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Background: Subclinical vascular brain lesions are highly prevalent in elderly patients with stroke. Little is known about predisposing factors and their impact on long-term outcome of patients with stroke at a young age. Methods: We quantified magnetic resonance-defined subclinical vascular brain lesions, including lacunes and white matter hyperintensities, perivascular spaces and cerebral microbleeds, and assessed total small-vessel disease (SVD) score in patients with first-ever acute ischemic stroke aged 18 to 45 years, and followed them up, as part of the multicentre Italian Project on Stroke in Young Adults. The primary end point was a composite of ischemic stroke, transient ischemic attack, myocardial infarction, or other arterial events. We assessed the predictive accuracy of magnetic resonance features and whether the addition of these markers improves outcome prediction over a validated clinical tool, such as the Italian Project on Stroke in Young Adults score. Results: Among 591 patients (males, 53.8%; mean age, 37.5±6.4 years), 117 (19.8%) had subclinical vascular brain lesions. Family history of stroke was associated with lacunes (odds ratio, 2.24 [95% CI, 1.30–3.84]) and total SVD score (odds ratio, 2.06 [95% CI, 1.20–3.53] for score≥1), hypertension with white matter hyperintensities (odds ratio, 2.29 [95% CI, 1.22–4.32]). After a median follow-up of 36.0 months (25th–75th percentile, 38.0), lacunes and total SVD score were associated with primary end point (hazard ratio, 2.13 [95% CI, 1.17–3.90] for lacunes; hazard ratio, 2.17 [95% CI, 1.20–3.90] for total SVD score ≥1), and the secondary end point brain ischemia (hazard ratio, 2.55 [95% CI, 1.36–4.75] for lacunes; hazard ratio, 2.61 [95% CI, 1.42–4.80] for total SVD score ≥1). The predictive performances of the models, including magnetic resonance features were comparable to those of the random model. Adding individual magnetic resonance features to the Italian Project on Stroke in Young Adults score did not improve model prediction. Conclusions: Subclinical vascular brain lesions affect ≈2 in 10 young adults with ischemic stroke. Although lacunes and total SVD score are associated with thrombotic recurrence, they do not improve accuracy of outcome prediction over validated clinical predictors.

Objective To estimate the incidence and describe clinical characteristics and outcome of GBS in COVID-19 patients (COVID19-GBS) in one of the most hit regions during the first pandemic wave, Lombardia. Methods Adult patients admitted to 20 Neurological Units between 1/3–30/4/2020 with COVID19-GBS were included as part of a multi-center study organized by the Italian society of Hospital Neuroscience (SNO). Results Thirty-eight COVID19-GBS patients had a mean age of 60.7 years and male frequency of 86.8%. CSF albuminocytological dissociation was detected in 71.4%, and PCR for SARS-CoV-2 was negative in 19 tested patients. Based on neurophysiology, 81.8% of patients had a diagnosis of AIDP, 12.1% of AMSAN, and 6.1% of AMAN. The course was favorable in 76.3% of patients, stable in 10.5%, while 13.2% worsened, of which 3 died. The estimated occurrence rate in Lombardia ranges from 0.5 to 0.05 GBS cases per 1000 COVID-19 infections depending on whether you consider positive cases or estimated seropositive cases. When we compared GBS cases with the pre-pandemic period, we found a reduction of cases from 165 to 135 cases in the 2-month study period in Lombardia. Conclusions We detected an increased incidence of GBS in COVID-19 patients which can reflect a higher risk of GBS in COVID-19 patients and a reduction of GBS events during the pandemic period possibly due to a lower spread of more common respiratory infectious diseases determined by an increased use of preventive measures.

Background and Purpose: Clinical trials on stroke prevention in patients with atrial fibrillation have consistently shown clinical benefit from either warfarin or non–vitamin K antagonist oral anticoagulants (NOACs). NOAC-treated patients have consistently reported to be at lower risk for intracerebral hemorrhage (ICH) than warfarin-treated patients. The aims of this prospective, multicenter, multinational, unmatched, case-control study were (1) to investigate for risk factors that could predict ICH occurring in patients with atrial fibrillation during NOAC treatment and (2) to evaluate the role of CHA 2 DS 2 -VASc and HAS-BLED scores in the same setting. Methods: Cases were consecutive patients with atrial fibrillation who had ICH during NOAC treatment. Controls were consecutive patients with atrial fibrillation who did not have ICH during NOAC treatment. As within the CHA 2 DS 2 -VASc and HAS-BLED scores there are some risk factors in common, several multivariable logistic regression models were performed to identify independent prespecified predictors for ICH events. Results: Four hundred nineteen cases (mean age, 78.8±8.1 years) and 1526 controls (mean age, 76.0±10.3 years) were included in the study. From the different models performed, independent predictors of ICH were increasing age, concomitant use of antiplatelet agents, active malignancy, high risk of fall, hyperlipidemia, low clearance of creatinine, peripheral artery disease, and white matter changes. Low doses of NOACs (given according to label or not) and congestive heart failure were inversely associated with the risk of ICH. HAS-BLED and CHA 2 DS 2 -VASc scores performed poorly in predicting ICH with areas under the curves of 0.496 (95% CI, 0.468–0.525) and 0.530 (95% CI, 0.500–0.560), respectively. Conclusions: Several risk factors were associated to ICH in patients treated with NOACs for stroke prevention but not HAS-BLED and CHA 2 DS 2 -VASc scores.

Multiple studies have suggested an immunomodulatory role of cholesterol. We investigated whether cholesterol levels are associated with the risk of infectious complications (ICs) in acute ischemic stroke patients.A single-center prospective cohort was analyzed. Total (TOTc), low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels were measured within 24 h from admission. The outcome of interest was the occurrence of any IC (pneumonia, urinary tract infection, sepsis, other infection) during hospitalization. Predictors of ICs were investigated with multivariable logistic regression.A total of 603 patients were included (median age 78 years, 49.3% males), of whom 134 (22.2%) developed an IC. Subjects with ICs had lower TOTc compared with patients without ICs (median 157 vs. 173 mg/dL; P 0.001). When TOTc was stratified in quartiles, we observed a linear decrease in the prevalence of ICs with higher TOTc levels (Q1,144 mg/dL, 32.7%; Q2, 145-168 mg/dL, 24.7%; Q3, 169-197 mg/dL, 17.8%; Q4,197 mg/dL, 13.3% P 0.001). The inverse relationship between TOTc and ICs remained significant after adjustment for confounders in logistic regression [odds ratio (OR) for 10 mg/dL increase, 0.92; 95% confidence intervals (CI), 0.87-0.97; P = 0.001]. This association was also confirmed for low-density lipoprotein cholesterol (OR, 0.93; 95% CI, 0.88-0.99; P = 0.013) and high-density lipoprotein cholesterol (OR, 0.85; 95% CI, 0.73-0.98; P = 0.026) and was not mediated by statin treatment.Higher cholesterol levels are independently associated with lower risk of ICs in ischemic stroke patients. Further studies are needed to confirm our findings and characterize the biological mechanisms underlying this association.

Long-term consequences of cervical artery dissection (CeAD), a major cause of ischemic stroke in young people, have been poorly investigated. The Italian Project on Stroke at Young Age - Cervical Artery Dissection (IPSYS CeAD) project is a multicenter, hospital-based, consecutively recruiting, observational, cohort study aimed to address clinically important questions about long-term outcome of CeAD patients, which are not covered by other large-scale registries. Patients with radiologically diagnosed CeAD were consecutively included in the registry. Baseline demographic and clinical variables, as well as information on risk factors, were systematically collected for each eligible patient. Follow-up evaluations were conducted between 3 and 6 months after the initial event (t1) and then annually (t2 at 1 year, t3 at 2 years , and so on), in order to assess outcome events (long-term recurrent CeAD, any fatal/nonfatal ischemic stroke, transient ischemic attack (TIA), or other arterial thrombotic event, and death from any cause). Between 2000 and 2019, data from 1530 patients (age at diagnosis, 47.2 ± 11.5 years; women, 660 [43.1%]) have been collected at 39 Italian neurological centers. Dissection involved a single vessel in 1308 (85.5%) cases and caused brain ischemia in 1303 (85.1%) (190 TIA/1113 ischemic stroke). Longitudinal data are available for 1414 (92.4%) patients (median follow-up time in patients who did not experience recurrent events, 36.0 months [25th to 75th percentile, 63.0]). The collaborative IPSYS CeAD effort will provide novel information on the long-term outcome of CeAD patients. This could allow for tailored treatment approaches based on patients' individual characteristics.

Background and Purpose— We investigated whether subarachnoid extension (SAHE) of intracerebral hemorrhage (ICH) is associated with hematoma expansion (HE). Methods— Retrospective analysis of patients with primary spontaneous ICH admitted at 3 academic hospitals in Italy. The study population was divided into a development and a replication cohort. SAHE was rated on baseline noncontrast computed tomography by investigators blinded to clinical data. The main outcome of interest was HE, defined as ICH growth >33% mL and/or >6 mL. Predictors of HE were explored with multivariable logistic regression stratified by ICH location (lobar versus nonlobar). Results— A total of 360 and 192 patients were included in the development and replication cohort, respectively. SAHE was identified with good interrater reliability ( K =0.82), and its frequency was 27.8% in the development and 24.5% in the replication cohort. In univariate analysis, HE was more common in patients with SAHE (52.0% versus 27.3%; P P =0.001) whereas there was no association with HE in nonlobar ICH (odds ratio, 0.55 [95% CI, 0.17–1.84]; P =0.334). The increased risk of HE in lobar ICH with SAHE was confirmed in the replication cohort (odds ratio, 3.46 [95% CI, 1.07–11.20]; P =0.038). Conclusions— SAHE predicts HE in lobar ICH. This may improve the stratification of HE risk in clinical practice or future trials targeting HE. Further research is needed to confirm our findings and characterize the underlying biological mechanisms.

Guillain–Barre Syndrome with Covid-19 Five patients who had Guillain–Barre syndrome 5 to 10 days after the onset of Covid-19 are described. Three had severe weakness and an axonal pattern on electr...

Background and PURPOSE Migraine has been shown to increase cerebral excitability, promote rapid infarct expansion into tissue with perfusion deficits, and result in larger infarcts in animal models of focal cerebral ischemia. Whether these effects occur in humans has never been properly investigated. METHODS In a series of consecutive patients with acute ischemic stroke, enrolled in the setting of the Italian Project on Stroke at Young Age, we assessed acute as well as chronic infarct volumes by volumetric magnetic resonance imaging, and compared these among different subgroups identified by migraine status. RESULTS A cohort of 591 patients (male, 53.8%; mean age, 37.5±6.4 years) qualified for the analysis. Migraineurs had larger acute infarcts than non-migraineurs (median, 5.9 cm3 [interquartile range (IQR), 1.4 to 15.5] vs. 2.6 cm3 [IQR, 0.8 to 10.1], P

Background: The clinical spectrum of coronavirus disease 2019 (COVID-19), due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, may be quite wide, including neurological symptoms. Among them, para-infectious or post-infectious neurological syndromes (PINS), caused by an inflammatory response against the central and/or peripheral nervous system, have been reported. The aim of this paper is to illustrate the functional and neurophysiological recovery in a series of subjects with COVID-19-related PINS who underwent intensive neurorehabilitation.Materials and Methods: Five patients with PINS associated with COVID-19 were evaluated at baseline and followed up for 6 months. Three of them had polyradiculoneuropathy and two patients had myelitis. The onset of the neurological syndromes was temporally associated with the SARS-CoV-2 infection. After completing the acute neurological treatments in the intensive care unit, patients underwent a personalized multidisciplinary rehabilitation program. An in-depth clinical, functional, and electrophysiological assessment was carried out at baseline and at 3- and 6-month follow-ups.Results: Among patients with polyradiculoneuropathy, the electrophysiological evaluation at baseline disclosed an acute inflammatory demyelinating polyradiculoneuropathy (AIDP) in two patients and an acute motor and sensory axonal neuropathy (AMSAN) in the third patient. At follow-up, the electrophysiological features improved in one subject with AIDP and were stable in the remaining two cases. The functional assessment after neurorehabilitation showed global recovery and full independence in walking and in activities of daily life in one patient and mild improvement in the other two cases. Of the two subjects with myelitis, the baseline electrophysiological examination showed a prolonged central motor conduction time, which returned to normal in one patient, whereas it improved but remained pathological in the other patient at follow-up. The neurorehabilitation led to a substantial functional improvement in both subjects.Discussion and Conclusions: This is the first study to describe clinical and electrophysiological aspects along with medium-term outcome in patients with COVID-19-related neurological manifestations who underwent an intensive rehabilitation program. The functional outcome following neurorehabilitation in patients with PINS related to SARS-CoV-2 infection is variable. In our small case series, subjects with polyradiculoneuropathy had a poorer recovery compared to patients with myelitis. The clinical course largely paralleled the follow-up electrophysiological findings.

Para-/tetraplegia can be a consequence of a heterogeneous group of spinal cord pathologies. Acute spinal chord syndromes representes one of he most critical neurologica emergencies. Making a prompt diagnosis is fundamental, since early treatment influences prognosis, both in cases requiring neurosurgery and in cases requiring “simple” medical treatment.

Neurological disorders are a common reason for admission to the ER; these conditions, excluding stroke, account for 10–20% of emergency department (ED) attendances [1, 2]. Epilepsy, meningoencephalitis, Guillain-Barre syndrome, subarachnoid hemorrhage, primary and secondary headache and myasthenia gravis, as well as medical decompensation of chronic neurological disorders, such as: multiple sclerosis, dementia, and Parkinson’s disease, may all lead to an emergency hospital admission. An Italian study, the NeuDay Initiative [3], in November 2018 surveyed Italian ERs that have access to neurological consultation; as expected the most common reason for requesting neurological consultations was cerebrovascular diseases (23.6%), followed by headaches (12%), head injuries (8.6%), dizziness (7.7%), transient disturbances of consciousness (7.1%), epileptic seizures (6.6%), delirium or confusional state (2.7%), other mental disorders (2.6%), as well as less frequent pathological conditions such as Guillain-Barre syndrome, meningoencephalitis, and others that would account all together for approximately 12.0% of all accesses.

Background It has been widely reported that anticoagulants (ACs) are underused for primary and secondary prevention of ischemic stroke in patients with atrial fibrillation (AFib). Furthermore, precise evidence-based guidelines about the best timing for AC initiation after acute stroke are currently lacking. Methods and Results In this retrospective, observational study, we analyzed prescription trends in AFib patients with acute ischemic stroke who were hospitalized in four neurologic stroke units of our region (Lombardia, Italy). In-hospital antithrombotic prescription was performed in highly heterogeneous patterns. A prestroke treatment with AC was the leading factor enhancing AC prescription during hospitalization. The other factors promoting AC were male gender, younger age, lower prestroke disability and stroke severity, and smaller stroke volumes. AFib subtype influenced AC prescription only in AC-naive patients. Interestingly, Congestive heart failure, Hypertension, Age higher than 75 years, Diabetes, previous Stroke or TIA or thromboembolism, Vascular disease, Age 64–75 years, female Sex (CHA 2 DS 2 -VASc) and Hypertension, Abnormal renal and liver function, Stroke, Bleeding, Labile INRs, Elderly, Drugs and alcohol (HAS-BLED) scores were not associated with AC prescription. However, patients who were treated with AC, including early treatment ( Conclusions Our findings potentially suggest that, although apparently neglecting the common risk stratification tools, our neurologists were able to select the more suitable candidates for prompt AC treatment. Further studies are needed to develop new scoring systems to aid ischemic and hemorrhagic risk estimation in the secondary prevention of stroke.

BackgroundFrontotemporal Spectrum Disorder (FTSD) and Amyotrophic Lateral Sclerosis (ALS) are neurodegenerative diseases often considered as a continuum from clinical, epidemiologic and genetic perspectives. We used localized brain volume alterations to evaluate common and specific features of FTSD, FTSD-ALS and ALS patients to further understand this clinical continuum.MethodsWe used voxel-based morphometry on structural MRI images to localize volume alterations in group comparisons: patients (20 FTSD, seven FTSD-ALS, 18 ALS) versus healthy controls (39 CTR), and patient groups between themselves. We used mean whole-brain cortical thickness to assess whether its correlations with local brain volume could propose mechanistic explanations of the heterogeneous clinical presentations. We also assessed whether volume reduction can explain cognitive impairment, measured with frontal assessment battery, verbal fluency and semantic fluency.ResultsCommon (mainly frontal) and specific areas with reduced volume were detected between FTSD, FTSD-ALS and ALS patients, confirming suggestions of a clinical continuum, while at the same time defining morphological specificities for each clinical group (e.g. a difference of cerebral and cerebellar involvement between FTSD and ALS). values suggested extensive network disruption in the pathological process, with indications of a correlation between cerebral and cerebellar volumes and in ALS. The analysis of the neuropsychological scores indeed pointed towards an important role for the cerebellum, along with fronto-temporal areas, in explaining impairment of executive and linguistic functions.ConclusionsWe identified common elements that explain the FTSD-ALS clinical continuum, while also identifying specificities of each group, partially explained by different cerebral and cerebellar involvement.

The BAT, BRAIN, and HEP scores have been proposed to predict hematoma expansion (HE) with noncontrast computed tomography (NCCT). We sought to validate these tools and compare their diagnostic performance. We retrospectively analyzed two cohorts of patients with primary intracerebral hemorrhage. HE expansion was defined as volume growth > 33% or > 6 mL. Two raters analyzed NCCT scans and calculated the scores, blinded to clinical and imaging data. The inter-rater reliability was assessed with the interclass correlation statistic. Discrimination and calibration were calculated with area under the curve (AUC) and Hosmer–Lemeshow χ2 statistic, respectively. AUC comparison between different scores was explored with DeLong test. We also calculated the sensitivity, specificity, positive, and negative predictive values of the dichotomized scores with cutoffs identified with the Youden’s index. A total of 230 subjects were included, of whom 86 (37.4%) experienced HE. The observed AUC for HE were 0.696 for BAT, 0.700 for BRAIN, and 0.648 for HEP. None of the scores had a significantly superior AUC compared with the others (all p > 0.4). All the scores had good calibration (all p > 0.3) and good-to-excellent inter-rater reliability (interclass correlation > 0.8). BAT ≥ 3 showed the highest specificity (0.81), whereas BRAIN ≥ 6 had the highest sensitivity (0.76). The BAT, BRAIN, and HEP scores can predict HE with acceptable discrimination and require just a baseline NCCT scan. These tools may be used to stratify the risk of HE in clinical practice or randomized controlled trials.

Objective Although a concern exists that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) might increase the risk of intracerebral haemorrhage (ICH), the contribution of these agents to the relationship between serum cholesterol and disease occurrence has been poorly investigated. Methods We compared consecutive patients having ICH with age and sex-matched stroke-free control subjects in a case–control analysis, as part of the Multicenter Study on Cerebral Haemorrhage in Italy (MUCH-Italy), and tested the presence of interaction effects between total serum cholesterol levels and statins on the risk of ICH. Results A total of 3492 cases (mean age, 73.0±12.7 years; males, 56.6%) and 3492 control subjects were enrolled. Increasing total serum cholesterol levels were confirmed to be inversely associated with ICH. We observed a statistical interaction between total serum cholesterol levels and statin use for the risk of haemorrhage (Interaction OR (IOR), 1.09; 95% CI 1.05 to 1.12). Increasing levels of total serum cholesterol were associated with a decreased risk of ICH within statin strata (average OR, 0.87; 95% CI 0.86 to 0.88 for every increase of 0.26 mmol/l of total serum cholesterol concentrations), while statin use was associated with an increased risk (OR, 1.54; 95% CI 1.31 to 1.81 of the average level of total serum cholesterol). The protective effect of serum cholesterol against ICH was reduced by statins in strictly lobar brain regions more than in non-lobar ones. Conclusions Statin therapy and total serum cholesterol levels exhibit interaction effects towards the risk of ICH. The magnitude of such effects appears higher in lobar brain regions.

Alzheimer disease (AD) and vascular dementia (VaD) together represent the majority of dementia cases. Since their neuropsychological profiles often overlap and white matter lesions are observed in elderly subjects including AD, differentiating between VaD and AD can be difficult. Characterization of these different forms of dementia would benefit by identification of quantitative imaging biomarkers specifically sensitive to AD or VaD. Parameters of microstructural abnormalities derived from diffusion tensor imaging (DTI) have been reported to be helpful in differentiating between dementias, but only few studies have used them to compare AD and VaD with a voxelwise approach. Therefore, in this study a whole brain statistical analysis was performed on DTI data of 93 subjects (31 AD, 27 VaD and 35 healthy controls - HC) to identify specific white matter patterns of alteration in patients affected by VaD and AD with respect to HC. Parahippocampal tracts were found to be mainly affected in AD, while VaD showed more spread white matter damages associated with thalamic radiations involvement. The genu of the corpus callosum was predominantly affected in VaD, while the splenium was predominantly affected in AD revealing the existence of specific patterns of alteration useful in distinguishing between VaD and AD. Therefore, DTI parameters of these regions could be informative to understand the pathogenesis and support the etiological diagnosis of dementia. Further studies on larger cohorts of subjects, characterized for brain amyloidosis, will allow to confirm and to integrate the present findings and, furthermore, to elucidate the mechanisms of mixed dementia. These steps will be essential to translate these advances to clinical practice.

Process model comparison and similar processes retrieval are key issues to be addressed in many real world situations, and particularly relevant ones in some applications (e.g., in medicine), where similarity quantification can be exploited in a quality assessment perspective. Most of the process comparison techniques described in the literature suffer from two main limitations : (1) they adopt a purely syntactic (vs. semantic) approach in process activity comparison, and/or (2) they ignore complex control flow information (i.e., other than sequence). These limitations oversimplify the problem, and make the results of similarity-based process retrieval less reliable, especially when domain knowledge is available, and can be adopted to quantify activity or control flow construct differences. In this paper, we aim at overcoming both limitations , by introducing a framework which allows to extract the actual process model from the available process execution traces, through process mining techniques, and then to compare (mined) process models, by relying on a novel distance measure . The novel distance measure, which represents the main contribution of this paper, is able to address issues (1) and (2) above, since: (1) it provides a semantic, knowledge-intensive approach to process activity comparison, by making use of domain knowledge; (2) it explicitly takes into account complex control flow constructs (such as AND and XOR splits/joins), thus fully considering the different semantic meaning of control flow connections in a reliable way. The positive impact of the framework in practice has been tested in stroke management, where our approach has outperformed a state-of-the art literature metric on a real world event log, providing results that were closer to those of a human expert. Experiments in other domains are foreseen in the future.

Simulation is a frontier for disseminating knowledge in almost all the fields of medicine and it is attracting growing interest because it offers a means of developing new teaching and training models, as well as of verifying what has been learned in a critical setting that simulates clinical practice. The role of simulation in neurology, until now limited by the obvious physical limitations of the dummies used to train students and learners, is now increasing since, today, it allows anamnestic data to be related to the instrumental evidence necessary for diagnosis and therapeutic decision-making, i.e., to the findings of neurophysiological investigations (EEG, carotid and vertebral echography and transcranial Doppler, for example) and neuroradiological investigations (CT, MRI imaging), as well as vital parameter monitoring (ECG, saturimetry, blood pressure, respiratory frequency, etc.). Simulation, by providing learners with opportunities to discuss, with experts, different profiles of biological parameters (both during the simulation itself and in the subsequent debriefing session), is becoming an increasingly important tool for training those involved in evaluation of critical neurological patients (stroke, Guillan Barrè syndrome, myasthenia, status epilepticus, headache, vertigo, confusional status, etc.) and complex cases. In this SIMMED (Italian Society for Simulation in Medicine) position paper, the applications (present and, possibly, future) of simulation in neurology are reported.

Background The pathogenesis of cerebral small-vessel disease (SVD) is still incompletely understood, although evidence from family and twin studies supports the hypothesis that genetic factors may contribute to SVD pathogenesis. Identification of genetic susceptibility factors for SVD may improve our knowledge on SVD pathogenesis. SVE-LA (Small Vessel and Lacunar) project is a multicenter prospective Lombardia region study aimed at applying innovative genetic technologies and accurate patient phenotyping to discover the genetic basis of SVD. Methods A continuous series of subjects (aged 15-80 years) with a clinically and radiologically defined lacunar stroke referring to the participating Lombardia region stroke centers and an adequate number of age- and sex-matched controls are being included into the study. For each patient, clinical, demographic, instrumental, and familial data are collected applying standardized forms. After informed consent, a DNA sample for genetic analysis from patients and controls has been collected. The next generation sequencing (NGS) technology was applied to systematically screen patients for the most important genetic factors both monogenic and polygenic associated with SVD. The study includes also a centralized quantitative and qualitative analysis of neuroimaging studies. Results Between March 2011 and October 2013, 212 lacunar stroke patients and 78 controls have been collected. Mean age of cases was 65.8 ± 11.1 years and 67% were men. Conclusions This is the first study applying systematically NGS technology on a wide series of lacunar stroke patients. A translational approach combining a systematic genetic screening with a detailed phenotyping may facilitate the discovery of genetic basis and improve our knowledge in the pathogenesis of SVD.

In clinical practice, physicians often need to take decisions based both on previous experience and medical evidence. Such evidence is usually available in the form of clinical practice guidelines, which elaborate and summarize the knowledge contained in multiple documents. During clinical practice the synthetic format of medical guidelines is an advantage. However, when guidelines are used for educational purposes or when a clinician wants to gain deeper insight into a recommendation, it could be useful to examine all the guideline references relevant to a specific question. In this work we explored IBM Watson services available on the Bluemix cloud to automatically retrieve information from the wide corpus of documents referenced in a recent Italian compendium on emergency neurology. We integrated this functionality in a web application that combines multiple Watson services to index and query the referenced corpus. To evaluate the proposed approach we use the original guideline to check whether the retrieved text matches the actions mentioned in the recommendations.

Epidemiological and family studies have provided evidence on the role of genetic factors in stroke, particularly in stroke occurring at young age. However, despite its impact, young stroke continues to be understudied. This article reviews the existing literature on the most investigated monogenic disorders (CADASIL, Fabry disease, MELAS, RVCL, COL4A1, Marfan and Ehlers-Danlos syndromes) causing stroke in young and a number of candidate genes associated with stroke occurring in patients younger than 50 years. Although our study failed in identifying strong and reliable associations between specific genes and young stroke, our detailed literature revision on the field allowed us to compile a panel of genes possibly generating a susceptibility to stroke, which could be a starting point for future research. Since stroke is a potentially preventable disease, the identification of genes associated with young stroke may promote novel prevention strategies and allow the identification of therapeutic disease targets.

Background— We sought to compare the benefit of percutaneous closure to that of medical therapy alone for the secondary prevention of embolism in patients with patent foramen ovale (PFO) and otherwise unexplained ischemic stroke, in a propensity scored study. Methods and Results— Between 2000 and 2012, we selected consecutive first-ever ischemic stroke patients aged 18 to 45 years with PFO and no other cause of brain ischemia, as part of the IPSYS registry (Italian Project on Stroke in Young Adults), who underwent either percutaneous PFO closure or medical therapy for comparative analysis. Primary end point was a composite of ischemic stroke, transient ischemic attack, or peripheral embolism. Secondary end point was brain ischemia. Five hundred and twenty-one patients qualified for the analysis. The primary end point occurred in 15 patients treated with percutaneous PFO closure (7.3%) versus 33 patients medically treated (10.5%; hazard ratio, 0.72; 95% confidence interval, 0.39–1.32; P =0.285). The rates of the secondary end point brain ischemia were also similar in the 2 treatment groups (6.3% in the PFO closure group versus 10.2% in the medically treated group; hazard ratio, 0.64; 95% confidence interval, 0.33–1.21; P =0.168). Closure provided a benefit in patients aged 18 to 36 years (hazard ratio, 0.19; 95% confidence interval, 0.04–0.81; P =0.026) and in those with a substantial right-to-left shunt size (hazard ratio, 0.19; 95% confidence interval, 0.05–0.68; P =0.011). Conclusions— PFO closure seems as effective as medical therapy for secondary prevention of cryptogenic ischemic stroke. Whether device treatment might be more effective in selected cases, such as in patients younger than 37 years and in those with a substantial right-to-left shunt size, deserves further investigation.

Migraine and depression are recognized as comorbid disorders on the basis of several epidemiological data and on the possibility of shared mechanisms. On the other hand, there is a lack of studies concerning therapeutic strategies in patients with this comorbidity. The aim of this paper is to briefly review the literature about the migraine and depression comorbidity and on the putative common neurobiological mechanisms, as well to discuss the possible therapeutic options in treating patients with both disorders.

Background: Variations in stroke onset are related to stroke type and severity. We evaluated the impact of hourly and daily stroke onset variations on the pattern of patient hospital referral and on the time interval from stroke onset to hospital admission and brain neuroimaging investigations. Methods: This multicenter observational study recorded all incident acute strokes within a 4-month period. Results: One hundred and three participating centers collected data on 3,018 stroke cases. Stroke onset was more frequent on Mondays and between 08.00 and 10.59 h. Median time to admission after symptom onset was higher on Fridays (173.5 min) and between 20.00 and 22.59 h (207 min). Rescue by ambulance was associated with a greater stroke severity. Median time from hospital admission to brain neuroimaging investigations was higher on Saturdays (178.5 min) and between 23.00 and 10.59 h when the most severe strokes were hospitalized. Conclusions: The pattern of patient hospital referral and the time interval from stroke onset to hospital admission and brain neuroimaging investigations varied widely according to the hour and weekday of onset as well as to the reduced availability of hospital resources. An adequate distribution of the available resources should be planned in order to meet the demand.

Signs and symptoms of autonomic nervous system (ANS) dysfunction are frequently reported after ischemic or haemorrhagic stroke and in many cases they exhibit peculiar patterns in relationship with the site and the extension of brain lesion. However if an ANS disorder can cause or predispose to a stroke is far from being correctly known. Evidences in favor of a pathogenetic mechanism of an ANS dysfunction are reported for myocardial infarction and such data are likely to be appropriate also for atherothrombotic type of ischemic stroke. On the other hand, it is well known that many risk factors for this pathology are strongly correlated with an altered functioning of ANS so that a reciprocal interdependence between ANS and stroke can be hypothesized. This review points to evidence the possible relationship existing between these two conditions and suggests a quite different diagnostic and therapeutic approach to both on the basis of their pathogenetic mechanisms.

To develop novel and effective treatments for ischemic stroke, we investigated the neuroprotective effects of the macrolide antibiotic azithromycin in a mouse model system of transient middle cerebral artery occlusion. Intraperitoneal administration of azithromycin significantly reduced blood-brain barrier damage and cerebral infiltration of myeloid cells, including neutrophils and inflammatory macrophages. These effects resulted in a dose-dependent reduction of cerebral ischemic damage, and in a remarkable amelioration of neurological deficits up to 7 days after the insult. Neuroprotection was associated with increased arginase activity in peritoneal exudate cells, which was followed by the detection of Ym1- and arginase I-immunopositive M2 macrophages in the ischemic area at 24-48 h of reperfusion. Pharmacological inhibition of peritoneal arginase activity counteracted azithromycin-induced neuroprotection, pointing to a major role for drug-induced polarization of migratory macrophages towards a protective, non-inflammatory M2 phenotype.

SummaryAims – To define the epidemiological and clinical characteristics of Post Stroke Depression (PSD) and to evaluate treatment options. Methods – Systematic search using Medline electronic database limited to studies published from year 2000 to 2004, was carried out. Manual search was also performed. Results – Depression after stroke is a common event. The same, stroke incidence in depressed patients is more frequent than by chance. Risk of underdiagnosing a patient with former stroke is high. Disability after stroke is frequent, with compromission of quality of life of patients and relatives. Antidepressants are efficacious in PSD treatment, even if complete remission is difficult to obtain. Conclusions – There is enough evidence concerning epidemiology, pathogenesis, clinical and therapy to justify psychiatrists' interest on relationship between stroke and depression.Declaration of Interest: in the past two years PP, GSL, PS have received no fees or other financial support from pharmaceutical companies, GM has received speaker fees from Sanofi-Aventis, Lundbeck, Bayer Health Care, Boehringer Ingelheim, Novo Mordisk.

PROSIT (research PROject on Stroke services in ITaly) is a study performed to evaluate number and work organisation of acute in-hospital services (stroke units, SU) and general wards (GW), in seven Italian regions (Liguria, Lombardia, Lazio, Veneto, Friuli-Venezia-Giulia, Emilia Romagna, Toscana), which have a population of 29,169,811 inhabitants and a relative ratio of 225/100,000 hospitalisations for acute stroke. The registers of hospital discharges from January to December 1999 were looked at identify to services recording at least 50 acute stroke discharges (DRG14) per year. A structured questionnaire investigating stroke service characteristics was submitted to the doctors in charge of the identified units and completed in the presence of an external observer between October 2000 and February 2001. SUs were identified as units with dedicated beds (at least 80%) and team (at least 1 physician and 1 nurse) for acute stroke patients. SUs are still uncommon in many Italian regions because only, as 7% of the wards evaluated were found to be a SU and less than 10% of acute stroke patients resulted to be admitted to a SU. Great heterogeneity was found between the different regions surveyed. The most striking differences between SUs and GW were related to the staffing and care organisation, with higher number/patients ratio in SUs as far as physicians and nurses, speech therapists and social workers were concerned.

Lipoprotein(a) [Lp(a)] level is a newly established vascular risk factor which has been suggested to play a role in dementia. However, the majority of Lp(a) cell-to-cell interactions are mediated by its specific apolipoprotein(a) [apo(a)] moiety. This suggests that the size polymorphism of apo(a) may be of importance in conveying the Lp(a)-related risk. Specifically, we postulated that variation in apo(a) isoform size may lead to increased risk of vascular dementia (VaD), Alzheimer’s disease (AD), stroke, or all three of them. Under a case-control design we compared Lp(a) plasma levels and the distribution of apo(a) phenotypes in groups of subjects consisting of 50 VaD patients, 162 sporadic AD patients, 95 non-demented stroke patients (NDS), and 105 normal controls. The prevalence of small-sized apo(a) isoforms in the VaD group was significantly higher than that in the stroke and normal control groups, with an odds ratio of 5.29 (95% CI 2.24–12.49, p = 0.0001) for the development of VaD for individuals with at least one apo(a) isoform of low molecular weight (LMW). Furthermore, the possession of at least one small-sized apo(a) isoform significantly increased the risk of AD to 1.92 (95% CI 1.02–3.61, p = 0.0434). Our results demonstrate that possession of at least one LMW apo(a) isoform is significantly associated with dementia and specifically offer new evidence of a strong association between the lipoprotein system and post-stroke dementia.

Background and Purpose— Although several studies have demonstrated the effectiveness of specialist Stroke Unit (SU) care of stroke patients, there is still disagreement over how these units are best organized. We sought to clarify the role of continuous monitoring of physiological parameters in acute ischemic stroke. Methods— We conducted a prospective study of 268 first-ever ischemic stroke patients admitted to our Cerebrovascular Department and allocated, according to the availability of beds, to the SU or Cerebrovascular Unit (CU). Statistical analysis compared mortality and outcome at discharge, medical and neurological complications, and length of hospitalization in the 2 care settings. Results— Two hundred sixty-eight patients were enrolled. A good outcome at discharge, observed in 114 SU patients (85%) and 78 CU patients (58%) (odds ratio, 2.63; 95% CI, 1.4 to 4.8; P P P P Conclusions— Admission of acute stroke patients to a monitoring SU may positively influence their outcome at discharge. Confirmation of our findings in larger trials will indicate the need for a revision of the minimum requirements of SUs, with the addition of monitoring as a new requirement.

Familial hemiplegic migraine (FHM) is a rare autosomal dominant disorder characterized by episodes of transient hemiparesis followed by headache. Two chromosomal loci are associated to FHM: FHM1 on chromosome 19 and FHM2 on chromosome 1q21-23. Mutations of the alpha-1A subunit of the voltage gated calcium channel (CACNA1A) are responsible for FHM1. FHM2 critical region spans 28 cM, hence hampering the identification of the responsible gene. Here, we report the FHM2 locus refining by linkage analysis on two large Italian families affected by pure FHM. The new critical region covers a small area of 0.9Mb in 1q23 and renders feasible a positional candidate approach. By mutation analysis, we excluded the calsequestrin and two potassium channel genes mapping within the narrowed FHM2 locus.

Process model comparison and similar processes retrieval are key issues to be addressed in many real world situations, and particularly relevant ones in medical applications, where similarity quantification can be exploited to accomplish goals such as conformance checking, local process adaptation analysis, and hospital ranking.

Most of the transcranial Doppler (TCD) experimental studies on cerebral haemodynamics have been performed in the rabbit because of the similarity between its Willis circle and that of the human, but these studies have mainly been limited to the basilar artery. The present study was aimed at extending the use of TCD sonography to all other large cerebral arteries. In anaesthetised rabbits, these arteries were insonated from three different recording sites, i.e. top-cranial, suboccipital and orbital, using a two-channel pulsed Doppler device equipped with 4 and 8 MHz probes. First, discrimination between intra- and extracranial arteries was achieved through a standard 'rebreathing' test (hypercapnic-hypoxic stimulation). The distinctive blood velocity response patterns, reflecting the different extents of metabolic reactivity in intra- and extracranial territories, are described and discussed. Intracranial arteries were then identified on the basis of their response to ipsi- and contralateral common carotid artery occlusion. This procedure allowed recording from the following arteries: anterior common trunk, anterior cerebral, internal carotid, middle cerebral and basilar; the latter could be simultaneously monitored with any of the others. This study provides an experimental model allowing investigation of regional differences in the haemodynamic response to neurogenic and pharmacological stimuli.

The aim of the present study was to evaluate, through a case-control study, the specificity of the upright tilt test with bromocriptine as a marker of neurally mediated syncope of unknown aetiology. We have compared upright tilt test with bromocriptine (2.5 mg p.o.) in patients with syncope of unknown aetiology and controls. A total of 23 patients and controls matched by age and sex had upright tilt test with bromocriptine. The upright tilt test procedure consisted of 10 min in supine position, 10 min of 60 degree head-up tilt and a further 10 min with the subject supine; this procedure was performed in baseline condition and 60, 120, 180 and 240 min after the administration of bromocriptine. The protocol end points were the development of syncope or presyncope in association with hypotension with or without bradycardia. A positive response to bromocriptine test was found in 78% (95% CI, 61% to 95%) of patients and in 13% (95% CI, 0% to 26%) of controls (P

Epidemiological, clinical, neuropsychological and neuroimaging features characterise vascular dementia (VaD) from other dementias of non-Alzheimer type. VaD does not represent a single entity, but quite a large group of conditions characterised by different pathophysiological correlates and various clinical findings. Subcortical VaD, in particular, is considered as a model of VaD because its well-defined diagnostic criteria allow identification of a homogeneous category for a better approach to investigation in diagnosis and treatment of vascular dementia.

Nitric oxide (NO), a gaseous molecule synthesized in the arteriolar endothelium from the amino acid L-arginine (L-arg), has been identified as the previously described Endothelium-Derived Relaxing Factor (EDRF): nitroderivatives such as nitroglycerin are known to induce vasodilation via NO release. The aim of this study was to evaluate by Transcranial Doppler (TCD) monitoring any changes in cerebral hemodynamics induced by both the infusion of L-arg and the sublingual administration of nitroglycerin in 20 healthy subjects. L-arg infusion induced a significant increase in blood velocity compared to the baseline value (mean +/- S.D. percent change = 18 +/- 8.71; p0.0001 ) and a slight but significant decrease in Pulsatility Index. By contrast, nitroglycerin was able to cause a significant decrease in blood velocity (mean +/- S.D. percent change = 24.8 +/- 7.68; p0.0001), while leaving Pulsatility Index unchanged. These data suggest that L-arg and nitroglycerin, both hypothesized to use NO as the final product at the vascular level, result in opposite blood velocity patterns within the cerebral circulation. This may be due to the particular type of artery and/or to the local endothelial environment whereby the released NO may act.

There have been several reports of disulfiram intoxication, but little evidence of neurologic conditions resulting from disulfiram-induced brain damage combined with Wernicke encephalopathy-associated lesions. We report a rare patient with both Wernicke encephalopathy and disulfiram intoxication. This 50-year-old woman, who was taking disulfiram for chronic alcohol abuse, presented with an acute confusional state, dysarthria, nystagmus, supranuclear ophthalmoplegia, and paraparesis. Biochemical serum and cerebrospinal fluid analyses were normal. An electromyogram detected a motor polyneuropathy. Cognitive assessment revealed severe impairment of memory, attention, and logical and executive abilities. Magnetic resonance imaging with gadolinium enhancement showed brain lesions consistent with Wernicke encephalopathy, but also symmetric hyperintensities on T2-weighted images in the globus pallidus. Stopping the disulfiram and treating with hydration, high-dose thiamine supplements, and benzodiazepines significantly improved the patient's consciousness and oculomotor function. A magnetic resonance imaging scan after 1 month of treatment showed complete disappearance of the brain lesions and the hyperintensities in the globus pallidus. After a further month of intensive neurorehabilitation, the patient was able to interact with the medical staff, and her neuropsychological tests showed only mild memory impairment. Patients with alcoholism who present at emergency departments are at high risk for misdiagnosis, especially because there is no specific routine laboratory test for detecting asymptomatic disulfiram intoxication. Although uncommon, the combination of Wernicke encephalopathy and disulfiram intoxication should be suspected in patients with alcoholism. The disorder can be detected through a careful history and prompt clinical evaluation, together with characteristic magnetic resonance imaging findings.

Objectives Process model comparison and similar process retrieval is a key issue to be addressed in many real-world situations, and a particularly relevant one in medical applications, where similarity quantification can be exploited to accomplish goals such as conformance checking, local process adaptation analysis, and hospital ranking. In this paper, we present a framework that allows the user to: (i) mine the actual process model from a database of process execution traces available at a given hospital; and (ii) compare (mined) process models. The tool is currently being applied in stroke management. Methods Our framework relies on process mining to extract process-related information (i.e., process models) from data. As for process comparison, we have modified a state-of-the-art structural similarity metric by exploiting: (i) domain knowledge; (ii) process mining outputs and statistical temporal information. These changes were meant to make the metric more suited to the medical domain. Results Experimental results showed that our metric outperforms the original one, and generated output closer than that provided by a stroke management expert. In particular, our metric correctly rated 11 out of 15 mined hospital models with respect to a given query. On the other hand, the original metric correctly rated only 7 out of 15 models. The experiments also showed that the framework can support stroke management experts in answering key research questions: in particular, average patient improvement decreased as the distance (according to our metric) from the top level hospital process model increased. Conclusions The paper shows that process mining and process comparison, through a similarity metric tailored to medical applications, can be applied successfully to clinical data to gain a better understanding of different medical processes adopted by different hospitals, and of their impact on clinical outcomes. In the future, we plan to make our metric even more general and efficient, by explicitly considering various methodological and technological extensions. We will also test the framework in different domains.

In a competitive healthcare market, hospitals have to focus on ways to deliver high quality care while at the same time reducing costs. To accomplish this goal, hospital managers need a thorough understanding of the actual processes. Process mining can be used to extract process related information (e.g., process models) from data. This process information can be exploited to understand and redesign processes to become efficient high quality processes. Process analysis and redesign can take advantage of Case Based Reasoning techniques.

Little is known about the structures and mechanisms involved in the autonomic response to sensory and nociceptive stimulation. In this study, we recorded simultaneously pupil diameter, blood pressure, heart rate and pain levels during a cold-pressor test in 10 healthy subjects. The aim was to evaluate the different components of the Autonomic Nervous System involved in the response to a thermal-painful stimulus. A biphasic pupillary response was observed: an initial, short-lasting mydriasis, followed by a miotic phase, this latter characterized by rhythmic fluctuations of pupil diameter. The blood pressure response was monophasic with a moderate increase observed from the second minute of the test. Pain intensities remained stable on medium-high levels throughout the test. The topical application of thymoxamine and homatropine clarified some aspects of the pupillary response. The systemic administration of naloxone suggested a role of opiates in the modulation of pupillary and cardiovascular response to the cold-pressor test.

Background/Objectives: The aim of this study was to survey acute in-hospital stroke services in seven Italian regions. Methods: Regional hospital discharge registers were searched to identify hospital services that record at least 50 acute stroke discharges per year and the doctors in charge of these services were interviewed. Results: Only 31 (7%) out of 447 services could be classified as stroke units (SUs). Of these, only 9 (29%) were found to have vital function monitoring systems available for all patients. The most striking differences between SUs and mixed stroke services emerged when comparing staff/patient ratios in the two types of unit. Conclusions: There are still not enough SUs in Italy, and fewer than 10% of stroke patients can be admitted to such units.

This paper describes a knowledge acquisition tool for translating a guideline recommendation into a computer-interpretable format. The novelty of the tool is that it is addressed to the domain experts, and it helps them to disambiguate the natural language, by decomposing the recommendation into elements, eliciting tacit and implicit knowledge hidden into a recommendation and its context, mapping patient's data, available from the electronic record, to standard terms and immediately testing the formalised rule using past cases data.

In this study we evaluated the efficacy of a new preparation (Fast Dissolving Dosage Form--FDDF) of piroxicam (40 mg in a single sublingual dose) in the acute treatment of migraine. The study plan was of single blind type versus placebo and involved 40 patients with migraine without aura (according to the IHS Classification criteria) who had to take Piroxicam FDDF (or placebo) within 2 hours from the beginning of a migraine attack. Pain intensity and associated symptoms were evaluated in the basal condition and then monitored at serial intervals for 24 hours. In the group of patients treated with the active drug (n = 20), a significant reduction of pain intensity (Visual Analogue Scale) was observed after only 15 minutes (P = 0.0034). After an hour, headache has disappeared in 15 patients, become mild in 4 and remained unchanged in only one subject. Associated symptoms also quickly disappeared after Piroxicam FDDF administration and headache recurred in only two patients within the 24 hour period. Sublingual administration of Piroxicam FDDF was well tolerated: no systemic side-effects were reported and only two subjects complained about mouth dysesthesias which were described as mild and short-lasting. In conclusion, Piroxicam FDDF has been shown in this preliminary study to have striking efficacy in the acute treatment of migraine. The treatment is characterized by quick onset, long duration and good tolerability.