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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.

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.

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.

Sudden unexpected death in epilepsy (SUDEP) is a sudden, unexpected, witnessed or unwitnessed, non‐traumatic and non‐drowning death, occurring in benign circumstances, in an individual with epilepsy, with or without evidence for a seizure and excluding documented status epilepticus in which postmortem examination does not reveal other causes of death. Lower diagnostic levels are assigned when cases met most or all of these criteria, but data suggested more than one possible cause of death. The incidence of SUDEP ranged from 0.09 to 2.4 per 1000 person‐years. Differences can be attributed to the age of the study populations (with peaks in the 20–40‐year age group) and the severity of the disease. Young age, disease severity (in particular, a history of generalized TCS), having symptomatic epilepsy, and the response to antiseizure medications (ASMs) are possible independent predictors of SUDEP. The pathophysiological mechanisms are not fully known due to the limited data available and because SUDEP is not always witnessed and has been electrophysiologically monitored only in a few cases with simultaneous assessment of respiratory, cardiac, and brain activity. The pathophysiological basis of SUDEP may vary according to different circumstances that make that particular seizure, in that specific moment and in that patient, a fatal event. The main hypothesized mechanisms, which could contribute to a cascade of events, are cardiac dysfunction (included potential effects of ASMs, genetically determined channelopathies, acquired heart diseases), respiratory dysfunction (included postictal arousal deficit for the respiratory mechanism, acquired respiratory diseases), neuromodulator dysfunction, postictal EEG depression and genetic factors.

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 number NCT04496310

Study Objectives: Sleep-related complaints are common in adolescents, but their impact on the rate of motor vehicle crashes accidents is poorly known. We studied subjective sleep quality, driving habits, and self-reported car crashes in high-school adolescents. Methods: Self-administered questionnaires (with items exploring driving habits) were distributed to 339 students who had a driver's license and attended 1 of 7 high schools in Bologna, Italy. Statistical analysis were performed to describe lifestyle habits, sleep quality, sleepiness, and their relationship with the binary dependent variable (presence or absence of car crashes) to identify the factors significantly affecting the probability of car crashes in a multivariate binary logistic regression model. Results: Nineteen percent of the sample reported bad sleep, 64% complained of daytime sleepiness, and 40% reported sleepiness while driving. Eighty students (24%), 76% of which were males, reported that they had already crashed at least once, and 15% considered sleepiness to have been the main cause of their crash. As compared with adolescents who had not had a crash, those who had at least 1 previous crash reported that they more frequently used to drive (79% vs 62%), drove at night (25% vs 9%), drove while sleepy (56% vs 35%), had bad sleep (29% vs 16%), and used stimulants such as caffeinated soft drinks (32% vs 19%), tobacco (54% vs 27%), and drugs (21% vs 7%). The logistic procedure established a significant predictive role of male sex (p < 0.0001; odds ratio = 3.3), tobacco use (p < 0.0001; odds ratio = 3.2), sleepiness while driving (p = 0.010; odds ratio = 2.1), and bad sleep (p = 0.047; odds ratio = 1.9) for the crash risk. Conclusions: Our results confirm the high prevalence of sleep-related complaints among adolescents and highlight their independent role on self-reported crash risk. Citation: Pizza F; Contardi S; Baldi Antognini A; Zagoraiou M; Borrotti M; Mostacci B; Mondini S; Cirignotta F. Sleep quality and motor vehicle crashes in adolescents. J Clin Sleep Med 2010;6(1):41–45.

We describe a case of epileptic encephalopathy in a young woman with undiagnosed medium‐chain acyl‐coenzyme A dehydrogenase deficiency (MCADD), who presented with an early‐onset focal motor status epilepticus (SE) then followed by permanent left hemiplegia and drug‐resistant epilepsy with neurodevelopmental delay. Throughout her clinical history, recurrent episodes of lethargy, feeding difficulties, and clustering seizures occurred, progressing into a super refractory SE and death at the age of 25 years. Although epilepsy is not a distinctive feature of MCADD, we advise considering this metabolic disease as a possible etiology of epileptic encephalopathy and hemiconvulsion‐hemiplegia‐epilepsy syndrome of unknown origin, on the chance to provide a timely and targeted treatment preventing development delay and evolution to SE. Adult patients with epilepsy of unknown etiology not screened at birth for inborn errors of metabolism, such as MCADD, should be promptly investigated for these treatable conditions.

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 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.

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.