The expanding field of genetic developmental and epileptic encephalopathies: current understanding and future perspectives.

Recent advances in genetic testing technologies have revolutionised the identification of genetic abnormalities in early onset developmental and epileptic encephalopathies (DEEs). In this Review, we provide an update on the expanding landscape of genetic factors contributing to DEEs, encompassing over 800 reported genes. We focus on the cellular and molecular mechanisms driving epileptogenesis, with an emphasis on emerging therapeutic strategies and effective treatment options. We explore noteworthy, novel genes linked to DEE phenotypes, such as gBRAT-1 and GNAO1, and gene families such as GRIN and HCN. Understanding the network-level effects of gene variants will pave the way for potential gene therapy applications. Given the diverse comorbidities associated with DEEs, a multidisciplinary team approach is essential. Despite ongoing efforts and improved genetic testing, DEEs lack a cure, and treatment complexities persist. This Review underscores the necessity for larger international prospective studies focusing on both seizure outcomes and developmental trajectories.

Children and Adolescent Patients with Variants in the ATP1A3 -encoded Sodium-Potassium ATPase Alpha-3 Subunit Demonstrate an Impaired QT Response to Bradycardia and Predisposition to Sinus Node Dysfunction.

Background: Alternating hemiplegia of childhood (AHC) is a rare disorder with both neurologic and cardiac manifestations. The ATP1A3-D801N variant is associated with a pathologically short QT interval and risk of ventricular arrhythmia following bradycardia; however, the mechanism of this remains unknown. We investigated the relationship between heart rate (HR), QT, and QTc, hypothesizing that individuals with ATP1A3-D801N have abnormal, impaired shortening of QT and QTc at lower HR leading to arrhythmia predisposition. Methods: We performed a retrospective observational study of individuals who underwent clinical evaluation, Holter monitoring, and genetic testing for AHC at Duke University Hospitals. We also compiled a group of healthy individuals as a control cohort. A larger, worldwide cohort of individuals with ATP1A3 - related phenotypes was compiled to investigate sinus node dysfunction. Linear regression analysis was then performed. Results: The cohort consisted of 44 individuals with ATP1A3 -related phenotypes with 81 Holter recordings (52.27% female; mean age at first Holter 8.04 years, range 0.58 - 33 years), compared to 36 healthy individuals with 57 Holter recordings (52.78% female; mean age at first Holter 9.84 years, range 0.08 - 38 years). Individuals with ATP1A3-D801N had reduced prolongation of QT at lower HR, manifest as a significantly lower slope for HR vs QT compared to healthy (P<0.0001). This resulted in a significantly higher slope of the relationship for HR vs QTc compared to healthy (P<0.0001). Individuals with ATP1A3 - related phenotypes and baseline QTc <350 milliseconds (ms) had increased shortening of QT and QTc at lower HR compared to those with normal QTc (P=0.003; P=0.001). Among worldwide cases, 3 out of 131 individuals with ATP1A3 -related phenotypes required device implantation and/or had sinus pauses >4 seconds. Conclusions: Individuals with the ATP1A3-D801N variant exhibit paradoxical shortening of QT and QTc at lower HR, which contribute to an increased risk of arrhythmias during bradycardia. This is exacerbated by an underlying risk of sinus node dysfunction. Clinical Perspective: What is Known: Individuals with ATP1A3-D801N have a short baseline QTc.Two individuals with AHC experienced ventricular fibrillation following bradycardia. What the Study Adds: The QT and QTc shorten to a greater extent at lower heart rate in individuals with ATP1A3-D801N than in healthy individuals. Individuals with ATP1A3 -related phenotypes and QTc <350ms show greater impairment of QT and QTc dynamics than those with normal QTc. There is low prevalence of device implantation and significant sinus pauses in individuals with ATP1A3 -related phenotypes, with a relatively greater prevalence in those with ATP1A3-D801N.

Bilateral Perisylvian Polymicrogyria, Intellectual Disability and Nephronophthisis Associated With Compound Heterozygous Pathogenic Variants in the CEP83 Gene.

The centrosomal protein 83 (CEP83) is a centriolar protein involved in primary cilium assembly, an early and critical step in ciliogenesis. Bi-allelic pathogenic variants in the CEP83 gene have been associated with infantile nephronophthisis and, in a few patients, retinitis pigmentosa. We describe a 5-year-old boy with bilateral perisylvian polymicrogyria, intellectual disability, and nephronophthisis in whom, using exome sequencing, we identified the c.1052T>G p.(Leu351*) stopgain variant inherited from the father and the c.2024T>C p.(Leu675Pro) missense variant inherited from the mother, in a compound heterozygous pattern. Polymicrogyria or, in general, malformations of cortical development had not been previously observed in patients with pathogenic CEP83 variants. However, defects in CEP83 can affect the formation and function of cilia or centrosomal structures, resulting in a polymicrogyric pattern overlapping with that associated with pathogenic variants affecting other genes coding for centrosomal components. This observation expands the spectrum of phenotypes associated with the CEP83 gene and adds it to the list of genes associated with bilateral perisylvian polymicrogyria.

Italian report on RARE epilepsies (i-RARE): A consensus on multidisciplinarity.

OBJECTIVE: Rare and complex epilepsies encompass a diverse range of disorders characterized by seizures. We aimed to establish a consensus on key issues related to these conditions through collaboration among experienced neurologists, neuropediatricians, and patient advocacy representatives. METHODS: Employing a modified Delphi method, a scientific board comprising 20 physicians and 4 patient advocacy representatives synthesized existing literature with their expertise to formulate statements on contentious topics. A final 32-member expert panel, representing diverse regions of Italy, validated these statements through a two-round voting process, with consensus defined as an average score ≥7. RESULTS: Sixteen statements reached a consensus, emphasizing the necessity for epidemiological studies to ascertain the true prevalence of rare epilepsies. Etiology emerged as a crucial factor influencing therapeutic strategies and outcome prediction, with particular concern regarding prolonged and tonic-clonic seizures. The importance of early implementation of specific drugs and non-pharmacological interventions in the treatment algorithm for developmental and epileptic encephalopathies (DEEs) was underscored. Multidisciplinary care involving experts with diverse skills was deemed essential, emphasizing non-seizure outcomes in adolescence and adulthood. SIGNIFICANCE: This national consensus underscores the imperative for personalized, comprehensive, and multidisciplinary management of rare epilepsies/DEEs. It advocates for increased research, particularly in epidemiology and therapeutic approaches, to inform clinical decision-making and healthcare policies, ultimately enhancing patients' outcomes. PLAIN LANGUAGE SUMMARY: The modified Delphi method is broadly used to evaluate debated topics. In this work, we sought the consensus on integrated and social care in epilepsy management. Both representatives of high-level epilepsy centers and patients' caregivers were directly involved.

Multiorgan manifestations of COL4A1 and COL4A2 variants and proposal for a clinical management protocol.

COL4A1/2 variants are associated with highly variable multiorgan manifestations. Depicting the whole clinical spectrum of COL4A1/2-related manifestations is challenging, and there is no consensus on management and preventative strategies. Based on a systematic review of current evidence on COL4A1/2-related disease, we developed a clinical questionnaire that we administered to 43 individuals from 23 distinct families carrying pathogenic variants. In this cohort, we extended ophthalmological and cardiological examinations to asymptomatic individuals and those with only limited or mild, often nonspecific, clinical signs commonly occurring in the general population (i.e., oligosymptomatic). The most frequent clinical findings emerging from both the literature review and the questionnaire included stroke (203/685, 29.6%), seizures or epilepsy (199/685, 29.0%), intellectual disability or developmental delay (168/685, 24.5%), porencephaly/schizencephaly (168/685, 24.5%), motor impairment (162/685, 23.6%), cataract (124/685, 18.1%), hematuria (63/685, 9.2%), and retinal arterial tortuosity (58/685, 8.5%). In oligosymptomatic and asymptomatic carriers, ophthalmological investigations detected retinal vascular tortuosity (5/13, 38.5%), dysgenesis of the anterior segment (4/13, 30.8%), and cataract (2/13, 15.4%), while cardiological investigations were unremarkable except for mild ascending aortic ectasia in 1/8 (12.5%). Our multimodal approach confirms highly variable penetrance and expressivity in COL4A1/2-related conditions, even at the intrafamilial level with neurological involvement being the most frequent and severe finding in both children and adults. We propose a protocol for prevention and management based on individualized risk estimation and periodic multiorgan evaluations.

COVID-19 response in a long-term care facility for people with epilepsy.

OBJECTIVE: To assess asymptomatic rates and severity of SARS-CoV-2 infection in people with epilepsy and their healthcare workers in a long-term care facility which had implemented weekly surveillance testing between April 2020 and June 2022. METHODS: Questionnaires focused on objective and subjective COVID-19 symptoms for people with epilepsy residing in and their healthcare workers at the Chalfont Centre for Epilepsy in June 2022. Demographic information, comorbidities, and seizure frequency were gathered from medical records. We also collected responses on objective and subjective COVID-19 symptoms from healthcare workers who participated in a prospective study assessing the reaction to COVID-19 vaccinations (SAFER). RESULTS: Fifty-five out of 89 (62%) residents tested positive at least once on weekly PCR testing for SARS-CoV-2 during the period of interest; 20 of those (37%) were asymptomatic. In comparison, of those 63 healthcare workers who tested positive at least once on weekly testing during the same period, only four (6%) were asymptomatic. Of the 159 healthcare workers who also participated in the SAFER study, 41 tested positive at least once, and seven (17%) were completely asymptomatic during infection with SARS-CoV-2. SIGNIFICANCE: People with epilepsy living in a long-term care facility were more likely to present with asymptomatic SARS-CoV-2 infections than healthcare workers at the same facility. Despite possible bias in the reporting of subjective symptoms due to management-by-proxy, there is no evidence that vulnerable people living in an epilepsy long-term care facility showed reduced resilience towards infections. PLAIN LANGUAGE SUMMARY: People with epilepsy living in care home facilities had a surprisingly high degree of asymptomatic infections with SARS-CoV-2. Very few residents had severe or fatal outcomes. This is in stark contrast to the widely reported bad outcomes for people without epilepsy in other care homes. People with epilepsy reported significantly less symptoms than their healthcare workers. No changes in seizure frequency during or after infection were observed.

Morphometric network-based abnormalities correlate with psychiatric comorbidities and gene expression in PCDH19-related developmental and epileptic encephalopathy.

Protocadherin-19 (PCDH19) developmental and epileptic encephalopathy causes an early-onset epilepsy syndrome with limbic seizures, typically occurring in clusters and variably associated with intellectual disability and a range of psychiatric disorders including hyperactive, obsessive-compulsive and autistic features. Previous quantitative neuroimaging studies revealed abnormal cortical areas in the limbic formation (parahippocampal and fusiform gyri) and underlying white-matter fibers. In this study, we adopted morphometric, network-based and multivariate statistical methods to examine the cortex and substructure of the hippocampus and amygdala in a cohort of 20 PCDH19-mutated patients and evaluated the relation between structural patterns and clinical variables at individual level. We also correlated morphometric alterations with known patterns of PCDH19 expression levels. We found patients to exhibit high-significant reductions of cortical surface area at a whole-brain level (left/right pvalue = 0.045/0.084), and particularly in the regions of the limbic network (left/right parahippocampal gyri pvalue = 0.230/0.016; left/right entorhinal gyri pvalue = 0.002/0.327), and bilateral atrophy of several subunits of the amygdala and hippocampus, particularly in the CA regions (head of the left CA3 pvalue = 0.002; body of the right CA3 pvalue = 0.004), and differences in the shape of hippocampal structures. More severe psychiatric comorbidities correlated with more significant altered patterns, with the entorhinal gyrus (pvalue = 0.013) and body of hippocampus (pvalue = 0.048) being more severely affected. Morphometric alterations correlated significantly with the known expression patterns of PCDH19 (rvalue = -0.26, pspin = 0.092). PCDH19 encephalopathy represents a model of genetically determined neural network based neuropsychiatric disease in which quantitative MRI-based findings correlate with the severity of clinical manifestations and had have a potential predictive value if analyzed early.

Which terms should be used to describe medications used in the treatment of seizure disorders? An ILAE position paper.

A variety of terms, such as "antiepileptic," "anticonvulsant," and "antiseizure" have been historically applied to medications for the treatment of seizure disorders. Terminology is important because using terms that do not accurately reflect the action of specific treatments may result in a misunderstanding of their effects and inappropriate use. The present International League Against Epilepsy (ILAE) position paper used a Delphi approach to develop recommendations on English-language terminology applicable to pharmacological agents currently approved for treating seizure disorders. There was consensus that these medications should be collectively named "antiseizure medications". This term accurately reflects their primarily symptomatic effect against seizures and reduces the possibility of health care practitioners, patients, or caregivers having undue expectations or an incorrect understanding of the real action of these medications. The term "antiseizure" to describe these agents does not exclude the possibility of beneficial effects on the course of the disease and comorbidities that result from the downstream effects of seizures, whenever these beneficial effects can be explained solely by the suppression of seizure activity. It is acknowledged that other treatments, mostly under development, can exert direct favorable actions on the underlying disease or its progression, by having "antiepileptogenic" or "disease-modifying" effects. A more-refined terminology to describe precisely these actions needs to be developed.

Bilateral temporal lobe dysplasia and seizure onset associated with biallelic CNTNAP2 variants.

Biallelic CNTNAP2 variants have been associated with Pitt-Hopkins-like syndrome. We describe six novel and one previously reported patients from six independent families and review the literature including 64 patients carrying biallelic CNTNAP2 variants. Initial reports highlighted intractable focal seizures and the failure of epilepsy surgery in children, but subsequent reports did not expand on this aspect. In all our patients (n = 7), brain MRI showed bilateral temporal gray/white matter blurring with white matter high signal intensity, more obvious on the T2-FLAIR sequences, consistent with bilateral temporal lobe dysplasia. All patients had focal seizures with temporal lobe onset and semiology, which were recorded on EEG in five, showing bilateral independent temporal onset in four. Epilepsy was responsive to anti-seizure medications in two patients (2/7, 28.5%), and pharmaco-resistant in five (5/7, 71.5%). Splice-site variants identified in five patients (5/7, 71.5%) were the most common mutational finding. Our observation expands the phenotypic and genetic spectrum of biallelic CNTNAP2 alterations focusing on the neuroimaging features and provides evidence for an elective bilateral anatomoelectroclinical involvement of the temporal lobes in the associated epilepsy, with relevant implications on clinical management.

Dissecting genetics of spectrum of epilepsies with eyelid myoclonia by exome sequencing.

OBJECTIVE: Epilepsy with eyelid myoclonia (EEM) spectrum is a generalized form of epilepsy characterized by eyelid myoclonia with or without absences, eye closure-induced seizures with electroencephalographic paroxysms, and photosensitivity. Based on the specific clinical features, age at onset, and familial occurrence, a genetic cause has been postulated. Pathogenic variants in CHD2, SYNGAP1, NEXMIF, RORB, and GABRA1 have been reported in individuals with photosensitivity and eyelid myoclonia, but whether other genes are also involved, or a single gene is uniquely linked with EEM, or its subtypes, is not yet known. We aimed to dissect the genetic etiology of EEM. METHODS: We studied a cohort of 105 individuals by using whole exome sequencing. Individuals were divided into two groups: EEM- (isolated EEM) and EEM+ (EEM accompanied by intellectual disability [ID] or any other neurodevelopmental/psychiatric disorder). RESULTS: We identified nine variants classified as pathogenic/likely pathogenic in the entire cohort (8.57%); among these, eight (five in CHD2, one in NEXMIF, one in SYNGAP1, and one in TRIM8) were found in the EEM+ subcohort (28.57%). Only one variant (IFIH1) was found in the EEM- subcohort (1.29%); however, because the phenotype of the proband did not fit with published data, additional evidence is needed before considering IFIH1 variants and EEM- an established association. Burden analysis did not identify any single burdened gene or gene set. SIGNIFICANCE: Our results suggest that for EEM, as for many other epilepsies, the identification of a genetic cause is more likely with comorbid ID and/or other neurodevelopmental disorders. Pathogenic variants were mostly found in CHD2, and the association of CHD2 with EEM+ can now be considered a reasonable gene-disease association. We provide further evidence to strengthen the association of EEM+ with NEXMIF and SYNGAP1. Possible new associations between EEM+ and TRIM8, and EEM- and IFIH1, are also reported. Although we provide robust evidence for gene variants associated with EEM+, the core genetic etiology of EEM- remains to be elucidated.

DNAJC12 deficiency: Mild hyperphenylalaninemia and neurological impairment in two siblings.

Background: DNAJC12 co-chaperone protein deficiency has been recently described as a stand-alone metabolic disorder explaining many cases of mild hyperphenylalaninemia (HPA) that are not caused by variants in the PAH gene, which encodes for the hepatic enzyme phenylalanine hydroxylase (PAH), or inGCH1, PTS, QDPR, PCBD1 and DHPR, involved in tetrahydrobiopterin (BH4) biosynthesis and activity. Results: We describe two sisters born to consanguineous parents. The youngest sister (Patient 1), initially asymptomatic, tested positive at NewBorn Screening (NBS) for mild HPA. After variants in the PAH and BH4 related-genes were excluded, we performed DNAJC12 genetic analysis and found a previously described homozygous deletion [NM_021800.3: c.58_59del p.(Gly20Metfs*2)]. The older sister (Patient 2), homozygous for the same variant and exhibiting mild HPA, was diagnosed subsequently and presented with ataxia and repeated falls, upper limb dyskinesia, intentional tremor, and mild intellectual disability. Patient 1 was started on treatment with low Phenylalanine (Phe) diet, BH4, l-3,4-dihydroxyphenylalanine/carbidopa (L-DOPA) and 5-OH-Tryptophan, soon after diagnosis, and despite poor adherence to the dietary regimen, only manifested language impairment at last follow-up (age 5 years and 4 months). Patient 2, who started the same treatment at school age, experienced a minimal progression of neurological symptoms, with some improvement in her motor skills. Conclusions: These two new patients with DNAJC12-associated HPA, in addition to previous reports, point to DNAJC12 deficiency as a new metabolic syndrome that must be considered in patients with unexplained HPA.

Methodology of a Natural History Study of a Rare Neurodevelopmental Disorder: Alternating Hemiplegia of Childhood as a Prototype Disease.

Here, we describe the process of development of the methodology for an international multicenter natural history study of alternating hemiplegia of childhood as a prototype disease for rare neurodevelopmental disorders. We describe a systematic multistep approach in which we first identified the relevant questions about alternating hemiplegia of childhood natural history and expected challenges. Then, based on our experience with alternating hemiplegia of childhood and on pragmatic literature searches, we identified solutions to determine appropriate methods to address these questions. Specifically, these solutions included development and standardization of alternating hemiplegia of childhood-specific spell video-library, spell calendars, adoption of tailored methodologies for prospective measurement of nonparoxysmal and paroxysmal manifestations, unified data collection protocols, centralized data platform, adoption of specialized analysis methods including, among others, Cohen kappa, interclass correlation coefficient, linear mixed effects models, principal component, propensity score, and ambidirectional analyses. Similar approaches can, potentially, benefit in the study of other rare pediatric neurodevelopmental disorders.

Stretch-activated ion channel TMEM63B associates with developmental and epileptic encephalopathies and progressive neurodegeneration.

By converting physical forces into electrical signals or triggering intracellular cascades, stretch-activated ion channels allow the cell to respond to osmotic and mechanical stress. Knowledge of the pathophysiological mechanisms underlying associations of stretch-activated ion channels with human disease is limited. Here, we describe 17 unrelated individuals with severe early-onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment associated with progressive neurodegenerative brain changes carrying ten distinct heterozygous variants of TMEM63B, encoding for a highly conserved stretch-activated ion channel. The variants occurred de novo in 16/17 individuals for whom parental DNA was available and either missense, including the recurrent p.Val44Met in 7/17 individuals, or in-frame, all affecting conserved residues located in transmembrane regions of the protein. In 12 individuals, hematological abnormalities co-occurred, such as macrocytosis and hemolysis, requiring blood transfusions in some. We modeled six variants (p.Val44Met, p.Arg433His, p.Thr481Asn, p.Gly580Ser, p.Arg660Thr, and p.Phe697Leu), each affecting a distinct transmembrane domain of the channel, in transfected Neuro2a cells and demonstrated inward leak cation currents across the mutated channel even in isotonic conditions, while the response to hypo-osmotic challenge was impaired, as were the Ca2+ transients generated under hypo-osmotic stimulation. Ectopic expression of the p.Val44Met and p.Gly580Cys variants in Drosophila resulted in early death. TMEM63B-associated DEE represents a recognizable clinicopathological entity in which altered cation conductivity results in a severe neurological phenotype with progressive brain damage and early-onset epilepsy associated with hematological abnormalities in most individuals.

Morphometry and network-based atrophy patterns in SCN1A-related Dravet syndrome.

Mutations of the voltage-gated sodium channel SCN1A gene (MIM#182389) are among the most clinically relevant epilepsy-related genetic mutations and present variable phenotypes, from the milder genetic epilepsy with febrile seizures plus to Dravet syndrome, a severe developmental and epileptic encephalopathy. Qualitative neuroimaging studies have identified malformations of cortical development in some patients and mild atrophic changes, partially confirmed by quantitative studies. Precise correlations between MRI findings and clinical variables have not been addressed. We used morphometric methods and network-based models to detect abnormal brain structural patterns in 34 patients with SCN1A-related epilepsy, including 22 with Dravet syndrome. By measuring the morphometric characteristics of the cortical mantle and volume of subcortical structures, we found bilateral atrophic changes in the hippocampus, amygdala, and the temporo-limbic cortex (P-value < 0.05). By correlating atrophic patterns with brain connectivity profiles, we found the region of the hippocampal formation as the epicenter of the structural changes. We also observed that Dravet syndrome was associated with more severe atrophy patterns with respect to the genetic epilepsy with febrile seizures plus phenotype (r = -0.0613, P-value = 0.03), thus suggesting that both the underlying mutation and seizure severity contribute to determine atrophic changes.

Risk-conferring HLA variants in an epilepsy cohort: benefits of multifaceted use of whole genome sequencing in clinical practice.

BACKGROUND: Whole genome sequencing is increasingly used in healthcare, particularly for diagnostics. However, its clinically multifaceted potential for individually customised diagnostic and therapeutic care remains largely unexploited. We used existing whole genome sequencing data to screen for pharmacogenomic risk factors related to antiseizure medication-induced cutaneous adverse drug reactions (cADRs), such as human leucocyte antigen HLA-B*15:02, HLA-A*31:01 variants. METHODS: Genotyping results, generated from the Genomics England UK 100 000 Genomes Project primarily for identification of disease-causing variants, were used to additionally screen for relevant HLA variants and other pharmacogenomic variants. Medical records were retrospectively reviewed for clinical and cADR phenotypes for HLA variant carriers. Descriptive statistics and the χ2 test were used to analyse phenotype/genotype data for HLA carriers and compare frequencies of additional pharmacogenomic variants between HLA carriers with and without cADRs, respectively. RESULTS: 1043 people with epilepsy were included. Four HLA-B*15:02 and 86 HLA-A*31:01 carriers were identified. One out of the four identified HLA-B*15:02 carriers had suffered antiseizure medication-induced cADRs; the point prevalence of cADRs was 16.9% for HLA-A*31:01 carriers of European origin (n=46) and 14.4% for HLA-A*31:01 carriers irrespective of ancestry (n=83). CONCLUSIONS: Comprehensive utilisation of genetic data spreads beyond the search for causal variants alone and can be extended to additional clinical benefits such as identifying pharmacogenomic biomarkers, which can guide pharmacotherapy for genetically-susceptible individuals.

Widespread genomic influences on phenotype in Dravet syndrome, a 'monogenic' condition.

Dravet syndrome is an archetypal rare severe epilepsy, considered 'monogenic', typically caused by loss-of-function SCN1A variants. Despite a recognizable core phenotype, its marked phenotypic heterogeneity is incompletely explained by differences in the causal SCN1A variant or clinical factors. In 34 adults with SCN1A-related Dravet syndrome, we show additional genomic variation beyond SCN1A contributes to phenotype and its diversity, with an excess of rare variants in epilepsy-related genes as a set and examples of blended phenotypes, including one individual with an ultra-rare DEPDC5 variant and focal cortical dysplasia. The polygenic risk score for intelligence was lower, and for longevity, higher, in Dravet syndrome than in epilepsy controls. The causal, major-effect, SCN1A variant may need to act against a broadly compromised genomic background to generate the full Dravet syndrome phenotype, whilst genomic resilience may help to ameliorate the risk of premature mortality in adult Dravet syndrome survivors.

Sex-based electroclinical differences and prognostic factors in epilepsy with eyelid myoclonia.

Although a striking female preponderance has been consistently reported in epilepsy with eyelid myoclonia (EEM), no study has specifically explored the variability of clinical presentation according to sex in this syndrome. Here, we aimed to investigate sex-specific electroclinical differences and prognostic determinants in EEM. Data from 267 EEM patients were retrospectively analyzed by the EEM Study Group, and a dedicated multivariable logistic regression analysis was developed separately for each sex. We found that females with EEM showed a significantly higher rate of persistence of photosensitivity and eye closure sensitivity at the last visit, along with a higher prevalence of migraine with/without aura, whereas males with EEM presented a higher rate of borderline intellectual functioning/intellectual disability. In female patients, multivariable logistic regression analysis revealed age at epilepsy onset, eyelid myoclonia status epilepticus, psychiatric comorbidities, and catamenial seizures as significant predictors of drug resistance. In male patients, a history of febrile seizures was the only predictor of drug resistance. Hence, our study reveals sex-specific differences in terms of both electroclinical features and prognostic factors. Our findings support the importance of a sex-based personalized approach in epilepsy care and research, especially in genetic generalized epilepsies.

A registry for Dravet syndrome: The Italian experience.

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

Transcranial magnetic stimulation-evoked electroencephalography responses as biomarkers for epilepsy: A review of study design and outcomes.

Transcranial magnetic stimulation (TMS) with electroencephalography (EEG), that is TMS-EEG, may assist in managing epilepsy. We systematically reviewed the quality of reporting and findings in TMS-EEG studies on people with epilepsy and healthy controls, and on healthy individuals taking anti-seizure medication. We searched the Cochrane Library, Embase, PubMed and Web of Science databases for original TMS-EEG studies comparing people with epilepsy and healthy controls, and healthy subjects before and after taking anti-seizure medication. Studies should involve quantitative analyses of TMS-evoked EEG responses. We evaluated the reporting of study population characteristics and TMS-EEG protocols (TMS sessions and equipment, TMS trials and EEG protocol), assessed the variation between protocols, and recorded the main TMS-EEG findings. We identified 20 articles reporting 14 unique study populations and TMS methodologies. The median reporting rate for the group of people with epilepsy parameters was 3.5/7 studies and for the TMS parameters was 13/14 studies. TMS protocols varied between studies. Fifteen out of 28 anti-seizure medication trials in total were evaluated with time-domain analyses of single-pulse TMS-EEG data. Anti-seizure medication significantly increased N45, and decreased N100 and P180 component amplitudes but in marginal numbers (N45: 8/15, N100: 7/15, P180: 6/15). Eight articles compared people with epilepsy and controls using different analyses, thus limiting comparability. The reporting quality and methodological uniformity between studies evaluating TMS-EEG as an epilepsy biomarker is poor. The inconsistent findings question the validity of TMS-EEG as an epilepsy biomarker. To demonstrate TMS-EEG clinical applicability, methodology and reporting standards are required.

Focal cortical dysplasia: a practical guide for neurologists.

Focal cortical dysplasia (FCD) is a malformation of cortical development characterised by disruption of cortical cytoarchitecture. Classification of FCDs subtypes has initially been based on correlation of the histopathology with relevant clinical, electroencephalographic and neuroimaging features. A recently proposed classification update recommends a multilayered, genotype-phenotype approach, integrating findings from histopathology, genetic analysis of resected tissue and presurgical MRI. FCDs are caused either by single somatic activating mutations in MTOR pathway genes or by double-hit inactivating mutations with a constitutional and a somatic loss-of-function mutation in repressors of the signalling pathway. Mild malformation with oligodendroglial hyperplasia in epilepsy is caused by somatic pathogenic SLC35A2 mutations. FCDs most often present with drug-resistant focal epilepsy or epileptic encephalopathy. Most patients respond to surgical treatment. The use of mechanistic target of rapamycin inhibitors may complement the surgical approach. Treatment approaches and outcomes have improved with advances in neuroimaging, neurophysiology and genetics, although predictors of treatment response have only been determined in part.