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Valproate is a broad-spectrum antiepileptic drug (AED) of particular interest in pediatric epilepsy syndromes and idiopathic generalized epilepsy, as it is relatively more effective in these syndromes than other AEDs. In 2018, the European Medicines Agency introduced new restrictions on the use of valproate in girls and women of childbearing potential to avoid exposure during pregnancy. The strengthening of existing restrictions sparked controversy and debate among patients and the medical community. The high prevalence of epilepsy syndromes amenable to valproate treatment in women of childbearing age and the little information available on the teratogenic potential of alternative treatments have created uncertainty on how to manage these patients. In this consensus statement, based on a review of the literature and the clinical experience of a panel of European epilepsy experts, we present general recommendations for the optimal clinical management of AED treatment in girls, women of childbearing potential, and pregnant women across the different epilepsy syndromes. [ABSTRACT FROM AUTHOR]

Regulatory agencies have recently discouraged the prescription of topiramate (TPM) to women of childbearing potential with epilepsy due to growing evidence of the teratogenic and neurodevelopmental risks associated with its use during pregnancy. It remains, however, unclear whether the use of TPM in this population can be supported to some extent by its high effectiveness. In this multicenter, retrospective, cohort study performed at 22 epilepsy centers, we investigated the comparative effectiveness of TPM and levetiracetam (LEV) given as first‐line antiseizure medication in a cohort of women of childbearing potential with idiopathic generalized epilepsy (IGE). A total of 336 participants were included, of whom 24 (7.1%) received TPM and 312 (92.9%) LEV. Women treated with TPM had significantly higher risks of treatment failure and treatment withdrawal and were less likely to achieve seizure freedom at 12 months compared to women treated with LEV. In conclusion, this study highlighted a low tendency among clinicians to use TPM in women of childbearing potential with IGE, anticipating the recently released restrictions on its use. Furthermore, the available data on effectiveness do not appear to support the use of TPM in this population. [ABSTRACT FROM AUTHOR]

Objective Most cases of sudden unexpected death in epilepsy (SUDEP) follow a seizure, and most deaths occur while people are in bed, presumably sleeping. Nocturnal seizures are reported to be a risk factor for SUDEP. People with nocturnal frontal lobe epilepsy (NFLE) have seizures predominantly or exclusively during sleep, often many times per night. The present study aimed to assess whether NFLE represents a high-risk condition for SUDEP. Methods The present study retrospectively assessed the incidence of SUDEP in a cohort reconstructed from a dedicated database of consecutive patients referred to the Epilepsy and Sleep Centres of the Institute of Neurological Sciences of Bologna from 1980 to 2012 with: (1) a diagnosis of NFLE, (2) at least 90% of seizures during sleep, and (3) at least one-year of follow-up. Results One hundred and three people were included. The median time from seizure onset to last observation was 26 years, equal to a follow-up of 2789 person-years. One person died of SUDEP during the follow-up period. The incidence rate of SUDEP was 0.36 per 1000 person-years (95% CI 0.01 to 2.0). Conclusions The incidence of SUDEP in the participant population was not higher than the rates previously reported in prevalent epilepsy populations (0.4 to 2.3 per 1000 person-years). The low prevalence of SUDEP might reflect the low occurrence of generalised tonic-clonic seizures in people with NFLE. [ABSTRACT FROM AUTHOR]

Abstract: Psychogenic nonepileptic seizures (PNES) are highly prevalent in selected populations, with a strong impact in terms of morbidity and social cost. The gold standard for PNES diagnosis is video/EEG recording of a typical attack. However this technique is costly and not always available. In addition, many patients are treated with antiepileptic drugs for several years before undergoing video/EEG recording. The diagnosis is further complicated by concomitant epileptic seizures in some patients with PNES. Therefore, a good knowledge of PNES semiology is important for early screening of patients for video/EEG recording and for correct interpretation of the examination. We reviewed the literature on video/EEG studies reporting ictal PNES semiology to identify features indicative of psychogenic or epileptic seizures. Several features appeared to be useful in the clinical setting. [Copyright &y& Elsevier]

Sleep disturbance and excessive daytime sleepiness have been reported in patients with hepatic cirrhosis. The objective of this study was to evaluate daytime somnolence and sleep complaints in a group of 178 patients with cirrhosis compared to a control group. Sleep features and excessive daytime sleepiness were evaluated by the Basic Nordic Sleep Questionnaire (BNSQ) and the Epworth Sleepiness Scale (ESS). We collected clinical and laboratory data, neurological assessment and EEG recordings in cirrhotic patients. Patients with cirrhosis complained of more daytime sleepiness ( p<0.005), sleeping badly at least three times a week ( p<0.005), difficulties falling asleep ( p<0.01) and frequent nocturnal awakening ( p<0.005) than controls. We found a poor correlation between sleep disorders and clinical or laboratory parameters. Our results confirm previous literature reports suggesting a high prevalence of sleep disturbance in patients with cirrhosis. Insomnia and daytime sleepiness are the main complaints. Sleep disorders are probably a multifactorial phenomenon. [ABSTRACT FROM AUTHOR]

Objective: Women of childbearing age with juvenile absence epilepsy (JAE) face treatment challenges due to limited access to safe and effective anti‐seizure medications (ASMs). In a previous study we compared the effectiveness of levetiracetam (LEV) and lamotrigine (LTG) in women with idiopathic generalized epilepsy (IGE), highlighting a superiority of LEV in juvenile myoclonic epilepsy. In this study, we specifically reanalyzed, through a Bayesian approach and by expanding the previously published cohort, the comparative effectiveness of these ASMs as initial monotherapy in JAE. Methods: We conducted a multicenter, retrospective, comparative effectiveness study on women of childbearing age diagnosed with JAE and prescribed LEV or LTG as the initial ASM. Inverse probability treatment weighting (IPTW) Bayesian Cox proportional hazard models were employed to evaluate treatment failure (TF) due to ineffectiveness and ASM retention. The patients' center of provenance and year of prescription were considered as random effect factors. Posterior probabilities and relative log‐risk distribution were computed, and the distribution of posterior draws was analyzed to assess the evidence supporting LTG superiority over LEV. Results: Of 123 patients, those treated with LTG (n = 67) demonstrated lower TF and higher ASM retention than those treated with LEV (n = 56), with the IPTW‐weighted Bayesian Cox proportional hazards model showing a 99.2% posterior probability of LTG being superior on TF and a 99.5% probability on ASM retention. Additional analyses on ≥50% and ≥75% seizure reduction through IPTW‐weighted Bayesian logistic regression largely confirmed these findings, whereas the two ASMs did not show evident differences in terms of seizure freedom. The two ASMs showed comparable safety profiles, with only a minority of patients discontinuing treatment due to side effects. Significance: Bayesian reanalysis supports LTG as first‐line monotherapy for JAE in women of childbearing age, emphasizing the importance of individualized treatment strategies in women with IGE. This study underscores the value of Bayesian methods in refining clinical research and treatment decisions. [ABSTRACT FROM AUTHOR]

Background: Sex differences in epilepsy have been described in prevalence, seizure propensity and response to treatment. Therefore, taking into account sex-based differences in epilepsy is important for both diagnostic purposes and therapeutic considerations. However, little is known about sex differences in adverse effects of antiseizure medications (ASMs). Objectives: We performed a systematic review searching for sex differences in adverse effects of ASMs in adult persons with epilepsy (PWE) as part of a wider project aimed to assess sex-based differences in efficacy and adverse effects of ASMs in PWE. Methods: We conducted a comprehensive literature search in the PubMed database. The search was conducted with no restriction on publication date, and all results up to April 2020 were included. We included articles written in English, Italian, Spanish, or French that evaluated adverse effects of one or more ASMs in PWE, with specific mention of the two sexes. When appropriate, Newcastle-Ottawa or Jadad scales were used to assess study quality. Results: Of 5164 identified studies, only 167 considered sex in the analysis and were therefore included. Significant sex-related differences were found in 58 of those studies. We found a consistently higher frequency of cutaneous adverse effects in females; higher risk of developing general adverse effects on different ASMs in females; stronger risk of adverse effects on bone metabolism in females, mainly on treatment with enzyme-inducing ASMs; a concordant higher risk of visual field loss was noted in males on vigabatrin; an overall worse lipid profile in males; as well as higher leptin levels and higher body mass index in females treated with various ASMs. Conclusions: Our analysis has identified some important sex differences in the adverse effects of ASMs. Clinicians should be aware of these differences when informing patients about the risks associated with ASM treatment in PWE. [ABSTRACT FROM AUTHOR]

Background: Ictal bradycardia (IB) and asystole (IA) represent a rare but potentially harmful feature of epileptic seizures. The aim of this study was to study IB/IA in patients with sleep-related hypermotor epilepsy (SHE). Methods: We retrospectively included cases with video-EEG-confirmed SHE who attended our Institute up to January 2021. We reviewed the ictal polysomnography recordings focusing on ECG and identified cases with IB (R-R interval ≥ 2 s or a ≥10% decrease of baseline heart rate) and IA (R-R interval ≥ 4 s). Results: We included 200 patients (123 males, 61.5%), with a mean age of 42 ± 16 years. Twenty patients (20%) had focal cortical dysplasia (FCD) on brain MRI. Eighteen (out of 104 tested, 17.3%) carried pathogenic variants (mTOR pathway, n = 10, nAchR subunits, n = 4, KCNT1, n = 4). We identified IB/IA in four cases (2%): three had IA (mean 10 s) and one had IB. Three patients had FCD (left fronto-insular region, left amygdala, right mid-temporal gyrus) and two had pathogenic variants in DEPDC5; both features were more prevalent in patients with IB/IA than those without (p = 0.003 and p = 0.037, respectively). Conclusions: We identified IB/IA in 2% of patients with SHE and showed that this subgroup more frequently had FCD on brain MRI and pathogenic variants in genes related to the mTOR pathway. [ABSTRACT FROM AUTHOR]

Background: Lafora disease (LD) is a fatal form of progressive myoclonic epilepsy caused by biallelic pathogenic variants in EPM2A or NHLRC1. With a few exceptions, the influence of genetic factors on disease progression has yet to be confirmed. We present a systematic review and meta-analysis of the known pathogenic variants to identify genotype–phenotype correlations. Methods: We collected all reported cases with genetically-confirmed LD containing data on disease history. Pathogenic variants were classified into missense (MS) and protein-truncating (PT). Three genotype classes were defined according to the combination of the variants: MS/MS, MS/PT, and PT/PT. Time-to-event analysis was performed to evaluate survival and loss of autonomy. Results: 250 cases described in 70 articles were included. The mutated gene was NHLRC1 in 56% and EPM2A in 44% of cases. 114 pathogenic variants (67 EPM2A; 47 NHLRC1) were identified. The NHLRC1 genotype PT/PT was associated with shorter survival [HR 2.88; 95% CI 1.23–6.78] and a trend of higher probability of loss of autonomy [HR 2.03, 95% CI 0.75–5.56] at the multivariable Cox regression analysis. The population carrying the homozygous p.Asp146Asn variant of NHLRC1 genotype was confirmed to have a more favourable prognosis in terms of disease duration. Conclusions: This study demonstrates the existence of prognostic genetic factors in LD, namely the genotype defined according to the functional impact of the pathogenic variants. Although the reasons why NHLRC1 genotype PT/PT is associated with a poorer prognosis have yet to be fully elucidated, it may be speculated that malin plays a pivotal role in LD pathogenesis. Key points: What is already known on this topic: Lafora disease (LD) is a fatal form of progressive myoclonic epilepsy caused by biallelic pathogenic variants in the EPM2A or NHLRC1 genes. With a few exceptions, the influence of genetic factors on disease progression has yet to be confirmed. What this study adds: The study identified prognostic genetic factors in LD and demonstrated a correlation between certain genotypes and worse prognosis. Specifically, biallelic truncating variants in NHLRC1 were associated with a higher probability of loss of autonomy and shorter survival. The study also confirmed that the homozygous p.Asp146Asn variant of NHLRC1 has a more favourable prognosis. How this study might affect research, practice, or policy: The study sheds light on the potential genetic factors affecting the prognosis of LD, which could inform future research into treatments and therapies. This study's findings should be taken into account when launching trials of disease-modifying therapies, to ensure that outcomes are correctly interpreted. [ABSTRACT FROM AUTHOR]

Background: Lafora disease (LD) is a fatal form of progressive myoclonic epilepsy caused by biallelic pathogenic variants in EPM2A or NHLRC1. With a few exceptions, the influence of genetic factors on disease progression has yet to be confirmed. We present a systematic review and meta-analysis of the known pathogenic variants to identify genotype–phenotype correlations. Methods: We collected all reported cases with genetically-confirmed LD containing data on disease history. Pathogenic variants were classified into missense (MS) and protein-truncating (PT). Three genotype classes were defined according to the combination of the variants: MS/MS, MS/PT, and PT/PT. Time-to-event analysis was performed to evaluate survival and loss of autonomy. Results: 250 cases described in 70 articles were included. The mutated gene was NHLRC1 in 56% and EPM2A in 44% of cases. 114 pathogenic variants (67 EPM2A; 47 NHLRC1) were identified. The NHLRC1 genotype PT/PT was associated with shorter survival [HR 2.88; 95% CI 1.23–6.78] and a trend of higher probability of loss of autonomy [HR 2.03, 95% CI 0.75–5.56] at the multivariable Cox regression analysis. The population carrying the homozygous p.Asp146Asn variant of NHLRC1 genotype was confirmed to have a more favourable prognosis in terms of disease duration. Conclusions: This study demonstrates the existence of prognostic genetic factors in LD, namely the genotype defined according to the functional impact of the pathogenic variants. Although the reasons why NHLRC1 genotype PT/PT is associated with a poorer prognosis have yet to be fully elucidated, it may be speculated that malin plays a pivotal role in LD pathogenesis. Key points: What is already known on this topic: Lafora disease (LD) is a fatal form of progressive myoclonic epilepsy caused by biallelic pathogenic variants in the EPM2A or NHLRC1 genes. With a few exceptions, the influence of genetic factors on disease progression has yet to be confirmed. What this study adds: The study identified prognostic genetic factors in LD and demonstrated a correlation between certain genotypes and worse prognosis. Specifically, biallelic truncating variants in NHLRC1 were associated with a higher probability of loss of autonomy and shorter survival. The study also confirmed that the homozygous p.Asp146Asn variant of NHLRC1 has a more favourable prognosis. How this study might affect research, practice, or policy: The study sheds light on the potential genetic factors affecting the prognosis of LD, which could inform future research into treatments and therapies. This study's findings should be taken into account when launching trials of disease-modifying therapies, to ensure that outcomes are correctly interpreted. [ABSTRACT FROM AUTHOR]

Objective: Due to significant risks to the offspring after intrauterine exposure, the European Medicines Agency issued recommendations in 2014 and 2018 restricting the use of valproate (VPA) in women of childbearing age (WOCA). We aimed to evaluate their impact in the Emilia‐Romagna region (ERR) of Northern Italy. Methods: Using administrative databases, we identified all the ERR residents who received antiseizure medication (ASM) prescriptions from 2010 to 2020. Time series of incidence rates by sex and age group were evaluated for all ASMs. Focusing on VPA, an interrupted time series analysis was applied to assess the impact of the restrictions in WOCA with epilepsy (WOCA‐E) and WOCA with psychiatric disorders (WOCA‐P). We then evaluated the chronological order of ASM prescriptions with regard to the position of VPA. Results: Incidence rates of VPA prescriptions overall decreased over time. A significant decrease was observed only for females. The effect was stronger for WOCA, after both the first (incidence rate ratio [IRR] =.85, 95% confidence interval [CI] =.75–.96) and the second restriction (IRR =.67, 95% CI =.55–.82). The decrease was significant after the second restriction both for WOCA‐E (IRR =.43, 95% CI =.27–.68) and for WOCA‐P (IRR =.49, 95% CI =.35–.70), as well as VPA as a first prescription in both populations. VPA prescriptions as further choice did not show the same trend. Significance: After the regulatory restrictions, an overall significant decline in the use of VPA in WOCA was observed in ERR. The second restriction has been effective in consolidating the prescription trend. However, VPA appears still to be a commonly used drug in WOCA when other ASMs have failed. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Sleepiness and driving is a dangerous combination that causes thousands of crashes each year resulting in injury and death. In the last few years, driving simulators have been used to study the performance decrements associated with drowsiness.We correlated performances of a driving simulation task in healthy volunteers in different alertness conditions with objective (MSLT: Multiple Sleep Latency Test) and subjective (SSS: Stanford Sleepiness Scale; VAS: Visual Analogue Scale) sleepiness measurements.The subjects were tested on two days, after a normal night of sleep and after a night of complete sleep deprivation. The study consists of four sessions of MSLT, each one followed by subjective measurements of sleepiness and by a 30 min driving simulation task with a monotonous driving scenario.The parameters that correlate most highly with MSLT are the standard deviation of lane position, the mean RT, crash frequency and exceeding the speed limit frequency.The monotonous driving simulation we adopted showed strong correlations with MSLT and subjective sleepiness scales in healthy subjects and is suitable to evaluate excessive daytime sleepiness in patients. [Copyright &y& Elsevier]

Background: Lafora 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.Methods: A 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.Results: Seventy-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 < 18 years emerged as negative prognostic factors, while type of mutated gene and symptoms at onset were not related to survival or disability.Conclusions: This 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. [ABSTRACT FROM AUTHOR]

Volumetric absorptive microsampling (VAMS) is increasingly proposed as a clinically reliable therapeutic drug monitoring (TDM) sampling methodology. The study aimed to establish the reliability and real-life feasibility of patient self-collected capillary VAMS for TDM of antiseizure medication (ASMs), using plasma ASMs concentrations from venous blood as a reference standard. Nurses collected venous and capillary blood samples using VAMS. Afterward, persons with epilepsy (PWE) performed VAMS sampling by themselves. All samples were analyzed by UHPLC-MS/MS. We performed a cross-validation study, comparing ASMs concentrations obtained by VAMS nurses and patients' self-collected versus plasma through Bland-Altman analysis and Passing-Bablok regression. We enrolled 301 PWE (M: F 42.5%:57.5%; mean age 44±16 years), treated with 13 ASMs, providing a total of 464 measurements. Statistical analysis comparing VAMS self-collected versus plasma ASMs concentrations showed a bias close to zero and slope and intercept values indicating a good agreement for CBZ, LCS, LEV, LTG, OXC, PB, and PHT, while a systematic difference between the two methods was found for VPA, PMP, TPM and ZNS. This is the first study showing the reliability and feasibility of the real-world application of PWE self-collected VAMS for most of the ASMs considered, giving a promising basis for at-home VAMS applications. [Display omitted] • Real-life data on using VAMS for antiseizure medication (ASMs) are lacking. • Cross-validation investigated reliability and feasibility of VAMS vs venous blood. • VAMS showed good accuracy and reliability for CBZ, LCS, LEV, LTG, OXC, PB, and PHT. • Comparison between self and nurse-collected VAMS demonstrates good correlation. • VAMS was demonstrated as a promising tool for future TDM at-home applications. [ABSTRACT FROM AUTHOR]

Background: Arousal Disorders (DoA) include Confusional Arousals, Sleepwalking and Sleep Terrors. DoA diagnosis is mainly clinical but no validated questionnaires exist for DoA screening according to the criteria of the International Classification of Sleep Disorders, Third Edition. Recently our group proposed the Arousal Disorders Questionnaire (ADQ) as a new diagnostic tool for DoA diagnosis. The objective of this study was to evaluate the diagnostic accuracy of the ADQ in a sleep and epilepsy center.Methods: One interviewer blinded to clinical and video-polysomnographic (VPSG) data administered the ADQ to 150 patients consecutively admitted to our Sleep and Epilepsy Centers for a follow-up visit. The final diagnosis, according to VPSG recordings of at least one major episode, classified patients either with DoA (DoA group) or with other sleep-related motor behaviors confounding for DoA (nDoA group).Results: 47 patients (31%) composed the DoA group; 56 patients with REM sleep behavior disorder, 39 with sleep-hypermotor epilepsy, six with night eating syndrome, and two with drug-induced DoA composed the nDoA group. The ADQ had a sensitivity of 72% (95% CI: 60-82) and a specificity of 96% (95% CI: 89-98) for DoA diagnosis; excluding the items regarding consciousness and episode recall, sensitivity was 83% (95% CI: 71-90) and specificity 93% (95% CI: 86-97).Conclusions: The ADQ showed good accuracy in screening patients with DoA in a sleep and epilepsy center setting. Diagnostic criteria related to cognition and episode recall reduced ADQ sensitivity, therefore a better definition of these criteria is required, especially in adults. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Developmental and epileptic encephalopathies (DEE) encompass rare, sporadic neurodevelopmental disorders and usually with pediatric onset. As these conditions are characterized by marked clinical and genetic heterogeneity, whole‐exome sequencing (WES) represents the strategy of choice for the molecular diagnosis. While its usefulness is well established in pediatric DEE cohorts, our study is aimed at assessing the WES feasibility in adult DEE patients who experienced a diagnostic odyssey prior to the advent of this technique. We analyzed exomes from 71 unrelated adult DEE patients, consecutively recruited from an Italian cohort for the EPI25 Project. All patients underwent accurate clinical and electrophysiological characterization. An overwhelming percentage (90.1%) had already undergone negative genetic testing. Variants were classified according to the American College of Medical Genetics and Genomics guidelines. WES disclosed 24 (likely) pathogenic variants among 18 patients in epilepsy‐related genes with either autosomal dominant, recessive or X‐linked inheritance. Ten of these were novel. We obtained a diagnostic yield of 25.3%, higher among patients with brain malformations, early‐onset epilepsy and dysmorphisms. Despite a median diagnostic delay of 38.7 years, WES analysis provided the long‐awaited diagnosis for 18 adult patients, which also had an impact on the clinical management of 50% of them. [ABSTRACT FROM AUTHOR]

• Epilepsy is the most frequent neurological manifestations in adult TSC. • The 64.1% of adult TSC patients have drug-resistant seizures. • Intellectual disability is a strong predictor of non-remission. • Multiple seizure types lifelong predict poor anti-seizure medication response. • Continuous follow-up needed for nephrological manifestations. Typically diagnosed in early childhood or adolescence, TSC is a chronic, multisystemic disorder with age-dependent manifestations posing a challenge for transition and for specific surveillance throughout the lifetime. Data on the clinical features and severity of TSC in adults and on the prognosis of epilepsy are scarce. We analyzed the clinical and genetic features of a cohort of adult patients with TSC, to identify the prognostic predictors of seizure remission after a long follow-up. We conducted a retrospective analysis of patients diagnosed with TSC according to the updated international diagnostic criteria. Pearson's chi-square or Fisher's exact test and Mann Whitney U test were used to compare variables among the Remission (R) and Non-Remission (NR) group. Univariate and multivariate logistic regression analyses were performed. We selected 43 patients with TSC and neurological involvement in terms of epilepsy and/or brain lesions, attending the Epilepsy Center of our Institute: of them, 16 (37.2%) were transitioning from the pediatric care and 6 (13.9%) were referred by other specialists. Multiorgan involvement includes cutaneous (86.0%), nephrological (70.7%), hepatic (40.0%), ocular (34.3%), pneumological (28.6%) and cardiac (26.3%) manifestations. Thirty-nine patients (90.7 %) had epilepsy. The mean age at seizure onset was 4 ± 7.3 years: most patients (29, 76.3 %) presented with focal seizures or spasms by age 3 years; only 2 (5.3 %) had seizure onset in adulthood. Twenty-seven patients (69.2 %) experienced multiple seizure types overtime, 23 (59.0 %) had intellectual disability (ID). At last assessment, 14 (35.9 %) were seizure free (R group) and 25 (64.1 %) had drug-resistant seizures (NR group). At logistic regression univariate analysis, ID (OR 7.9, 95 % CI 1.8––34.7), multiple seizure types lifelong (OR 13.2, 95 % CI 2.6– 67.2), spasms/tonic seizures at presentation (OR 6.5, 95 % CI 1.2––35.2), a higher seizure frequency at onset (OR 5.4, 95 % CI 1.2––24.3), abnormal neurological examination (OR 9.8, 95 % CI 1.1––90.6) and pathogenic variants in TSC2 (OR 5.4, 95 % CI 1.2––24.5) were significantly associated with non-remission. In the multivariate analysis, both ID and multiple seizure types lifelong were confirmed as independent predictors of poor seizure outcome. In our cohort of adult patients with TSC, epilepsy remains one of the main neurological challenges with only 5.3% of cases manifesting in adulthood. Approximately 64% of these patients failed to achieve seizure remission. ID and multiple seizure types were the main predictors of poor outcome. Nephrological manifestations require continuous specific follow-up in adults. [ABSTRACT FROM AUTHOR]

Sleep‐related hypermotor epilepsy (SHE) is characterized by hyperkinetic seizures arising from sleep. Awake seizures occasionally occur and are associated with a worse prognosis, with important implications for driving and quality of life. We evaluated the clinical features and sleep/wakefulness distribution of seizures at onset and lifelong in a large cohort of clinical/confirmed SHE. Chi‐square test and a multivariate logistic regression model were used to identify predictors of awake seizures lifelong (primary endpoint). Positive and negative likelihood ratio (LR+, LR‐) were calculated. We included 165 patients (male/female: 105/60) with a 27.6‐year median follow‐up. Most (67.9%) presented with seizures exclusively from sleep; 32.1% presented with seizures both while asleep and while awake, or exclusively during wakefulness. Presentation with seizures in wakefulness shows a sensitivity of 62.5% and a specificity of 96.5% to predict the occurrence of awake seizures lifelong, with an LR + of 18 (95% confidence interval [CI] = 5.75‐55) and LR‐ of 0.39 (95% CI = 0.29‐0.52). On multivariate analysis, distribution of sleep/awake seizures at onset was confirmed as an independent risk factor of awake seizures lifelong (odds ratio = 56.7). Patients presenting with awake seizures have a 94% probability of awake seizures lifelong, whereas in those presenting with asleep seizures only, the percentage lowers to 27%. This aspect should be mentioned during physician‐to‐patient communication about prognosis. [ABSTRACT FROM AUTHOR]

After the European Medicines Agency (EMA) warning on the use of valproate (VPA) in female patients, we explored the antiepileptic drug (AED) prescribing attitudes of Italian epileptologists with regard to sex and VPA use in patients with epilepsy. A specifically designed 30-item questionnaire was distributed at the annual multicenter meeting of the Italian League Against Epilepsy (LICE), held in Rome on January 2018. One hundred and sixty-nine physicians answered the questionnaire. In females, VPA was significantly less prescribed as first-choice AED in childhood absence epilepsy (22% females vs 64% males, p < 0.001), Dravet syndrome (54% vs 71%, p = 0.01), juvenile myoclonic epilepsy (JME) (2% vs 74%, p < 0.001), and undetermined epilepsy (0% vs 32%, p < 0.001). Ninety-six percent of the respondents inform teenage girls of the detrimental effects of intrauterine exposure to VPA; 74% recommend contraceptive measures when prescribing VPA. All the respondents stated that they were aware of the recommendations on VPA in female patients, and 64% claimed to have had difficulties in implementing them. The main challenges were represented by women with JME, who were seizure-free on VPA and failed to respond to levetiracetam and lamotrigine, and by little girls for whom VPA was considered the best choice. According to many Italian epileptologists, the decision to withdraw VPA should be shared with the patient. • Sex is an important determiner of prescriptions for Italian epileptologists. • Most epileptologists reported difficulties in adherence to the warnings on VPA. • Many epileptologists share decision with patients rather than a priori withdrawing VPA. • Sex affects epileptologists' AED choice also in girls with self-limiting epilepsy such as childhood absence epilepsy. • Sex affects epileptologists' AED choice also in girls with severe epilepsy such as Dravet syndrome. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to characterize the neuropsychological features of a representative sample of Sleep-related Hypermotor Epilepsy (SHE) patients and to highlight clinical associations.Methods: This cross-sectional study included 60 consecutive patients with video/video-electroencephalography-documented SHE. All were assessed by measures of intelligence. Individuals with normal scores underwent a standardized battery of tests. The Fisher exact test and Wilcoxon rank-sum test for statistical analysis.Results: Mean total IQ was 96.96 ± 21.50, with significant differences between verbal and performance scores (p < 0.0001). Nine patients (15%) had intellectual disability (ID)/cognitive deterioration. Of the 49 assessed by the extensive battery, 23 (46.9%) showed deficits in at least one test evaluating phonemic fluency (24.5%), memory (24.5%), inhibitory control (22.4%), or working memory (10.2%). Patients with mutations in SHE genes had lower IQ than patients without mutations, irrespective of the specific gene (p = 0.0176). Similarly, pathological neurological examination (NE) and "any underlying brain disorder" (at least one among pathological NE, abnormal brain magnetic resonance imaging findings, perinatal insult) were associated with ID (p = 0.029, p = 0.036). A higher seizure frequency at last assessment and poor prognosis correlated with worse scores in visuo-spatial memory (p = 0.038, p = 0.040) and visuo-spatial abilities (p = 0.016). Status epilepticus (p = 0.035), poor response to antiepileptic drugs (p = 0.033), and poor prognosis (p = 0.020) correlated with lower shifting abilities, whereas bilateral convulsive seizures correlated with worse working memory (p = 0.049).Conclusion: In all, 53.3% of SHE patients had neuropsychological deficits. The profile of impairment showed worse verbal IQ, as well as deficits in extrafrontal and selective frontal functions. Our data support the contribution of genetics in ID by different biological mechanisms. Variables of clinical severity affect memory and executive functioning. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

Glucose transporter type 1 (GLUT1) deficiency due to SLC2A1 mutations causes a wide spectrum of neurologic disorders ranging from severe encephalopathy with developmental delay, epilepsy, ataxia, and acquired microcephaly to atypical less severe variants. Early diagnosis is crucial for prompt initiation of a ketogenic diet. Recognizing GLUT1 deficiency syndrome (GLUT1DS) may be challenging and results in delayed diagnosis. Here we describe the clinical and molecular findings of patients with SLC2A1 mutations referred to our adult Epilepsy Center. Patients with a clinical history suggestive of GLUT1DS were screened for SLC2A1 mutations. Blood samples were collected from probands and first-degree relatives. A lumbar puncture was performed in two patients in fasting state, and cerebrospinal fluid and blood glucose measurement were undertaken at the same time. Since 2010, 19 GLUT1DS probands have been screened for SLC2A1 mutations. We identified four different SLC2A1 mutations in three sporadic cases and one family. Three mutations (c.130_135delTACAAC, c.342_343insA, and c.845A > G) were novel, whereas one was previously reported in the literature associated with a different phenotype (c.497_499delTCG). Here we describe a small case series of patients with sporadic and familial GLUT1DS presenting with a broad phenotypic heterogeneity which is likely to be responsible for the considerable delay in diagnosis. [ABSTRACT FROM AUTHOR]

Objective To describe the anatomo-electro-clinical findings of patients with nocturnal hypermotor seizures (NHS) preceded by auditory symptoms, to evaluate the localizing value of auditory aura. Methods Our database of 165 patients with nocturnal frontal lobe epilepsy (NFLE) diagnosis confirmed by videopolysomnography (VPSG) was reviewed, selecting those who reported an auditory aura as the initial ictal symptom in at least two NHS during their lifetime. Results Eleven patients were selected (seven males, four females). According to the anatomo-electro-clinical data, three groups were identified. Group 1 [defined epileptogenic zone (EZ)]: three subjects were studied with stereo-EEG. The EZ lay in the left superior temporal gyrus in two cases, whereas in the third case seizures arose from a dysplastic lesion located in the left temporal lobe. One of these three patients underwent left Heschl's gyrus resection, and is currently seizure-free. Group 2 (presumed EZ): three cases in which a presumed EZ was identified; in the left temporal lobe in two cases and in the left temporal lobe extending to the insula in one subject. Group 3 (uncertain EZ): five cases had anatomo-electro-clinical correlations discordant. Conclusions This work suggests that auditory aura may be a helpful anamnestic feature suggesting an extra-frontal seizure origin. This finding could guide secondary investigations to improve diagnostic definition and selection of candidates for surgical treatment. [ABSTRACT FROM AUTHOR]

Abstract: The beneficial effect of nicotine has been reported in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) patients, but not tested in sporadic cases. Recently, a nicotine defect in the arousal pathway has been hypothesized even in sporadic NFLE patients and their relatives. This case–control family study was designed to test whether NFLE subjects were more likely to use tobacco than controls, as an indirect marker of cholinergic arousal system dysregulation. At least four relatives were included for each NFLE proband and control. Each subject was questioned about tobacco habits; 434 individuals were recruited. Moreover, we compared NFLE patients with age- and sex-matched controls to determine whether they are more likely to use tobacco. We found a slightly higher trend of tobacco use in NFLE probands compared to that in control subjects; we did not find any significant difference in the distribution of tobacco use among NFLE group compared to that in the control group. [Copyright &y& Elsevier]

The intra vitam diagnosis of prion disease is challenging and a definite diagnosis still requires neuropathological examination in non-familial cases. Magnetic resonance imaging has gained increasing importance in the diagnosis of prion disease. The aim of this study was to compare the usefulness of different magnetic resonance imaging sequences and proton magnetic resonance spectroscopy in the differential diagnosis of patients with rapidly progressive neurological signs compatible with the clinical diagnosis of sporadic prion disease. Twenty-nine consecutive patients with an initial diagnosis of possible or probable sporadic prion disease, on the basis of clinical and electroencephalography features, were recruited. The magnetic resonance protocol included axial fluid-attenuated inversion recovery-T2- and diffusion-weighted images, and proton magnetic resonance spectroscopy of the thalamus, striatum, cerebellum and occipital cortex. Based on the clinical follow-up, genetic studies and neuropathology, the final diagnosis was of prion disease in 14 patients out of 29. The percentage of correctly diagnosed cases was 86% for diffusion-weighted imaging (hyperintensity in the striatum/cerebral cortex), 86% for thalamic N-acetyl-aspartate to creatine ratio (cutoff ≤1.21), 90% for thalamic N-acetyl-aspartate to myo-inositol (mI) ratio (cutoff ≤1.05) and 86% for cerebral spinal fluid 14-3-3 protein. All the prion disease patients had N-acetyl-aspartate to creatine ratios ≤1.21 (100% sensitivity and 100% negative predictive value) and all the non-prion patients had N-acetyl-aspartate to myo-inositol ratios >1.05 (100% specificity and 100% positive predictive value). Univariate logistic regression analysis showed that the combination of thalamic N-acetyl-aspartate to creatine ratio and diffusion-weighted imaging correctly classified 93% of the patients. The combination of thalamic proton magnetic resonance spectroscopy (10 min acquisition duration) and brain diffusion-weighted imaging (2 min acquisition duration) may increase the diagnostic accuracy of the magnetic resonance scan. Both sequences should be routinely included in the clinical work-up of patients with suspected prion disease. [ABSTRACT FROM PUBLISHER]

Abstract: Narcolepsy with cataplexy is characterised by excessive daytime sleepiness, sudden drops of muscle tone triggered by emotions, termed cataplexy, disrupted nocturnal sleep and other dissociated rapid eye movement (REM) sleep phenomena. Narcolepsy has been linked to a loss of hypothalamic neurons producing hypocretins, neuropeptides implicated in the regulation of the arousal system. Neuroimaging and neurometabolic studies have shown the pathophysiological involvement of other brain structures such as cerebral cortex and thalamus, but, overall with inconsistent results. We investigated, by using an advanced quantitative MR technique, proton MR spectroscopy (1H-MRS), the distribution of brain neurochemical abnormalities in narcolepsy with cataplexy patients. Single voxel 1H-MRS study was performed in the thalamus, hypothalamus, and parietal–occipital cortex of hypocretin deficient, narcolepsy with cataplexy patients, HLA-DQB1*0602-positive, drug free. No significant changes were detected in the thalamus and parietal–occipital cortex of the patients. On the other hand, the neuronal marker N-acetyl-aspartate was reduced in the hypothalamus of narcolepsy with cataplexy patients compared to controls. These 1H-MRS findings further support that in narcolepsy with cataplexy patients, the hypothalamus is the primary site of neural lesions. The absence of 1H-MRS neurodegenerative changes in the thalamus and cerebral cortex suggests that the abnormalities detected in these brain regions by other neuroimaging techniques are likely of functional nature. [Copyright &y& Elsevier]

Background: Portable devices are used for unattended recording of patients with suspected obstructive sleep apnea syndrome (OSAS). The MESAM 4 (MAP; Martinsried, Germany) is a computerized ambulatory polysomnographic system that records four parameters: breathing noise, heart rate, arterial oxygen saturation (SaO(2)), and body position.Design and Method: We evaluated the reliability of the oxygen desaturation index (ODI) automatically calculated by the MESAM 4 device in evaluating patients with "complicated" OSAS. These patients present SaO(2) drops due to apneas associated with a fall in baseline SaO(2) during sleep, as occurs in the "overlap syndrome." Ten patients with complicated OSAS underwent nocturnal MESAM 4 recordings, and we compared the visual and automatic scorings of the ODI.Results: The ODI obtained with visual scoring was significantly higher than ODI automatically calculated by the MESAM 4 in all patients. In some patients, this difference was so significant that it could bias clinical judgment of OSAS severity. We demonstrated that the system did not identify those desaturation events that were superimposed on a fall in baseline SaO(2). The error depends on the algorithm by which the device recognizes the desaturation events and calculates the baseline SaO(2).Conclusion: Automatic analysis of MESAM 4 recordings may be misleading in evaluating OSAS patients who have a fall in baseline SaO(2) during sleep. In this case, visual scoring performed by a trained polysomnographer is recommended. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]