Tuberous sclerosis complex in adulthood: focus on epilepsy prognosis.

OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.

Magnetic resonance imaging scoring system of the lower limbs in adult patients with suspected idiopathic inflammatory myopathy.

PURPOSE: We aim to propose a visual quantitative score for muscle edema in lower limb MRI to contribute to the diagnosis of idiopathic inflammatory myopathy (IIM). MATERIAL AND METHODS: We retrospectively evaluated 85 consecutive patients (mean age 57.4 ± 13.9 years; 56.5% female) with suspected IIM (muscle weakness and/or persistent hyper-CPK-emia with/without myalgia) who underwent MRI of lower limbs using T2-weighted fast recovery-fast spin echo images and fat-sat T2 echo planar images. Muscle inflammation was evaluated bilaterally in 11 muscles of the thigh and eight muscles of the leg. Edema in each muscle was graded according to a four-point Likert-type scale adding up to 114 points ([11 + 8)] × 3 × 2). Diagnostic accuracy of the total edema score was explored by assessing sensitivity and specificity using the area under the ROC curve. Final diagnoses were made by a multidisciplinary Expert Consensus Panel applying the Bohan and Peter diagnostic criteria whenever possible. RESULTS: Of the 85 included patients, 34 (40%) received a final diagnosis of IIM (IIM group) while 51 (60%) received an alternative diagnosis (non-IIM group). A cutoff score ≥ 18 was able to correctly classify patients having an IIM with an area under the curve of 0.85, specificity of 96%, and sensitivity of 52.9%. CONCLUSION: Our study demonstrates that a quantitative MRI score for muscle edema in the lower limbs (thighs and legs) aids in distinguishing IIM from conditions that mimic it.

Validation of Administrative Health Data Algorithms for Identifying Persons with Parkinson's Disease and the 10-Year Prevalence Trend in Bologna, Italy.

INTRODUCTION: Health administrative databases are widely used for the estimation of the prevalence of Parkinson's disease (PD). Few in general, and none used in Italy, have been validated by testing their diagnostic accuracy. The primary objective was to validate two algorithms for the identification of persons with PD using clinical diagnosis as the reference standard on an Italian sample of people with PD. The second objective was to estimate 10-year trends in PD prevalence in the Bologna Local Health Trust from 2010 to 2019. METHODS: Two algorithms (index tests) applied to health administrative databases (hospital discharge, drug prescriptions, exemptions for medical costs) were validated against clinical diagnosis of PD by an expert neurologist (reference standard) in a cohort of consecutive outpatients. Sensitivity and specificity with relative 95% confidence intervals (CIs) were calculated. The prevalence of PD in a specific year was estimated as the ratio between the number of subjects fulfilling any criteria of the algorithm with better diagnostic accuracy and the total population in the same year (×1,000), stratified by age, sex, and district of residence. RESULTS: The two algorithms showed high accuracy for identifying patients with PD: one with greater sensitivity of 94.2% (CI: 88.4-97.6) and the other with greater specificity of 98.1% (CI: 97.7-98.5). For the estimation of prevalence, we chose the most specific algorithm with the fewest total number of misclassified cases. We identified 3,798 people with PD as of December 31, 2019, corresponding to a prevalence of 4.3 per 1,000 inhabitants (CI: 4.2-4.4). Prevalence was higher in males (4.7, CI: 4.5-5.0) than females (3.8, CI: 3.7-4.0) and increased with age. The crude prevalence over time was slightly elevated as it followed a progressive aging of the population. When stratifying the prevalence for age groups, we did not observe a trend except in the 45-64 year category where we observed an increasing trend over time. CONCLUSION: Algorithms based on administrative data are accurate when detecting people with PD in the Italian public health system. In a large northern Italian population, increased prevalence of about 10% was observed in the decade 2010-2019 and is explained by increased life expectancy. These data may be useful in planning the allocation of health care resources for people with PD.

Impact of regulatory restrictions on the use of valproic acid in women of childbearing age: An Italian study.

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.

Risk of SARS-CoV-2 infection, hospitalization and death for COVID-19 in people with Parkinson's disease or parkinsonism over a 15-month period: a cohort study.

BACKGROUND: The patterns of long term risk of SARS-CoV-2 infection, hospitalization for COVID-19 and related death are uncertain in people with Parkinson's disease (PD) or parkinsonism (PS). The aim of the study was to quantify these risks compared to a control population cohort, during the period March 2020-May 2021, in Bologna, northern Italy. METHOD: ParkLink Bologna cohort (759 PD; 192 PS) and controls (9,226) anonymously matched (ratio 1:10) for sex, age, district, comorbidity were included. Data were analysed in the whole period and in the two different pandemic waves (March-May 2020 and October 2020-May 2021). RESULTS: Adjusted hazard ratio of SARS-CoV-2 infection was 1.3 (95% CI 1.04-1.7) in PD and 1.9 (1.3-2.8) in PS compared to the controls. The trend was detected in both the pandemic waves. Adjusted hazard ratio of hospitalization for COVID-19 was 1.1 (95% CI 0.8-1.7) in PD and 1.8 (95% CI 0.97-3.1) in PS. A higher risk of hospital admission was detected in PS only in the first wave. The 30-day mortality risk after hospitalization was higher (p=0.048) in PS (58%) than in PD (19%) and controls (26%). CONCLUSIONS: Compared with controls, after adjustment for key covariates, people with PD and PS showed a higher risk of SARS-CoV-2 infection throughout the first 15 months of the pandemic. COVID-19 hospitalization risk was increased only in people with PS and only during the first wave. This group of patients was burdened by a very high risk of death after infection and hospitalization.

New-generation drug-eluting stents reduce stent thrombosis and myocardial infarction: a propensity-score-adjusted analysis from the multicenter REAL registry (REgistro Regionale AngiopLastiche Dell'Emilia-Romagna).

OBJECTIVES: The aim of this study was to compare long-term clinical outcomes in patients treated with new-generation drug-eluting stent (DES) or early-generation DES in a real-world registry. BACKGROUND: New-generation DESs have proved to be more effective and safer than early-generation DES in randomized trials. However, the effects of new-generation DES versus early-generation DES in everyday clinical practice deserve further verification. METHODS: A propensity-score and inverse-probability weighted analysis of 5,332 patients undergoing DES implantation (2,557 new-generation and 2,775 early-generation) between January 1, 2007 and June 30, 2011 was performed, with a median follow-up of 3 years. We assessed the incidence of major adverse cardiovascular events (MACE: all-cause death, nonfatal myocardial infarction [MI], and target vessel revascularization [TVR]), and angiographic stent thrombosis (ST) during follow-up. RESULTS: At 3-years, new-generation DES in comparison with early-generation DES were associated with a reduced risk of MI (5% versus 7.4%, hazard ratio [HR]=0.65, 95% confidence interval [CI]=0.51-0.82, P=0.0004) and angiographic ST (0.5% vs. 1.1%, HR=0.35, 95% CI 0.17-0.72, P=0.004), whereas, the risk of TVR (10.9% vs. 13.5%; HR 0.99, 95% CI 0.84-1.16, P=0.99) and overall MACE was not significantly different (19.2% vs. 22.4%, HR=0.94, 95% CI=0.83-1.07, P=0.35). CONCLUSIONS: Our data from a large all-comers multicenter registry confirm that, in comparison with early-generation DES, the use of new-generation DES is associated with similar efficacy and increased long-term safety, because of a reduced risk of ST and MI.

Fingerprick volumetric absorptive microsampling for therapeutic drug monitoring of antiseizure medications: Reliability and real-life feasibility in epilepsy patients.

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.

Factors affecting 30-day mortality in poor-grade aneurysmal subarachnoid hemorrhage: a 10-year single-center experience.

Background: The management of patients with poor-grade aneurysmal subarachnoid hemorrhage (aSAH) is burdened by an unfavorable prognosis even with aggressive treatment. The aim of the present study is to investigate the risk factors affecting 30-day mortality in poor-grade aSAH patients. Methods: We performed a retrospective analysis of a prospectively collected database of poor-grade aSAH patients (World Federation of Neurosurgical Societies, WFNS, grades IV and V) treated at our institution from December 2010 to December 2020. For all variables, percentages of frequency distributions were analyzed. Contingency tables (Chi-squared test) were used to assess the association between categorical variables and outcomes in the univariable analysis. Multivariable analysis was performed by using the multiple logistic regression method to estimate the odds ratio (OR) for 30-day mortality. Results: A total of 149 patients were included of which 32% had WFNS grade 4 and 68% had WFNS grade 5. The overall 1-month mortality rate was 21%. On univariable analysis, five variables were found to be associated with the likelihood of death, including intraventricular hemorrhage (IVH ≥ 50 mL, p = 0.005), the total amount of intraventricular and intraparenchymal hemorrhage (IVH + ICH ≥ 90 mL, p = 0.019), the IVH Ratio (IVH Ratio ≥ 40%, p = 0.003), posterior circulation aneurysms (p = 0.019), presence of spot sign on initial CT scan angiography (p = 0.015).Nonetheless, when the multivariable analysis was performed, only IVH Ratio (p = 0.005; OR 3.97), posterior circulation aneurysms (p = 0.008; OR 4.05) and spot sign (p = 0.022; OR 6.87) turned out to be independent predictors of 30-day mortality. Conclusion: The risk of mortality in poor-grade aSAH remains considerable despite maximal treatment. Notwithstanding the limitations of a retrospective study, our report highlights some neuroradiological features that in the emergency setting, combined with leading clinical and anamnestic parameters, may support the multidisciplinary team in the difficult decision-making process and communication with family members from the earliest stages of poor-grade aSAH. Further prospective studies are warranted.

Impact of adherence to disease-modifying drugs in multiple sclerosis: A study on Italian real-world data.

BACKGROUND: Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system requiring complex diagnostic and therapeutic management. Treatment with Disease Modifying Drugs (DMDs) is aimed at reducing relapse rate and disease disability. Few real-world, population-based data are available on the impact of adherence on relapse rate. The objective of this study was to assess the impact of adherence to DMDs on relapses in a real-world Italian setting. METHODS: Population-based cohort study. People with MS (PwMS) older than 18 years and residing in the Emilia-Romagna region, Northern Italy, were identified through administrative databases using a validated algorithm. A Cox regression model with a time-varying exposure was performed to assess the association between level of adherence to DMDs and relapses over a 5-year period. RESULTS: A total of 2,528 PwMS receiving a first prescription of DMDs between 2015 and 2019 were included (average age of 42, two-thirds female). Highly adherent PwMS had a 25 % lower hazard of experiencing moderate or severe relapses than non-adherent PwMS (Hazard Ratio 0.75, 95 % CI 0.58 to 0.98), after adjusting for age and sex. Several sensitivity analyses supported the main result. CONCLUSION: The results of our study support the hypothesis that a high level of DMD adherence in MS is associated with a lower risk of moderate or severe relapse. Therefore, choosing the DMD with which to start drug treatment and recommending adherence to treatment appear to be crucial aspects involving both physicians and patients.

Magnetic Resonance-Based Assessment of Optic Nerve Sheath Diameter: A Prospective Observational Cohort Study on Inter- and Intra-Rater Agreement.

BACKGROUND: The measurement of optic nerve sheath diameter (ONSD) as a non-invasive method of estimating intracranial pressure has been widely reported in the literature. However, few studies have evaluated the accuracy of magnetic resonance imaging (MRI) in assessing ONSD measurements, although it is considered a very reliable method, it is not easily repeatable, expensive and is not readily available bedside. Herein, an assessment of the intra- and inter-rater reliability of ONSD assessment using MRI was conducted. METHODS: A consecutive, prospective cohort of patients with suspected idiopathic normal-pressure hydrocephalus was analyzed. ONSD MRI measurements of the transverse and sagittal diameters at a distance of 3 mm behind the papilla were evaluated twice each by two expert neuroradiologists. The correlations between MRI examiners were calculated using the concordance correlation coefficient (CCC). RESULTS: Fifty patients were included in the study. ONSD MRI average measurements were substantially higher than clinically expected (>5 mm). Considering intra-rater concordance, only one of the two neuroradiologists achieved an excellent score at CCC. Only a moderate inter-observer CCC for MRI assessment was found at all diameters. CONCLUSIONS: The use of a widespread MRI sequence (3D T1) to measure ONSD is not an accurate method since it may overestimate measurements and is dependent upon an operator.

Impact of computed tomography coronary angiography on other diagnostic tests.

OBJECTIVES: Information on the impact of computed tomography coronary angiography (CTCA) on patterns of care is scarce. In particular, it is not clear if, and to what extent, its adoption actually leads to a reduction in the use of other diagnostics tools. The aim of this study was to evaluate whether the adoption of CTCA in Emilia-Romagna (an Italian region with a population of 4.4 million) had any effect on utilization rates of myocardial perfusion scintigraphy (MPS) and coronary angiography (CA). METHODS: Interrupted time series (ITS) were applied to monthly volumes of MPS and CA tests performed from 2003 to 2010, to assess trends in usage rates for those procedures before and after CTCA was adopted by all the healthcare organizations operating in the region. RESULTS: After an increase in the first year of CTCA introduction, its use remained stable over the study period. After September 2006, a significant decrease in MPS volumes (31 percent; p < .0001) and a much less tangible decrease in CA volumes (5 percent; p < .0001), were detected by ITS analyses. CONCLUSIONS: This study demonstrates that the use of CTCA had a greater impact on MPS usage rates than on CA.

The CLOSED protocol to assess optic nerve sheath diameter using color-Doppler: a comparison study in a cohort of idiopathic normal pressure hydrocephalus patients.

BACKGROUND: Sonographic assessment of the optic nerve sheath diameter represents a promising non-invasive technique for estimation of the intracranial pressure. A wide inter-observer variability, along with a lack of a standardized protocol for the optic nerve sheath diameter measurements, could lead to over- or under-estimation. The present study was aimed at evaluating feasibility of color-Doppler for better delineating optic nerve sheath borders, comparing it to B-mode imaging, using the magnetic resonance measurements as a comparison. METHODS: Optic nerve sheath diameters were evaluated using magnetic resonance by an expert radiologist in a cohort of patients with suspected idiopathic normal pressure hydrocephalus. Magnetic resonance findings were evaluated twice. In the first half of this cohort, optic nerve sheath diameters were measured using B-mode only, in the second half applying color-Doppler. Measurements obtained using these two techniques were compared to magnetic resonance imaging measurements. The Bland-Altman analysis and concordance correlation coefficient were computed to quantify the strength of agreement between the two magnetic resonance assessments. Box plots and average (± SD) were used to compare assessments by sonographic and magnetic resonance methods. RESULTS: Fifty patients were included. MRI assessment showed a moderate concordance correlation coefficient. Optic nerve sheath diameters measured applying color-Doppler were lower (p < 0.001) and less scattered compared to B-mode assessment, which approached more to magnetic resonance measurements. CONCLUSIONS: In this cohort of patients, magnetic resonance showed high intra-rater variability in optic nerve sheath diameter assessments. Optic nerve sheath diameter assessments using color-Doppler yielded lower and less scattered diameters compared to B-mode only.

Long-term Outcome of Epilepsy and Cortical Malformations Due to Abnormal Migration and Postmigrational Development: A Cohort Study.

OBJECTIVE: To evaluate the long-term outcomes of patients with epilepsy and malformations of cortical development (MCD). METHODS: We conducted a historical cohort study of patients with epilepsy and MCD due to impaired neuronal migration and postmigration organization with a follow-up period of ≥5 years. For each patient, MCD was classified after accurate neuroimaging reappraisal by an expert neuroradiologist. The primary outcome was remission, defined as a period of seizure freedom ≥5 years at any time from epilepsy onset. We used Kaplan-Meier estimates for survival analysis and univariate and multivariate Cox regression analyses to evaluate baseline variables as possible factors associated with remission. RESULTS: The cohort included 71 patients (M/F 31/40) with a 17-year median follow-up (1,506 person-years). About half (49.3%) had heterotopia, 35.2% polymicrogyria, 7% lissencephaly, and 8.5% the combination of 2 MCD. The mean age at seizure onset was 12.4 ± 7.2 years. Intellectual disability and neurologic deficits were observed in 30.4% and 40.9%, respectively. More than 60% of patients had refractory epilepsy. In 3 patients who underwent epilepsy surgery, MCD diagnosis was confirmed by histology. At the last visit, 44% of patients had been seizure-free during the previous year, but none of them had stopped antiseizure medication. Thirty patients achieved remission (42.2%) at some point in their disease history, whereas 41 individuals (57.8%) had never been in remission for ≥5 years. The cumulative remission rate was 38% by 20 years from inclusion. In the Cox model, unilateral distribution of MCD (hazard ratio [HR] 2.68, 95% CI 1.04-6.92) and a low seizure frequency at onset (HR 5.01, 95% CI 1.12-22.5) were significantly associated with remission. DISCUSSION: Patients with epilepsy and MCD showed a remission rate of 38% by 20 years from onset. Unilateral distribution of the MCD is associated with a 3-fold probability of achieving remission. About 40% of patients showed a drug-sensitive condition with risk of relapse during their epilepsy course. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with epilepsy and MCD, unilateral MCD and low seizure frequency at onset are associated with achieving epilepsy remission.

The Indirect Impact of COVID-19 on Major Clinical Outcomes of People With Parkinson's Disease or Parkinsonism: A Cohort Study.

Background: The indirect impact of the COVID-19 epidemic on major clinical outcomes of people with Parkinson's disease (PD) or other parkinsonism is unknown. Objectives: The study aimed to (1) describe changes in healthcare services during the first epidemic bout in people with PD or parkinsonism; (2) compare the occurrence of hospitalization for any PD-related major clinical outcomes in 2020 with 2019; (3) investigate the factors, including changes in healthcare services, associated with major clinical outcomes and death. Methods: All healthcare services of the province of Bologna and major clinical outcomes were assessed through a record linkage study (ParkLink Bologna) using clinical data and health databases. Same analyses were performed in a random cohort of controls matched for age, sex, district of residence, and comorbidities with the ParkLink cohort (ratio of 1:10). Results: A cohort of subjects with PD (759) or other parkinsonism (192) was included together with a cohort of controls (9,226). All indicators of healthcare services dropped at least below 50% during the lockdown period in all cohorts, mostly impacting physiotherapy in people with PD (-93%, 95% CI 88-96%). In 2020, compared to 2019, a three-fold risk of major injuries (RR 3.0, 95% CI 1.5-6.2) and infections (RR 3.3, 95% CI 1.5-7.2), excluding COVID-19, was observed only in people with PD, and neither in people with parkinsonism nor in controls. Decreased physiotherapy was associated with the occurrence of at least one major clinical outcome (OR 3.3, 95% CI 1.1-9.8) in people with PD. Experiencing at least one major clinical outcome was the strongest risk factor for death (OR 30.4, 95% CI 11.1-83.4) in people with PD. Conclusions: During the first COVID-19 epidemic peak, healthcare services were drastically reduced in a province of northern Italy, regardless of the disease condition. However, compared to 2019, in 2020, only people with PD had a higher risk of major clinical outcomes, that were associated with higher mortality. Strategies to maintain physical activity in people with PD should be implemented in possible future health emergencies.

Brivaracetam add-on treatment in pediatric patients with severe drug-resistant epilepsy: Italian real-world evidence.

PURPOSE: To report the efficacy and tolerability of brivaracetam (BRV) in add-on therapy in pediatric patients with severe drug-resistant epilepsy. Prognostic factors of clinical outcome were also analyzed. METHODS: This Italian multicenter retrospective observational study was conducted on 45 pediatric patients with severe drug-resistant epilepsy, treated with BRV for at least 1 month and with a follow-up >6 months. Demographic, clinical, and treatment variables were assessed at T0 (baseline, BRV introduction) and T1 (6 months after BRV introduction). The response was defined as ≥50% seizure frequency reduction; responders and non-responders were then compared to assess potential prognostic factors. RESULTS: Forty-five patients (M = 28, mean age 12.4+/-4.4 years) were enrolled (focal epilepsy=14; generalized epilepsy=2; epileptic encephalopathy=29). At T1, 19/45 patients (42.2%) were responders (≥50% seizure frequency reduction), with 4 patients (8.9%) achieving a ≥ 75% seizure reduction and 2 patients (4.4%) becoming seizure free. Epilepsy onset at >12 months of age (p = 0.001), disease duration ≤6 years (p = 0.036), and lower seizure frequency at baseline (p = 0.008) were the prognostic factors significantly associated with a better prognosis. No significant difference emerged for demographics, epilepsy types/etiology, intellectual disability, or therapy variables. At T1, 21 patients (46.6%) discontinued BRV, mainly due to lack of efficacy (13 subjects; 28.9%) and adverse events in 8 patients (17.8%). CONCLUSION: Brivaracetam was an effective and tolerated treatment in pediatric patients with severe drug-resistant epilepsy, especially when the seizure onset was at >12 months of age, the epilepsy duration ≤6 years, and the seizure frequency before BRV treatment was low. Further and controlled studies are needed.

Developing and validating a novel multisource comorbidity score from administrative data: a large population-based cohort study from Italy.

OBJECTIVE: To develop and validate a novel comorbidity score (multisource comorbidity score (MCS)) predictive of mortality, hospital admissions and healthcare costs using multiple source information from the administrative Italian National Health System (NHS) databases. METHODS: An index of 34 variables (measured from inpatient diagnoses and outpatient drug prescriptions within 2 years before baseline) independently predicting 1-year mortality in a sample of 500 000 individuals aged 50 years or older randomly selected from the NHS beneficiaries of the Italian region of Lombardy (training set) was developed. The corresponding weights were assigned from the regression coefficients of a Weibull survival model. MCS performance was evaluated by using an internal (ie, another sample of 500 000 NHS beneficiaries from Lombardy) and three external (each consisting of 500 000 NHS beneficiaries from Emilia-Romagna, Lazio and Sicily) validation sets. Discriminant power and net reclassification improvement were used to compare MCS performance with that of other comorbidity scores. MCS ability to predict secondary health outcomes (ie, hospital admissions and costs) was also investigated. RESULTS: Primary and secondary outcomes progressively increased with increasing MCS value. MCS improved the net 1-year mortality reclassification from 27% (with respect to the Chronic Disease Score) to 69% (with respect to the Elixhauser Index). MCS discrimination performance was similar in the four regions of Italy we tested, the area under the receiver operating characteristic curves (95% CI) being 0.78 (0.77 to 0.79) in Lombardy, 0.78 (0.77 to 0.79) in Emilia-Romagna, 0.77 (0.76 to 0.78) in Lazio and 0.78 (0.77 to 0.79) in Sicily. CONCLUSION: MCS seems better than conventional scores for predicting health outcomes, at least in the general population from Italy. This may offer an improved tool for risk adjustment, policy planning and identifying patients in need of a focused treatment approach in the everyday medical practice.

Cardiac device therapy in patients with left ventricular dysfunction and heart failure: 'real-world' data on long-term outcomes (mortality, hospitalizations, days alive and out of hospital).

BACKGROUND: The impact on long-term outcomes of implantable cardioverter defibrillators (ICDs) and biventricular defibrillators for cardiac resynchronization (CRT-D) devices in 'real world' patients with heart failure (HF) needs to be assessed in terms of clinical effectiveness. METHODS AND RESULTS: A registry including consecutive HF patients who underwent a first implant of an ICD (891 patients) or a CRT-D device (709 patients) in 2006-2010 was followed (median 1487 days and 1516 days, respectively), collecting administrative data on survival, all-cause hospitalizations, cardiovascular or HF hospitalizations, and days alive and out of hospital (DAOH). Survival free from death/cardiac transplant was 61.9% and 63.8% at 5 years for ICD and CRT-D patients, respectively. Associated comorbidities (Charlson Comorbidity Index) had a significant impact on death/cardiac transplant, as well as on hospitalizations. The median values of DAOH% were 97.4% for ICD and 97.7% for CRT-D patients, but data were highly skewed, with the lower quartile of DAOH% values including values ranging between 0% and 52.8% for ICD and between 0% and 56.1% for CRT-D patients. Charlson Comorbidity Index was a very strong predictor of DAOH%. CONCLUSIONS: Patients who were implanted in 'real world' clinical practice with an ICD or a CRT-D device have, on average, a relatively favourable outcome, with a survival of around 62-64% at 5 years, but with an important burden of hospitalizations. Comorbidities, as evaluated by means of the Charlson Comorbidity Index, have a significant impact on outcomes in terms of mortality/heart transplant, hospitalizations and days spent alive and out of hospital.

Risk of Adverse Cardiac and Bleeding Events Following Cardiac and Noncardiac Surgery in Patients With Coronary Stent: How Important Is the Interplay Between Stent Type and Time From Stenting to Surgery?

BACKGROUND: Epidemiology and consequences of surgery in patients with coronary stents are not clearly defined, as well as the impact of different stent types in relationship with timing of surgery. METHODS AND RESULTS: Among 39 362 patients with previous coronary stenting enrolled in a multicenter prospective registry and followed for 5 years, 13 128 patients underwent 17 226 surgical procedures. The cumulative incidence of surgery at 30 days, 6 months, 1 year, and 5 years was 3.6%, 9.4%, 14.3%, and 40.0%, respectively, and of cardiac and noncardiac surgery was 0.8%, 2.1%, 2.6%, and 4.0% and 1.3%, 5.1%, 9.1%, and 31.7%, respectively. We assessed the incidence and the predictors of cardiac death, myocardial infarction, and serious bleeding event within 30 days from surgery. Cardiac death occurred in 438 patients (2.5%), myocardial infarction in 256 (1.5%), and serious bleeding event in 1099 (6.4%). Surgery increased 1.58× the risk of cardiac death during follow-up. Along with other risk factors, the interplay between stent type and time from percutaneous coronary intervention to surgery was independently associated with cardiac death/myocardial infarction. In comparison with bare-metal stent implanted >12 months before surgery, old-generation drug-eluting stent was associated with higher risk of events at any time point. Conversely, new-generation drug-eluting stent showed similar safety as bare-metal stent >12 months and between 6 and 12 months and appeared trendly safer between 0 and 6 months. CONCLUSIONS: Surgery is frequent in patients with coronary stents and carries a considerable risk of ischemic and bleeding events. Ischemic risk is inversely related with time from percutaneous coronary intervention to surgery and is influenced by stent type.

Cardiac resynchronization therapy: implant rates, temporal trends and relationships with heart failure epidemiology.

BACKGROUND: Consensus guidelines define indications for cardiac resynchronization therapy (CRT), but the variability in implant rates in 'real world' clinical practice, as well as the relationship with the epidemiology of heart failure are not defined. METHODS AND RESULTS: In Emilia-Romagna, an Italian region with around 4.4 million inhabitants, a registry was instituted to collect data on implanted devices for CRT, with (CRT-D) or without defibrillation (CRT-P) capabilities. Data from all consecutive patients resident in this region who underwent a first implant of a CRT device in years 2006-2010 were collected and standardized (considering each of the nine provinces of the region). The number of CRT implants increased progressively, with a 71% increase in 2010 compared to 2006. Between 84 and 90% of implants were with CRT-D devices. The variability in standardized implant rates among the provinces was substantial and the ratio between the provinces with the highest and the lowest implant rates was always greater than 2. Considering prevalent cases of heart failure in the period 2006-2010, the proportion of patients implanted with CRT per year ranged between 0.23 and 0.30%. CONCLUSIONS: The application in 'real world' clinical practice of CRT in heart failure is quite heterogeneous, with substantial variability even among areas belonging to the same region, with the need to make the access to this treatment more equitable. Despite the increased use of CRT, its overall rate of adoption is low, if a population of prevalent heart failure patients is selected on the basis of administrative data on hospitalizations.

Acute type A aortic dissection: significance of multiorgan malperfusion.

OBJECTIVES: Acute type A aortic dissection (AAAD) remains one of the most challenging diseases in cardiothoracic surgery, and despite numerous innovations, early mortality still remains high. The aim of this study was to review the Emilia-Romagna experience in the treatment of AAAD and to evaluate the effect of malperfusion on mortality and morbidity. METHODS: We examined data of 502 patients between January 2000 and December 2008, from the Emilia-Romagna Regional Registry of AAAD. The mean age was 62.4 ± 13 years and 66.5% were male. At presentation, various types of malperfusion syndromes (cerebral, cardiac, ileo-femoral, renal, mesenteric and spinal cord) were present in 103 patients (20.5%; malperfusion [MPS] group). Three hundred ninety-nine patients (No-MPS group) did not have pre-operative malperfusion. Arterial access for cardiopulmonary bypass was usually via the femoral artery (81.9%), while the axillary artery was used only in 14.7%. The aortic repair was performed using the 'open technique' in 348 patients (69.3%) and with aortic cross-clamping without circulatory arrest in 154 patients (30.7%). RESULTS: Overall in-hospital mortality was 20.9%: 43.7% in the MPS group vs 15% in the No-MPS group (P = 0.001). The operative technique and the cannulation site did not influence post-operative outcomes. Multivariate regression analysis identified mesenteric (odds ratio [OR] 9.5, confidence interval [CI] 2.4-37.4; P = 0.0012), cardiac malperfusion (OR 3.7, CI 1.7-8.0; P < 0.0001) and shock (OR 2.1, CI 1.2-3.5; P = 0.007) as significant risk factors for in-hospital mortality after surgery for type A dissection. Patients who presented single-organ malperfusion had a mortality rate of 34.7%, which increased to 61.9% and to 85.7% if two or more than two organ systems were involved, respectively. CONCLUSIONS: The results of the surgical treatment of AAAD are acceptable and mainly influenced by patient's status at presentation. Malperfusion of more organ systems makes the prognosis unfavourable and immediate proximal aortic repair may be sub-optimal. In these situations, alternative management strategies should be considered.