic seizures representing the beginning of a major seizure. Distinguishing SPAs from disorders of arousal (DOAs) and their briefest episodes called simple arousal movements (SAMs) is difficult. We performed a characterization of SPAs and SAMs to identify video-polysomnographic (VPSG) features that can contribute to the diagnosis of SHE or DOA. Methods: Fifteen SHE, 30 DOA adult patients, and 15 healthy subjects underwent full-night VPSG. Two neurologist experts in sleep disorders and epilepsy classified all the sleep-related movements and episodes recorded. For each SPAs and SAMs, sleep stage at onset, duration, limb involvement, progression, and semiology have been identified. Results: A total of 121 SPAs were recorded, emerging mostly during stage 1-2 non–rapid eye movement (NREM) sleep (median duration: 5seconds). At the beginning, the SPAs motor pattern was hyperkinetic in 78 cases (64%), involving more than three non-contiguous or all body parts. The standard was a constant progression of movements during SPAs without any motor arrests. In DOA patients a total of 140 SAMs were recorded (median duration: 12seconds) mostly emerging during stage 3 NREM sleep. In SAMs, we did not observe any tonic/dystonic or hypermotor patterns or stereotypy; motor arrest was present over the course of about half of the episodes. In comparison with both DOA and healthy subjects, SHE patients showed a higher number of sleep-related movements per night and a reduction of sleep efficiency. Significance: SPAs and SAMs present different semiological and clinical features. Their recognition could be useful to drive the diagnosis when major episodes are not recorded during VPSG in patients with a clear clinical history of SHE or DOA.

Purpose Genetics of Sleep-related Hypermotor Epilepsy (SHE) includes mutations in several genes that cumulatively account for 30 % of families. This approximate estimate comes from different case-series, each focused on the screening of a single gene. We systematically investigated a large cohort of SHE patients to estimate the frequency of pathogenic variants in the main genes thus far implicated in this epilepsy syndrome. Methods We selected familial and isolated cases diagnosed with clinical/confirmed SHE who underwent genetic analysis by comparable next generation sequencing (NGS) techniques (WES/ multigene epilepsy panel). The identified heterozygous variants were classified according to the American College of Medical Genetics and Genomics guidelines. Results We included 103 SHE patients (M/F:61/42) who underwent NGS. Sixteen (15.5 %) were familial cases, 16.5 % had focal cortical dysplasia (FCD). We identified three pathogenic variants in CHRNA4 (2.9 %, CI: 0.6–8.3 %), two of whom novel; one pathogenic variant in KCNT1 (1 %, CI: 0.02–5.29 %); four loss-of-function variants in DEPDC5 (3.9 %, CI: 1.1–9.7 %), one of whom never reported; finally, one missense change in NPRL2 (1 %, CI: 0.02–5.29 %), already reported as pathogenic. Three out of the four patients with DEPDC5 variants had FCD. Conclusions The overall frequency of pathogenic variants in our SHE cohort was 8.7 %, 19 % and 7 % considering familial and sporadic cases, respectively. Pathogenic variants in the GATOR1-complex genes account for 5 % of the cases. DEPDC5 shows the highest variants frequency, especially in patients with genetic-structural etiology. From a practical perspective, analysis of this gene is recommended even in isolated cases, because of possible implications for patient management.

Epilepsy with eyelid myoclonias, originally depicted by Jeavons in 1977, is a reflex epilepsy characterized by jerking of the eyelids with or without absences precipitated by eye closure or by light (eyelid myoclonia, EM), eye closure-induced EEG paroxysms and photosensitivity. Childhood-onset, female predominance and a normal development are typical features, though a mild intellectual disability has been reported. Sotos syndrome is a disorder characterized by a distinctive facial appearance, learning disability and overgrowth in childhood with macrocephaly, caused by heterozygous pathogenic variants or deletions in NSD1 gene. Generalized and focal seizures have been reported in up to 25 % of patients, though EM was never documented. Here we report the novel association of Epilepsy with EM and Sotos syndrome features in a patient with two likely pathogenic missense variants in APC2 gene.

Objective: To assess the long-term outcome of epilepsy with auditory features (EAF) and to identify the clinical predictors for prognosis. Methods: The study involved consecutive EAF patients with a follow-up of ≥5 years. Terminal remission (TR) was defined as a period of ≥5 consecutive years of seizure freedom at the last follow-up. We used Kaplan-Meier estimate to calculate the cumulative time-dependent probability of conversion to TR. Log-rank test and multivariate Cox regression analyses were performed to study the association between time to TR and prognostic determinants. Results: We included 123 EAF patients (male/female = 58/65) with a median follow-up of 11 years (1626.9 person-years). Most were sporadic cases (68.3%), whereas 31.7% reported a family history of epilepsy. At last assessment, 42 patients had achieved TR (34.1%). Of the remaining 81 cases with no TR (65.9%), 37% had been in remission for 1-4 years and 62.9% still had seizures within the past year. The cumulative rates of TR were 26.6%, 35.7%, and 51.6% at 10, 20, and 30 years from inclusion. On multivariate analysis, age at onset > 10 years (hazard ratio [HR] = 3.2, P = .028), auditory aura characterized by distortions only versus simple/complex hallucinations (HR = 2.9, P = .041), and unremarkable scalp electroencephalogram (EEG) versus EEG with focal epileptiform activity (HR = 3.5, P = .041) were associated with TR. Significance: Our data show a wide prognostic spectrum of EAF, ranging from mild forms with spontaneous remission, to severely refractory epilepsy addressed to surgery. The outcome, less favorable than expected from previous studies, appears to be primarily a function of 3 prognostic negative risk factors: age at onset < 10 years, auditory aura characterized by complex auditory hallucinations, and focal epileptiform abnormalities on scalp EEG. These predictors, easy to collect even at the first visit, may inform both clinicians and patients about the long-term prognosis and aid patient management.

OBJECTIVE: To comprehensively describe the new syndrome of myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK), including cellular electrophysiological characterization of observed clinical improvement with fever.METHODS: We analyzed clinical, electroclinical, and neuroimaging data for 20 patients with MEAK due to recurrent KCNC1 p.R320H mutation. In vitro electrophysiological studies were conducted using whole cell patch-clamp to explore biophysical properties of wild-type and mutant KV 3.1 channels.RESULTS: Symptoms began at between 3 and 15 years of age (median = 9.5), with progressively severe myoclonus and rare tonic-clonic seizures. Ataxia was present early, but quickly became overshadowed by myoclonus; 10 patients were wheelchair-bound by their late teenage years. Mild cognitive decline occurred in half. Early death was not observed. Electroencephalogram (EEG) showed generalized spike and polyspike wave discharges, with documented photosensitivity in most. Polygraphic EEG-electromyographic studies demonstrated a cortical origin for myoclonus and striking coactivation of agonist and antagonist muscles. Magnetic resonance imaging revealed symmetrical cerebellar atrophy, which appeared progressive, and a prominent corpus callosum. Unexpectedly, transient clinical improvement with fever was noted in 6 patients. To explore this, we performed high-temperature in vitro recordings. At elevated temperatures, there was a robust leftward shift in activation of wild-type KV 3.1, increasing channel availability.INTERPRETATION: MEAK has a relatively homogeneous presentation, resembling Unverricht-Lundborg disease, despite the genetic and biological basis being quite different. A remarkable improvement with fever may be explained by the temperature-dependent leftward shift in activation of wild-type KV 3.1 subunit-containing channels, which would counter the loss of function observed for mutant channels, highlighting KCNC1 as a potential target for precision therapeutics. Ann Neurol 2017;81:677-689.