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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.

Narcolepsy type 1 (NT1) is a chronic neurological disorder characterized by symptoms such as excessive daytime sleepiness, sudden sleep episodes, disrupted nocturnal sleep, cataplexy, sleep paralysis, and hypnagogic hallucinations, which significantly impact the overall well-being and quality of life of individuals. While psychological factors have gained attention, there is limited research on the coping strategies employed by patients with NT1 and their association with quality of life. This study aimed to compare coping strategies in patients with NT1 and controls, as well as assess the relationship between coping strategies and quality of life in patients with NT1. A total of 122 individuals diagnosed with NT1 and 138 controls were enrolled in this cross-sectional study. Participants completed questionnaires assessing coping strategies and health-related quality of life. A Mann–Whitney U test was conducted to compare the use of different coping strategies by patients with NT1 and controls. Spearman's rho correlation was performed to examine the association between coping strategies and quality of life in the NT1 group. Results showed that patients with NT1 exhibited differences in the use of coping strategies compared to controls. They reported lower use of active coping, planning, instrumental, and emotional social support, and higher use of behavioral and mental disengagement. Denial and behavioral disengagement were significantly and negatively associated with quality of life. Identifying coping strategies and their association with quality of life may aid in the development of tailored interventions aimed at improving the adoption of effective coping strategies and reducing the use of maladaptive coping strategies.

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.

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

IntroductionLafora disease (LD) is an ultrarare fatal progressive myoclonic epilepsy, causing drug-resistant epilepsy, myoclonus and psychomotor deterioration. LD is caused by mutations in EPM2A or NHLRC1, which lead to the accumulation of polyglucosans in the brain and neurodegeneration. There are no approved treatments for LD. VAL-1221 is a fusion protein comprising the Fab portion of a cell-penetrating antibody and recombinant human acid alpha glucosidase, and has demonstrated an ability to clear polyglucosans. We hypothesise that intravenous infusion of VAL-1221 might be able to degrade cerebral polyglucosans and stabilise or improve disease outcomes. The aim of this study is to assess the safety and preliminary efficacy of VAL-1221 in patients with LD.Methods and analysisThe study is a phase 2, single-arm, open-label, baseline-controlled clinical trial which will be conducted in a single investigational study centre in Italy, namely the sponsor ‘IRCCS Istituto delle Scienze Neurologiche di Bologna—Azienda USL di Bologna’. The study will enrol six genetically confirmed patients with mid- to late-stage LD. The global duration of the study for each participant will be 18 months, including screening period, open-label treatment (12 months) and follow-up period. VAL-1221 20 mg/kg will be administered as an intravenous infusion every week for 3 weeks, then every other week. Patients will undergo full clinical assessments at baseline, at an intermediate and at the end-of-treatment visit. The primary objective is to evaluate the safety. The exploratory efficacy endpoints will be related to epilepsy, neuropsychological and motor functions, global assessment and disease burden, in addition to biomarkers. Statistical analyses will be primarily descriptive.Ethics and disseminationThe study protocol was approved by the local ethics committee (number 232-2023-FARM-AUSLBO-23020, 22 March 2023). The results of this study will be disseminated by the investigators through presentations at international scientific conferences and reported in peer-reviewed scientific journals.Trial registration numberEuropean Union Clinical Trials Register (EudraCT 2023-000185-34).

Background Although chronic diseases represent a growing global health priority, significant gaps remain in understanding the burden of multimorbidity. This study developed an original methodology to estimate the burden of thirty major chronic diseases at the individual patient level, in terms of Disability-Adjusted Life years (DALYs), Years Lived with Disability (YLD), and Years of Life Lost due to premature death (YLL). Methods The Disability weights (DWs) estimated by the Global Burden of Disease (GBD) study were integrated with information from healthcare databases. A panel of medical specialists established the criteria for assigning the level of severity, and thus a specific DW, to each chronic disease. The patient-centred YLD metric was estimated as the cumulative of the combined DWs over the previous ten years. We also measured the Disability Weight Fraction of each coexisting disease (DWF). We illustrated this method using healthcare databases from a large Italian region to assess the impact of chronic diseases and multimorbidity at progressive levels of analysis: health status of the regional chronic disease population, burden of individual chronic diseases and patient clinical complexity. Results Unlike the standard GBD estimates, the new method provided precise metrics for multimorbidity, as shown by the comparison on the disability calculated for 4 main chronic diseases. Real-world estimates from the new method highlighted that comorbidity accounted for most of the YLD: for instance, about 88% of the YLD of patients with heart failure was explained by concomitant conditions. DALYs were higher among females than males in most age groups. In the younger groups, psychiatric conditions explained approximately 40% and 25% of YLD among males and females, respectively. Finally, the patient-centred YLD metric was a good predictor of death (c-statistic = 0.779). Conclusions This novel method provides insights into the measurement of multimorbidity, based on the disability fraction of each concomitant health condition, which is crucial for defining priority areas for healthcare interventions. The patient-centred estimates may serve to identify subgroups of chronic disease patients with specific healthcare needs and trajectories among a given population. Importantly, measuring the relative contribution of each disease to the patient’s burden of multimorbidity favours the planning of multidisciplinary care pathways that are more responsive to individual needs.

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

Background Narcolepsy is a rare chronic sleep disorder that typically begins in youth. Excessive daytime sleepiness is the main disabling symptom, but the disease is often associated with severe endocrine-metabolic and psychosocial issues, worsened by a long diagnostic delay, requiring a multidisciplinary approach. The scarcity of reference Sleep Centres forces the patient and family to travel for seeking medical consultations, increasing the economic and psychosocial burden of the disease. Growing evidence suggests that Telemedicine may facilitate patient access to sleep consultations and its non-inferiority in terms of patient satisfaction, adherence to treatment, and symptom improvement for sleep disorders. However, Telemedicine clinical and economic benefits for patients with narcolepsy are still unknown. Methods TENAR is a two-part project, including: 1. a cross-sectional study (involving 250 children and adults with suspected narcolepsy) evaluating the accuracy of Teletriage (i.e., a synchronous live interactive sleep assessment through a Televisit) for narcolepsy diagnosis compared to the reference standard; and 2. a two-arm, parallel, open randomized controlled trial (RCT) to demonstrate the non-inferiority of the multidisciplinary care of narcolepsy through Televisits versus standard care. In this RCT, 202 adolescents (> 14 y.o.) and adults with narcolepsy will be randomly allocated (1:1 ratio) either to Televisits via videoconference or to standard in-person outpatient follow-up visits (control arm). The primary outcome is sleepiness control (according to the Epworth Sleepiness Scale). Secondary outcomes are other symptoms control, compliance with treatment, metabolic control, quality of life, feasibility, patient and family satisfaction with care, safety, and disease-related costs. At baseline and at 12 months, patients will undergo neurologic, metabolic, and psychosocial assessments and we will measure primary and secondary outcomes. Primary outcomes will be also measured at 6 months (remotely or in person, according to the arm). Discussion TENAR project will assess, for the first time, the feasibility, accuracy, efficacy and safety of Telemedicine procedures applied to the diagnosis and the multidisciplinary care of children and adults with narcolepsy. The study may be a model for the remote management of other rare disorders, offering care access for patients living in areas lacking medical centres with specific expertise. Trial registration Number of the Tele-multidisciplinary care study NCT04316286 . Registered 20 March 2020.

Background/Objectives: Dementia is a major public health challenge, with age as its primary non-modifiable risk factor. Several modifiable conditions, such as hypertension, diabetes, and depression, have been identified as potential targets for prevention. The aim is to describe the methodology and preliminary results of a study that will be conducted within the Italian National Health Service (INHS), designed to assess the impact of hypertension, diabetes, depression, and their interactions on the onset of dementia. Methods: This population-based cohort study, part of the PREV-ITA-DEM project, was conducted using a Common Data Model (CDM) approach across five Italian regions and cities participating in the NeuroEpiNet network. Individuals aged ≥ 50 years without prior diagnoses of dementia, depression, diabetes, or hypertension were followed from cohort entry (2011–2013) until dementia diagnosis, death, emigration, or study end (2019–2022). Exposures were time-dependent and defined using validated algorithms applied to Healthcare Utilization Databases (HUDs). Associations between chronic conditions and dementia risk will be estimated using competing risks regression models adjusted for confounders. Results: The final cohort comprised more than 3 million individuals, with a mean baseline age of 63–65 years and a female proportion of 52–55%. On 1 January 2011, the prevalence of individuals aged ≥ 50 years with dementia ranged from 8.7 to 14.7 per 1000 population. A harmonized methodological framework based on a CDM was developed and implemented across all sites, incorporating a shared protocol, standardized local databases, and uniform analytic scripts, and the results will be pooled using meta-analytic techniques. Conclusions: Preliminary findings confirm the feasibility of a standardized, multi-regional CDM approach and the potential for HUDs to support large-scale dementia prevention studies in real-world settings.

Study Objectives Narcolepsy type 1 (NT1) is a chronic rare hypersomnia of central origin requiring a combination of behavioral and pharmacological treatments. During the coronavirus disease 2019 (COVID‐19) pandemic, in Italy the population was forced into a lockdown. With this study, we aimed to describe the lockdown impact on NT1 symptom management, according to different patients' working schedule. Methods In the period between 10 April and 15 May 2020, we performed routine follow‐up visits by telephone (as recommended during the COVID‐19 emergency) to 50 patients >18 years old (40% males) under stable long‐term treatment. We divided patients into three groups: unchanged working schedule, forced working/studying at home, and those who lost their job (“lost occupation”). Current sleep–wake habit and symptom severity were compared with prelockdown assessment (six months before) in the three patient groups. Results At assessment, 20, 22, and eight patients belonged to the unchanged, working/studying at home, and lost occupation groups, respectively. While in the lost occupation group, there were no significant differences compared with prepandemic assessment, the patients with unchanged schedules reported more nocturnal awakenings, and NT1 patients working/studying at home showed an extension of nocturnal sleep time, more frequent daytime napping, improvement of daytime sleepiness, and a significant increase in their body mass index. Sleep‐related paralysis/hallucinations, automatic behaviors, cataplexy, and disturbed nocturnal sleep did not differ. Conclusions Narcolepsy type 1 patients working/studying at home intensified behavioral interventions (increased nocturnal sleep time and daytime napping) and ameliorated daytime sleepiness despite presenting with a slight, but significant, increase of weight. The graphical displays that NT1 patients working/studying at home slept more with improved subjective daytime sleepiness, while both NT1 patients working/studying at home and loosing occupation because of the pandemic significantly increased BMI.