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

Efficacy of ketamine in refractory convulsive status epilepticus in children: A protocol for a sequential design, multicentre, randomised, controlled, open-label, non-profit trial (KETASER01)

Introduction: Status epilepticus (SE) is a lifethreatening neurological emergency. SE lasting longer than 120 min and not responding to first-line and second-line antiepileptic drugs is defined as 'refractory' (RCSE) and requires intensive care unit treatment. There is currently neither evidence nor consensus to guide either the optimal choice of therapy or treatment goals for RCSE, which is generally treated with coma induction using conventional anaesthetics (high dose midazolam, thiopental and/or propofol). Increasing evidence indicates that ketamine (KE), a strong N-methyl-D-aspartate glutamate receptor antagonist, may be effective in treating RCSE. We hypothesised that intravenous KE is more efficacious and safer than conventional anaesthetics in treating RCSE. Methods and analysis: A multicentre, randomised, controlled, open-label, non-profit, sequentially designed study will be conducted to assess the efficacy of KE compared with conventional anaesthetics in the treatment of RCSE in children. 10 Italian centres/ hospitals are involved in enrolling 57 patients aged 1 month to 18 years with RCSE. Primary outcome is the resolution of SE up to 24 hours after withdrawal of therapy and is updated for each patient treated according to the sequential method. Ethics and dissemination: The study received ethical approval from the Tuscan Paediatric Ethics Committee (12/2015). The results of this study will be published in peer-reviewed journals and presented at international conferences

Prescription appropriateness of anti-diabetes drugs in elderly patients hospitalized in a clinical setting: evidence from the REPOSI Register

Diabetes is an increasing global health burden with the highest prevalence (24.0%) observed in elderly people. Older diabetic adults have a greater risk of hospitalization and several geriatric syndromes than older nondiabetic adults. For these conditions, special care is required in prescribing therapies including anti- diabetes drugs. Aim of this study was to evaluate the appropriateness and the adherence to safety recommendations in the prescriptions of glucose-lowering drugs in hospitalized elderly patients with diabetes. Data for this cross-sectional study were obtained from the REgistro POliterapie-Società Italiana Medicina Interna (REPOSI) that collected clinical information on patients aged ≥ 65 years acutely admitted to Italian internal medicine and geriatric non-intensive care units (ICU) from 2010 up to 2019. Prescription appropriateness was assessed according to the 2019 AGS Beers Criteria and anti-diabetes drug data sheets.Among 5349 patients, 1624 (30.3%) had diagnosis of type 2 diabetes. At admission, 37.7% of diabetic patients received treatment with metformin, 37.3% insulin therapy, 16.4% sulfonylureas, and 11.4% glinides. Surprisingly, only 3.1% of diabetic patients were treated with new classes of anti- diabetes drugs. According to prescription criteria, at admission 15.4% of patients treated with metformin and 2.6% with sulfonylureas received inappropriately these treatments. At discharge, the inappropriateness of metformin therapy decreased (10.2%, P &lt; 0.0001). According to Beers criteria, the inappropriate prescriptions of sulfonylureas raised to 29% both at admission and at discharge. This study shows a poor adherence to current guidelines on diabetes management in hospitalized elderly people with a high prevalence of inappropriate use of sulfonylureas according to the Beers criteria

Antidiabetic Drug Prescription Pattern in Hospitalized Older Patients with Diabetes

Objective: To describe the prescription pattern of antidiabetic and cardiovascular drugs in a cohort of hospitalized older patients with diabetes. Methods: Patients with diabetes aged 65 years or older hospitalized in internal medicine and/or geriatric wards throughout Italy and enrolled in the REPOSI (REgistro POliterapuie SIMI—Società Italiana di Medicina Interna) registry from 2010 to 2019 and discharged alive were included. Results: Among 1703 patients with diabetes, 1433 (84.2%) were on treatment with at least one antidiabetic drug at hospital admission, mainly prescribed as monotherapy with insulin (28.3%) or metformin (19.2%). The proportion of treated patients decreased at discharge (N = 1309, 76.9%), with a significant reduction over time. Among those prescribed, the proportion of those with insulin alone increased over time (p = 0.0066), while the proportion of those prescribed sulfonylureas decreased (p &lt; 0.0001). Among patients receiving antidiabetic therapy at discharge, 1063 (81.2%) were also prescribed cardiovascular drugs, mainly with an antihypertensive drug alone or in combination (N = 777, 73.1%). Conclusion: The management of older patients with diabetes in a hospital setting is often sub-optimal, as shown by the increasing trend in insulin at discharge, even if an overall improvement has been highlighted by the prevalent decrease in sulfonylureas prescription

The “Diabetes Comorbidome”: A Different Way for Health Professionals to Approach the Comorbidity Burden of Diabetes

(1) Background: The disease burden related to diabetes is increasing greatly, particularly in older subjects. A more comprehensive approach towards the assessment and management of diabetes’ comorbidities is necessary. The aim of this study was to implement our previous data identifying and representing the prevalence of the comorbidities, their association with mortality, and the strength of their relationship in hospitalized elderly patients with diabetes, developing, at the same time, a new graphic representation model of the comorbidome called “Diabetes Comorbidome”. (2) Methods: Data were collected from the RePoSi register. Comorbidities, socio-demographic data, severity and comorbidity indexes (Cumulative Illness rating Scale CIRS-SI and CIRS-CI), and functional status (Barthel Index), were recorded. Mortality rates were assessed in hospital and 3 and 12 months after discharge. (3) Results: Of the 4714 hospitalized elderly patients, 1378 had diabetes. The comorbidities distribution showed that arterial hypertension (57.1%), ischemic heart disease (31.4%), chronic renal failure (28.8%), atrial fibrillation (25.6%), and COPD (22.7%), were the more frequent in subjects with diabetes. The graphic comorbidome showed that the strongest predictors of death at in hospital and at the 3-month follow-up were dementia and cancer. At the 1-year follow-up, cancer was the first comorbidity independently associated with mortality. (4) Conclusions: The “Diabetes Comorbidome” represents the perfect instrument for determining the prevalence of comorbidities and the strength of their relationship with risk of death, as well as the need for an effective treatment for improving clinical outcomes

Clinical features and outcomes of elderly hospitalised patients with chronic obstructive pulmonary disease, heart failure or both

Background and objective: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) mutually increase the risk of being present in the same patient, especially if older. Whether or not this coexistence may be associated with a worse prognosis is debated. Therefore, employing data derived from the REPOSI register, we evaluated the clinical features and outcomes in a population of elderly patients admitted to internal medicine wards and having COPD, HF or COPD + HF. Methods: We measured socio-demographic and anthropometric characteristics, severity and prevalence of comorbidities, clinical and laboratory features during hospitalization, mood disorders, functional independence, drug prescriptions and discharge destination. The primary study outcome was the risk of death. Results: We considered 2,343 elderly hospitalized patients (median age 81 years), of whom 1,154 (49%) had COPD, 813 (35%) HF, and 376 (16%) COPD + HF. Patients with COPD + HF had different characteristics than those with COPD or HF, such as a higher prevalence of previous hospitalizations, comorbidities (especially chronic kidney disease), higher respiratory rate at admission and number of prescribed drugs. Patients with COPD + HF (hazard ratio HR 1.74, 95% confidence intervals CI 1.16-2.61) and patients with dementia (HR 1.75, 95% CI 1.06-2.90) had a higher risk of death at one year. The Kaplan-Meier curves showed a higher mortality risk in the group of patients with COPD + HF for all causes (p = 0.010), respiratory causes (p = 0.006), cardiovascular causes (p = 0.046) and respiratory plus cardiovascular causes (p = 0.009). Conclusion: In this real-life cohort of hospitalized elderly patients, the coexistence of COPD and HF significantly worsened prognosis at one year. This finding may help to better define the care needs of this population

Clinical features and outcomes of elderly hospitalised patients with chronic obstructive pulmonary disease, heart failure or both

Background and objective: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) mutually increase the risk of being present in the same patient, especially if older. Whether or not this coexistence may be associated with a worse prognosis is debated. Therefore, employing data derived from the REPOSI register, we evaluated the clinical features and outcomes in a population of elderly patients admitted to internal medicine wards and having COPD, HF or COPD + HF. Methods: We measured socio-demographic and anthropometric characteristics, severity and prevalence of comorbidities, clinical and laboratory features during hospitalization, mood disorders, functional independence, drug prescriptions and discharge destination. The primary study outcome was the risk of death. Results: We considered 2,343 elderly hospitalized patients (median age 81&nbsp;years), of whom 1,154 (49%) had COPD, 813 (35%) HF, and 376 (16%) COPD + HF. Patients with COPD + HF had different characteristics than those with COPD or HF, such as a higher prevalence of previous hospitalizations, comorbidities (especially chronic kidney disease), higher respiratory rate at admission and number of prescribed drugs. Patients with COPD + HF (hazard ratio HR 1.74, 95% confidence intervals CI 1.16-2.61) and patients with dementia (HR 1.75, 95% CI 1.06-2.90) had a higher risk of death at one year. The Kaplan-Meier curves showed a higher mortality risk in the group of patients with COPD + HF for all causes (p = 0.010), respiratory causes (p = 0.006), cardiovascular causes (p = 0.046) and respiratory plus cardiovascular causes (p = 0.009). Conclusion: In this real-life cohort of hospitalized elderly patients, the coexistence of COPD and HF significantly worsened prognosis at one year. This finding may help to better define the care needs of this population

Long term effectiveness and outcomes of vagal nerve stimulation for drug resistant epilepsy: a single centre experience

Scopo: Negli ultimi due decenni la stimolazione del nervo vago (VNS), è diventata una modalità di trattamento consolidata per l'epilessia farmaco resistente sia nei pazienti adulti sia nei bambini che non possono beneficiare di trattamenti chirurgici resettivi. La maggior parte degli studi condotti fino ad oggi, hanno valutato l’efficacia di questa terapia palliativa con un follow-up dai 12 mesi ai 5 anni. Solo pochi studi hanno valutato un follow-up più esteso. Lo scopo di questo studio è quello di valutare l’evoluzione della stimolazione vagale in pazienti epilettici farmaco resistenti con un follow-up di 10 anni, studiati e impiantati in un unico centro di diagnosi e cura per l’epilessia. L’outcome è stato valutato in relazione all’età di impianto, l’eziologia, il tipo di crisi e la durata dell’epilessia. Metodo: Dal Gennaio 2000 al Gennaio 2019, 160 pazienti con epilessia farmaco resistente, esclusi da un trattamento di chirurgia resettiva, sono stati trattati con la stimolazione vagale presso il Centro Regionale per la diagnosi e cura dell’epilessia Infantile e Adolescenziale dell’Azienda Ospedaliera Universitaria di Ancona. Nello studio sono stati analizzati i dati di 158 pazienti su 160 totali, due pazienti sono stati esclusi in quanto presentavano al momento dello studio, un tempo di valutazione di soli 3 mesi. L'eziologia dell'epilessia è stata identificata in 115 su 158 pazienti, suddivisa in: strutturale in 82 pz (51,9%), infettiva in 12 pz (7,6%), genetica in 17 pz (10,7%), immune in 4 pz (1,89%). In 43 pazienti (27,2%) non è stata identificata una causa della malattia. Il tipo di epilessia è stata identificata come: generalizzata in 33 pazienti (20,9%), combinata (focali e generalizzate) in 39 pazienti (24,7%) e focale (focali e multifocali) in 86 pazienti (54,4%). L'età mediana all'impianto è di 14,68 anni (intervallo: 0,64 - 60,87, IQR 9,07-19,93), il numero mediano di crisi pre-VNS è 100 (intervallo: 4 - 1200, IQR: 30-200). La mediana dell’età dell’inizio dell'epilessia è di 1,16 anni (intervallo: 0-38,52, IQR: 0,41-5,58), la mediana della durata dell'epilessia prima della VNS è di 11,02 anni (intervallo: 0-45,4, IQR: 6,76-17,03). Il tempo di follow-up mediano è di 60,3 mesi (intervallo: 3,3-235,23; IQR: 36,5 - 107,36). L'efficacia della VNS in termini di risposta sulla riduzione delle crisi e di retention-rate, è stata analizzata ai 3, 6, 18 mesi , 2, 3, 5, 10, 15 anni e all’ultimo follow-up disponibile. Come "responder” sono stati classificati i pazienti che presentavano una riduzione della frequenza delle crisi uguale o maggiore del 50% rispetto al baseline; quest’ultimo identificato con i 3 mesi prima dell’inizio della terapia. Risultati: La riduzione della frequenza delle crisi dopo la stimolazione con VNS è significativa, e la risposta clinica aumenta fino ai 12 mesi post stimolazione. Su 155 pazienti disponibili alla valutazione, la riduzione media del tasso delle crisi è del 36,38% (test di Wilcoxon p &lt;0,001) e il tasso di riduzione delle crisi rispetto al basale, si è visto persistere per ogni follow-up seguente (p &lt;0,001). L'analisi univariata ha mostrato che l'età all'impianto e la minore durata dell’epilessia prima della VNS, ha una correlazione con la risposta sulla riduzione della frequenza delle crisi. I risultati migliori sono stati osservati in pazienti che all’impianto presentavano un’età inferiore ai 6 anni, con una significativa riduzione delle crisi se paragonati ai pazienti adulti ( p = 0.03). I pazienti che al momento dell’impianto avevano un’epilessia da più di 18 anni, mostravano una risposta ridotta rispetto a quelli con una storia di malattia minore ai 6 anni (p &lt;0,01). Per quanto riguarda l'eziologia e il tipo di epilessia, non abbiamo riscontrato differenze significative nella riduzione media della frequenza delle crisi epilettiche dopo la stimolazione vagale. L’analisi dei pazienti “responder” mostra che nel periodo dal 5 ° al 10° anno di follow-up c'è il più alto tasso di fine stimolazione (p &lt;0,01). Dal calcolo della retention-rate si evidenzia che il tempo mediano di stimolazione con la VNS è di 83 mesi. Dopo un periodo di almeno cinque anni di stimolazione vagale attiva, molti pazienti mostrano una riduzione stabile delle crisi. Questa risposta persiste anche dopo un periodo prolungato di sospensione della stimolazione. Conclusione: Questo studio evidenzia che i migliori candidati alla stimolazione vagale sono i pazienti con una breve storia di epilessia e con un’età all’inizio della stimolazione inferiore ai 6 anni. I risultati mostrano inoltre, che la VNS dopo alcuni anni di stimolazione, porta ad una riduzione stabile della frequenza delle crisi che permane anche quando questa viene disattivata. Questi dati inducono ad ipotizzare che la VNS presenta effetti anticonvulsivanti e non si limita ad una azione sulle crisi solo con stimolazione attiva. Si può quindi ipotizzare che dopo una lunga stimolazione vagale di 5 o più anni, i pazienti che hanno risposto con una riduzione delle crisi potrebbero aver cambiato la rete neuronale, modificando stabilmente il meccanismo epilettogenico. Per una migliore applicazione clinica della VNS, sono necessarie ulteriori ricerche scientifiche di base per comprendere quali possono essere i processi che intervengono in questi cambiamenti sulle reti neurali.Purpose: Over the past two decades, vagus nerve stimulation (VNS) has become an accepted and viable treatment modality for intractable epilepsy, both in children and adults who are not eligible for other forms of surgical treatment. Earlier studies have demonstrated short-term seizure outcomes, usually for up to 5 years; so far, few studies have reported an extended outcome. The aim of this study is to report the seizure outcome after VNS systems implantation in a longitudinal follow-up longer than 10 years in patients with drug-resistant epilepsy followed in a single specialized epilepsy center. There were compare the outcome with respect to age of implant, aetiology, seizure type and epilepsy duration. Methods: One hundred sixty drug-resistant epileptic patients, excluded from ablative surgery, were submitted to vagal nerve stimulation from January 2000 to January 2019. We analyzed 158 out of 160 patients with follow up more than 24 months, two patients are excluded from the study cause of fewer than three months of follow up. Median age at implantation was 14.68 years (range: 0.64 –60.87, IQR 9.07-19.93), median number of seizures pre-VNS was 100 (range: 4 – 1200, IQR: 30-200). The median age at the epilepsy onset was 1.16 years (range: 0 – 38.52, IQR: 0.41-5.58), the median years of epilepsy duration prior VNS was 11.02 years (range: 0 – 45.4, IQR: 6.76-17.03). The median time of follow-up is 60.3 months (range: 3.3 – 235,23; IQR: 36.5 – 107.36). The aetiology of the epilepsy was identified in 115/158 patients: structural in 82 pz (51,9%), infection in 12 pz (7,6%), genetic in 17 pz (10,7%), immune 4 pz (2,5 %) and unknown in 43 pz (27,2%). The epilepsy type were identified: generalized in 33 (20.9%), combined (focal and generalized) in 39 (24.7%) and focal (focal and multifocal) in 86 patients (54.4%). The efficacy of VNS on seizure reduction is analyzed at 3, 6, 18 months, 2, 3, 5, 10, 15 years, and at last available follow up with the previous 3 months of stimulation, in terms of responder rates and retention rate for the entire study period from stimulation onset to study completion. ‘Responders’ patients experiencing a seizure frequency reduction of 50% or more during follow-up. Results: The seizure frequency reduction was significant in the group, as a whole between baseline and the first follow-up. The positive effect of VNS increases until 12 months (155 patients available, mean seizure rate reduction 36.38%, Wilcoxon test p&lt;0.001) and the seizure reduction rate compared with baseline (p&lt;0.001) persists, for each follow-up. Univariate analysis showed a significant effect of implant age on seizure frequency reduction: the best results were observed in ‘very young’ patients (0–6 years); the largest difference is between ‘very young’ and adult patients (p=0.03). Lesser duration of epilepsy had positive influence on outcome: patients with longer history of seizures (&gt;18 years) had a significantly worse clinical outcome compared with patients with less than 6 years of seizures duration (p&lt;0.01). We found no significant difference regarding the aetiology and seizure type of epilepsies in the average seizure frequency reduction. Furthermore the analysis of best responders, show that in the period since 5th year of follow-up to 10th, there was the higher rate of VNS end of stimulation (p&lt;0.01). From evaluation of retention rate the median time of VNS stop stimulation is 83 months. Most of the patients at the end of battery service, without any remarkable change in seizures frequency, did not replacement the generator. Conclusion: Young patients with shorter duration of epilepsy may be better candidates for VNS. The results of this study provide evidence that the VNS could induce anticonvulsant effect, and probably it is not limited to the active stimulation. The processes that mediated these sustained changes are unknown. It is possible to speculate that the patients who reach the best response after 5 or more years of stimulation could change the neuronal network from the epileptogenic mechanism and for this, they could have stable reduction of seizure frequency, despite stimulation is in off. For a better clinical application of the VNS, we need further scientific research to understand what processes are involved in neural networks changes

Vagal nerve stimulation in intractable epilepsy: clinical experience on 100 patients and review of the literature

Introduction: Vagus Nerve Stimulation (VNS) is an effective alternative treatment for patients with refractory epilepsy. Nevertheless, information regarding VNS is still limited. Materials and Methods: In the present non randomized, prospectic study we report our clinical safety and effectiveness of VNS in 100 patients (52 Males and 48 Females) with drug resistant epilepsy. Patient’s age at implant ranged from 0,64 to 51,04 years (mean age 15.3 years). The mean follow-up time was 54,8 months ( range 2 to 108,3 months). Seventeen patients suffered from Lennox-Gastaut Syndrome, 34 patients suffered from partial epilepsy with drop attacks and secondary bysinchronism on the EEG (Lennox Gastaut-like) and 49 patients had Partial Epilepsy without drop attacks. Data collection forms were designed for prospectively gathering data on each patient’s history, seizures, drug therapy, implant device settings and side effects. Patients were assessed prior the implant and 3, 12 and 24 months after surgery. Results: Seventy-eight patients completed the 24 months follow-up session. VNS produced a mean seizure rate reduction of 32% at 3 months, 41% at 12 months, and 45% at 24 months. At 24 months, only the Partial Epilepsy patients showed a seizures reduction of 50%, which is considered clinically significant. Moreover both the age at implant and epilepsy duration were inversely correlated with the percentage of seizure reduction at 24 months. Side effects were minor and transient; the most common were voice alteration and coughing during stimulation. In 7 patients electrode breakage occurred three years after the surgical procedure. Conclusion: In our study, clinical effectiveness is higher in younger children implanted before than 12 years with shorter epilepsy duration suggesting a precocious useful role of VNS. Patients with Lennox Gastaut Syndrome show a worse clinical response rather than other epileptic syndromes