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Background and Purpose— Bridging therapy with low-molecular-weight heparin reportedly leads to a worse outcome for acute cardioembolic stroke patients because of a higher incidence of intracerebral bleeding. However, this practice is common in clinical settings. This observational study aimed to compare (1) the clinical profiles of patients receiving and not receiving bridging therapy, (2) overall group outcomes, and (3) outcomes according to the type of anticoagulant prescribed. Methods— We analyzed data of patients from the prospective RAF and RAF-NOACs studies. The primary outcome was defined as the composite of ischemic stroke, transient ischemic attack, systemic embolism, symptomatic cerebral bleeding, and major extracerebral bleeding observed at 90 days after the acute stroke. Results— Of 1810 patients who initiated oral anticoagulant therapy, 371 (20%) underwent bridging therapy with full-dose low-molecular-weight heparin. Older age and the presence of leukoaraiosis were inversely correlated with the use of bridging therapy. Forty-two bridged patients (11.3%) reached the combined outcome versus 72 (5.0%) of the nonbridged patients ( P =0.0001). At multivariable analysis, bridging therapy was associated with the composite end point (odds ratio, 2.3; 95% CI, 1.4–3.7; P P =0.005) and hemorrhagic (odds ratio, 2.4; 95% CI, 1.2–4.9; P =0.01) end points separately. Conclusions— Our findings suggest that patients receiving low-molecular-weight heparin have a higher risk of early ischemic recurrence and hemorrhagic transformation compared with nonbridged patients.

Background There are few large population-based studies of outcomes after subarachnoid hemorrhage (SAH) than other stroke types. Methods We pooled data from 13 population-based stroke incidence studies (10 studies from the INternational STRroke oUtComes sTudy (INSTRUCT) and 3 new studies; N=657). Primary outcomes were case-fatality and functional outcome (modified Rankin scale score 3-5 [poor] vs. 0-2 [good]). Harmonized patient-level factors included age, sex, health behaviours (e.g. current smoking at baseline), comorbidities (e.g.history of hypertension), baseline stroke severity (e.g. NIHSS >7) and year of stroke. We estimated predictors of case-fatality and functional outcome using Poisson regression and generalized estimating equations using log-binomial models respectively at multiple timepoints. Results Case-fatality rate was 33% at 1 month, 43% at 1 year, and 47% at 5 years. Poor functional outcome was present in 27% of survivors at 1 month and 15% at 1 year. In multivariable analysis, predictors of death at 1-month were age (per decade increase MRR 1.14 [1.07-1.22]) and SAH severity (MRR 1.87 [1.50-2.33]); at 1 year were age (MRR 1.53 [1.34-1.56]), current smoking (MRR 1.82 [1.20-2.72]) and SAH severity (MRR 3.00 [2.06-4.33]) and; at 5 years were age (MRR 1.63 [1.45-1.84]), current smoking (MRR 2.29 [1.54-3.46]) and severity of SAH (MRR 2.10 [1.44-3.05]). Predictors of poor functional outcome at 1 month were age (per decade increase RR 1.32 [1.11-1.56]) and SAH severity (RR 1.85 [1.06-3.23]), and SAH severity (RR 7.09 [3.17-15.85]) at 1 year. Conclusion Although age is a non-modifiable risk factor for poor outcomes after SAH, however, severity of SAH and smoking are potential targets to improve the outcomes.

Background: Patients who are in a coma, a vegetative state or a minimally conscious state present a clinical challenge for neurological assessment, which is a prerequisite for establishing a prognosis and planning management. Several scales have been developed to evaluate these patients. The Wessex Head Injury Matrix is a comprehensive tool but is currently available only in the French and English languages. The aim of this study was to translate and evaluate the reliability of the Italian version of the scale. Methods: The original scale was translated according to a standard protocol: three separate translations were made, and a selected version was back-translated to check for any errors in order to obtain the most accurate Italian translation. A final back translation of the agreed version was made as a further check. The final version was then administered blind to a consecutive series of patients with severe acquired brain injury by two examiners. Inter-rater and test-retest reliability were assessed using a weighted Cohen’s kappa (Kw). Concurrent validity of the WHIM was evaluated by ρ Spearman’s correlation coefficient using the Glasgow Coma Scale (GCS) and the Coma Recovery Scale Revised (CRS-R) as the available gold standard. Results: Twenty-four patients (12 males and 12 females; mean age 59.9 ± 20.1; mean duration from index event 17.7 ± 20.0 days) with stroke (n = 15), traumatic brain injury (n = 7) and anoxic encephalopathy (n = 2) were included. Inter-rater [Kw 0.80 (95% CI 0.75–0.84)] and test-retest reliability [Kw 0.77 (95% CI 0.72–0.81)] showed good values. WHIM total scores correlated significantly with total scores on the GCS (ρ = 0.776; p < 0.001) and the CRS-R (ρ = 0.881; p < 0.001) demonstrating concurrent validity; Conclusion: The Italian version of the scale is now available for clinical practice and research.

Background: Outcomes after subarachnoid hemorrhage (SAH) have been rarely examined in large cohorts. Methods: This is an extension of the International Stroke Outcomes Study (INSTRUCT) pooling 13 ‘ideal’ stroke incidence studies (n=657 with SAH from 1993-2017, median age 56 years; 46% men). The primary outcomes were mortality and functional outcome (mRS score 3-5). Harmonized study factors included age, sex, behaviors (current smoking, alcohol intake), comorbidities (history of hypertension, ischemic heart disease, atrial fibrillation), stroke severity (e.g. NIHSS score) and year of stroke. In the pooled dataset, we estimated predictors of mortality using Poisson regression, to estimate incidence rate ratio (IRR) at 1 month (11 studies), 1 year (12 studies) and 5 years (7 studies). Generalized equation estimates in the log-binomial family were used to calculate risk ratios (RRs) for predictors of poor functional outcome at 1 month (5 studies) and 1 year (8 studies). Results: Mortality was 33% at 1 month, 43% at 1 year, and 47% at 5 years (Fig 1). Poor functional outcome was 25% at 1 month and 15% at 1 year (Fig 1). In multivariable analysis, age and stroke severity were associated with mortality at all time points, together with current smoking at 1 and 5 years, and history of hypertension at 5 years (Fig 2). Poor functional outcome was predicted by age (RR 1.03; 95% CI 1.01-1.04) at 1 month and by age (RR 1.04; 95% CI 1.00-1.08) and stroke severity (RR 1.94; 95% CI 1.02-2.87) at 1 year. Conclusion: Risk factors that predict SAH incidence including hypertension and smoking make outcomes worse. Better management of older patients and those with severe strokes could improve outcomes after SAH.

Facial expressions are important threat cues that can induce attentional biases, particularly among anxious individuals, facilitating precautionary behaviour. However, no study has assessed earthquake victims for attentional bias related to emotional facial expressions. In this study, we set out to bridge this gap by testing biases for emotional facial expressions in relation to psychopathological symptoms in a group of victims of the 2009 L’Aquila (Italy) earthquake. In a between-subjects design, 14 earthquake victims and 14 controls completed an exogenous cueing task to assess attentional biases in respect of seven facial expressions (happy, sad, angry, disgust, surprise, fearful and neutral). In each trial, one face was briefly presented on the right or left side of the screen as a cue and was followed by a target (a small dot). Participants had to indicate the position of the target shown on the same side as the emotional face (valid trials) or the opposite side (invalid trials). MANOVA performed on the engagement and disengagement scores demonstrated that earthquake victims and controls differed only in the engagement scores for fearful expression. Moreover, single-sample t-tests demonstrated that victims showed attentional avoidance of both fearful and happy expressions. Finally, in earthquake victims, avoidance of fearful expressions negatively correlated with anxiety-related cognitive concerns. Although the results are preliminary, we provide evidence of attentional avoidance of emotional faces among earthquake victims that is present years after the traumatic event. Cognitive mechanisms underlying such a bias and their implications are discussed.

Moving from the central role of the thalamus in the integration of inner and external stimuli and in the implementation of a stress-related response, the objective of the present study was to investigate the presence of any MRI structural and volumetric changes of the thalamic structures in earthquake witnesses. Forty-one subjects were included, namely 18 university students belonging to the experimental earthquake-exposed group (8 males and 10 females, mean age 24.5 ± 1.8 years) and a control group of 23 students not living in any earthquake-affected areas at the time of the earthquake (14 males and 9 females, mean age 23.7 ± 2.0 years). Instrumental MRI evaluation was performed using a 3-Tesla scanner, by acquiring a three-dimensional fast spoiled gradient-echo (FSPGR) sequence for volumetric analysis and an EPI (echoplanar imaging) sequence to extract fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values. As compared to the control one, the experimental group showed significantly lower gray matter volume in the mediodorsal nucleus of the left thalamus (p < 0.001). The dominant hemisphere thalamus in the experimental group showed higher mean ADC values and lower mean FA values as compared to the control group.

Accumulating data have linked migraine to cerebrovascular and heart diseases. The relationship between migraine and stroke is complex and bidirectional. A stroke, either ischaemic or haemorrhagic, may produce symptoms mimicking a migraine attack; a migraine attack may mimic a stroke; migraine may be directly associated with an ischaemic stroke (migrainous infarction); migraine may represent a risk factor for stroke; several diseases, mostly genetically determined, include among their clinical manifestations attacks of migraine and stroke; lastly, migraine has been associated with subclinical infarct-like brain lesions and white matter hyperintensities. The risk of cardiac vascular events in migraineurs varies greatly among studies, ranging from a lower-than-average to a moderately increased risk as suggested by the most recent data. Initial evidence also suggested an association between migraine and patent foramen ovale, but this possibility has been recently challenged. The mechanisms underlying the relationship of migraine with cerebrovascular and cardiovascular diseases are still cryptic and rather complex. In migraineurs, a heightened vigilance toward some comorbid risk factor is warranted together with caution in prescribing oral contraceptives.

The main aim of acute ischemic stroke treatment is the as much possible prompt, safe and effective arterial recanalisation, in order to restore reperfusion into the ischemic brain area. The procedures obtaining this result are rapidly evolving and in the last years, we observed new evidences that affirmed the therapeutical benefit of the concomitant treatment using endovenous thrombolysis and mechanical thrombectomy in selected patients with ischemic stroke. However, all treatments are time-sensitive and the main limitation for their application is represented by the time. For this reason, the optimisation of the acute stroke management that includes a pre-hospital and an in-hospital phase is essential to reduce the avoidable delay, increasing the number of patients potentially treatable. The purpose of this document is to define the main elements and to suggest the principal key points constituting the optimal pathway of stroke management in Italian care settings, in line with the recommendations coming from the current national and international guidelines.

Objectives: To examine sex differences in disease profiles, management, and survival at 1 and 5 years after ischemic stroke (IS) among people with atrial fibrillation (AF). Methods: We performed a systematic literature search of reports of AF at IS onset according to sex. We undertook an individual participant data meta-analysis (IPDMA) of nine population-based stroke incidence studies conducted in Australasia, Europe, and South America (1993–2014). Poisson regression was used to estimate women:men mortality rate ratios (MRRs). Study-specific MRRs were combined using random effects meta-analysis. Results: In our meta-analysis based on aggregated data from 101 studies, the pooled AF prevalence was 23% (95% confidence interval [CI]: 22%–25%) in women and 17% (15%–18%) in men. Our IPDMA is of 1,862 IS-AF cases, with women (79.2 ± 9.1, years) being older than men (76.5 ± 9.5, years). Crude pooled mortality rate was greater for women than for men (1-year MRR 1.24; 1.01–1.51; 5-year 1.12; 1.03–1.22). However, the sex difference was greatly attenuated after accounting for age, prestroke function, and stroke severity (1-year 1.09; 0.97–1.22; 5-year 0.98; 0.84–1.16). Women were less likely to have anticoagulant prescription at discharge (odds ratio [OR] 0.94; 95% CI: 0.89–0.98) than men when pooling IPDMA and aggregated data. Conclusions: AF was more prevalent after IS among women than among men. Among IS-AF cases, women were less likely to receive anticoagulant agents at discharge; however, greater mortality rate in women was mostly attributable to prestroke factors. Further information needs to be collected in population-based studies to understand the reasons for lower treatment of AF in women.

Background The applicability of the current models for predicting functional outcome after thrombectomy in strokes with large vessel occlusion (LVO) is affected by a moderate predictive performance. Aims We aimed to develop and validate a nomogram with pre- and post-treatment factors for prediction of the probability of unfavorable outcome in patients with anterior and posterior LVO who received bridging therapy or direct thrombectomy Methods We conducted a cohort study on patients data collected prospectively in the Italian Endovascular Registry (IER). Unfavorable outcome was defined as three-month modified Rankin Scale (mRS) score 3–6. Six predictors, including NIH Stroke Scale (NIHSS) score, age, pre-stroke mRS score, bridging therapy or direct thrombectomy, grade of recanalization according to the thrombolysis in cerebral ischemia (TICI) grading system, and onset-to-end procedure time were identified a priori by three stroke experts. To generate the IER-START, the pre-established predictors were entered into a logistic regression model. The discriminative performance of the model was assessed by using the area under the receiver operating characteristic curve (AUC-ROC). Results A total of 1802 patients with complete data for generating the IER-START was randomly dichotomized into training ( n = 1219) and test ( n = 583) sets. The AUC-ROC of IER-START was 0.838 (95% confidence interval [CI]): 0.816–0.869) in the training set, and 0.820 (95% CI: 0.786–0.854) in the test set. Conclusions The IER-START nomogram is the first prognostic model developed and validated in the largest population of stroke patients currently candidates to thrombectomy which reliably calculates the probability of three-month unfavorable outcome.

Objective:\ud It is not known whether patients with atrial fibrillation (AF) with ischemic stroke despite oral anticoagulant therapy are at increased risk for further recurrent strokes or how ongoing secondary prevention should be managed.\ud \ud Methods:\ud We conducted an individual patient data pooled analysis of 7 prospective cohort studies that recruited patients with AF and recent cerebral ischemia. We compared patients taking oral anticoagulants (vitamin K antagonists [VKA] or direct oral anticoagulants [DOAC]) prior to index event (OACprior ) with those without prior oral anticoagulation (OACnaive ). We further compared those who changed the type (ie, from VKA or DOAC, vice versa, or DOAC to DOAC) of anticoagulation (OACchanged ) with those who continued the same anticoagulation as secondary prevention (OACunchanged ). Time to recurrent acute ischemic stroke (AIS) was analyzed using multivariate competing risk Fine-Gray models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs).\ud \ud Results:\ud We included 5,413 patients (median age = 78 years [interquartile range (IQR) = 71-84 years]; 5,136 [96.7%] had ischemic stroke as the index event, median National Institutes of Health Stroke Scale on admission = 6 [IQR = 2-12]). The median CHA2 DS2 -Vasc score (congestive heart failure, hypertension, age≥ 75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65-74 years, sex category) was 5 (IQR = 4-6) and was similar for OACprior (n = 1,195) and OACnaive (n = 4,119, p = 0.103). During 6,128 patient-years of follow-up, 289 patients had AIS (4.7% per year, 95% CI = 4.2-5.3%). OACprior was associated with an increased risk of AIS (HR = 1.6, 95% CI = 1.2-2.3, p = 0.005). OACchanged (n = 307) was not associated with decreased risk of AIS (HR = 1.2, 95% CI = 0.7-2.1, p = 0.415) compared with OACunchanged (n = 585).\ud \ud Interpretation:\ud Patients with AF who have an ischemic stroke despite previous oral anticoagulation are at a higher risk for recurrent ischemic stroke despite a CHA2 DS2 -Vasc score similar to those without prior oral anticoagulation. Better prevention strategies are needed for this high-risk patient group.

Background and purpose The incidence and case-fatality rate (CFR) of primary intracerebral hemorrhage (PICH) over two decades were assessed in a prospective population-based study. Methods Cases of incident first-ever PICH were recorded over a 2-year period (2011–2012) from multiple sources in the district of L'Aquila, central Italy. Included patients were followed up to 1 year after the event to ascertain CFRs. Current data were compared with those previously collected from 1994 through 1998. Results In all, 115 patients (52 men; 45.2%) with a first-ever PICH were included. Mean age ± SD was 77.4 ± 11.8 years. The hemorrhage was lobar in 43 (37.4%) patients, deep in 56 (48.7%), in the posterior fossa in 11 (9.6%) and intraventricular or multiple localized in five (4.3%). Crude annual incidence rate was 19.3 per 100 000 and 14.8 per 100 000 when standardized to the 2011 European population, indicating a 48% reduction comparing data of 2011–2012 to those of 1994–1998 (incidence rate ratio 0.52; 95% confidence interval 0.43–0.64; P < 0.001). In 2011–2012, the 7-day CFR was 27.8%, the 30-day CFR was 42.6% and the 1-year CFR was 52.2%; the 1-year standardized mortality ratio was 0.81 (95% confidence interval 0.63–1.04) compared with 1994–1998. Conclusions The annual incidence rate of PICH was lower than that found two decades before and close to the rates recently found in other western countries. Data also indicated a non-significant trend towards a decrease in mortality, which nonetheless remained high, pointing to the need for more appropriate treatments in order to reduce PICH severity and mortality.

Non-communicative brain damaged patients raise important clinical and scientific issues. Here, we review three major pathological disorders of consciousness: coma, the unresponsive wakefulness syndrome and the minimally conscious state. A number of clinical studies highlight the difficulty in making a correct diagnosis in patients with disorders of consciousness based only on behavioral examinations. The increasing use of neuroimaging techniques allows improving clinical characterization of these patients. Recent neuroimaging studies using positron emission tomography, functional magnetic resonance imaging, electroencephalography and transcranial magnetic stimulation can help assess diagnosis, prognosis, and therapeutic treatment. These techniques, using resting state, passive and active paradigms, also highlight possible dissociations between consciousness and responsiveness, and are facilitating a more accurate understanding of brain function in this challenging population.

Patients with ischemic stroke or transient ischemic attack (TIA) are at increased risk for future cardiovascular events despite current preventive therapies. The identification of insulin resistance as a risk factor for stroke and myocardial infarction raised the possibility that pioglitazone, which improves insulin sensitivity, might benefit patients with cerebrovascular disease.In this multicenter, double-blind trial, we randomly assigned 3876 patients who had had a recent ischemic stroke or TIA to receive either pioglitazone (target dose, 45 mg daily) or placebo. Eligible patients did not have diabetes but were found to have insulin resistance on the basis of a score of more than 3.0 on the homeostasis model assessment of insulin resistance (HOMA-IR) index. The primary outcome was fatal or nonfatal stroke or myocardial infarction.By 4.8 years, a primary outcome had occurred in 175 of 1939 patients (9.0%) in the pioglitazone group and in 228 of 1937 (11.8%) in the placebo group (hazard ratio in the pioglitazone group, 0.76; 95% confidence interval [CI], 0.62 to 0.93; P=0.007). Diabetes developed in 73 patients (3.8%) and 149 patients (7.7%), respectively (hazard ratio, 0.48; 95% CI, 0.33 to 0.69; P0.001). There was no significant between-group difference in all-cause mortality (hazard ratio, 0.93; 95% CI, 0.73 to 1.17; P=0.52). Pioglitazone was associated with a greater frequency of weight gain exceeding 4.5 kg than was placebo (52.2% vs. 33.7%, P0.001), edema (35.6% vs. 24.9%, P0.001), and bone fracture requiring surgery or hospitalization (5.1% vs. 3.2%, P=0.003).In this trial involving patients without diabetes who had insulin resistance along with a recent history of ischemic stroke or TIA, the risk of stroke or myocardial infarction was lower among patients who received pioglitazone than among those who received placebo. Pioglitazone was also associated with a lower risk of diabetes but with higher risks of weight gain, edema, and fracture. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT00091949.).

Background— Women are reported to have greater mortality after stroke than men, but the reasons are uncertain. We examined sex differences in mortality at 1 and 5 years after stroke and identified factors contributing to these differences. Methods and Results— Individual participant data for incident strokes were obtained from 13 population-based incidence studies conducted in Europe, Australasia, South America, and the Caribbean between 1987 and 2013. Data on sociodemographics, stroke-related factors, prestroke health, and 1- and 5-year survival were obtained. Poisson modeling was used to estimate the mortality rate ratio (MRR) for women compared with men at 1 year (13 studies) and 5 years (8 studies) after stroke. Study-specific adjusted MRRs were pooled to create a summary estimate using random-effects meta-analysis. Overall, 16 957 participants with first-ever stroke followed up at 1 year and 13 216 followed up to 5 years were included. Crude pooled mortality was greater for women than men at 1 year (MRR 1.35; 95% confidence interval, 1.24–1.47) and 5 years (MRR 1.24; 95% confidence interval, 1.12–1.38). However, these pooled sex differences were reversed after adjustment for confounding factors (1 year MRR, 0.81; 95% confidence interval, 0.72–0.92 and 5-year MRR, 0.76; 95% confidence interval, 0.65–0.89). Confounding factors included age, prestroke functional limitations, stroke severity, and history of atrial fibrillation. Conclusions— Greater mortality in women is mostly because of age but also stroke severity, atrial fibrillation, and prestroke functional limitations. Lower survival after stroke among the elderly is inevitable, but there may be opportunities for intervention, including better access to evidence-based care for cardiovascular and general health.

Although comorbidities have a well-known impact on the functional recovery of patients with disorders of consciousness, including coma, vegetative state (VS), and minimally conscious state (MCS), a specific tool for their assessment in this challenging group of patients is lacking. For this aim, a multistep process was used to develop and validate the Comorbidities Coma Scale (CoCoS) in a sample of 162 patients with a diagnosis of coma, VS or MCS admitted to four Acute Inpatient Rehabilitation Units. To establish the psychometric properties of the scale, content validity, and internal consistency were investigated through Exploratory Factor Analysis in the whole sample (n = 162). Interrater reliability, assessed by the weighted Cohen's kappa (Kw), and concurrent validity of the scale as compared to the Greenfield Scale, assessed by ρ Spearman's correlation coefficient, were investigated in a subsample of patients (n = 52) within two of the above units. Our findings provided evidence of a good content validity of the scale, with the identification of a 12-factor structure representing the different comorbid dimensions of the target population. Inter-rater reliability was excellent in both the rehabilitation units where the assessment was made [Kw 0.98 (95% CI 0.96–0.99)]. CoCoS total scores correlated significantly with total scores of the Greenfield Scale (ρ = 0.932, 95% CI 0.89–0.96; P < 0.0001) indicating that CoCoS has concurrent validity while being more informative about the specific pattern of comorbidities of these challenging patients. The CoCos is a new tool which standardizes the approach to assessment of comorbid conditions and reliably identifies the category and severity of each comorbidity detected. It may be used for both clinical and research applications.

Background The relationship between different patterns of atrial fibrillation and early recurrence after an acute ischaemic stroke is unclear. Purpose In a prospective cohort study, we evaluated the rates of early ischaemic recurrence after an acute ischaemic stroke in patients with paroxysmal atrial fibrillation or sustained atrial fibrillation which included persistent and permanent atrial fibrillation. Methods In patients with acute ischaemic stroke, atrial fibrillation was categorised as paroxysmal atrial fibrillation or sustained atrial fibrillation. Ischaemic recurrences were the composite of ischaemic stroke, transient ischaemic attack and symptomatic systemic embolism occurring within 90 days from acute index stroke. Results A total of 2150 patients (1155 females, 53.7%) were enrolled: 930 (43.3%) had paroxysmal atrial fibrillation and 1220 (56.7%) sustained atrial fibrillation. During the 90-day follow-up, 111 ischaemic recurrences were observed in 107 patients: 31 in patients with paroxysmal atrial fibrillation (3.3%) and 76 with sustained atrial fibrillation (6.2%) (hazard ratio (HR) 1.86 (95% CI 1.24–2.81)). Patients with sustained atrial fibrillation were on average older, more likely to have diabetes mellitus, hypertension, history of stroke/ transient ischaemic attack, congestive heart failure, atrial enlargement, high baseline NIHSS-score and implanted pacemaker. After adjustment by Cox proportional hazard model, sustained atrial fibrillation was not associated with early ischaemic recurrences (adjusted HR 1.23 (95% CI 0.74–2.04)). Conclusions After acute ischaemic stroke, patients with sustained atrial fibrillation had a higher rate of early ischaemic recurrence than patients with paroxysmal atrial fibrillation. After adjustment for relevant risk factors, sustained atrial fibrillation was not associated with a significantly higher risk of recurrence, thus suggesting that the risk profile associated with atrial fibrillation, rather than its pattern, is determinant for recurrence.

GENetics of mOyaMoyA (GEN-O-MA) project is a multicenter observational study implemented in Italy aimed at creating a network of centers involved in moyamoya angiopathy (MA) care and research and at collecting a large series and bio-repository of MA patients, finally aimed at describing the disease phenotype and clinical course as well as at identifying biological or cellular markers for disease progression. The present paper resumes the most important study methodological issues and preliminary results. Nineteen centers are participating to the study. Patients with both bilateral and unilateral radiologically defined MA are included in the study. For each patient, detailed demographic and clinical as well as neuroimaging data are being collected. When available, biological samples (blood, DNA, CSF, middle cerebral artery samples) are being also collected for biological and cellular studies. Ninety-eight patients (age of onset mean ± SD 35.5 ± 19.6 years; 68.4% females) have been collected so far. 65.3% of patients presented ischemic (50%) and haemorrhagic (15.3%) stroke. A higher female predominance concomitantly with a similar age of onset and clinical features to what was reported in previous studies on Western patients has been confirmed. An accurate and detailed clinical and neuroimaging classification represents the best strategy to provide the characterization of the disease phenotype and clinical course. The collection of a large number of biological samples will permit the identification of biological markers and genetic factors associated with the disease susceptibility in Italy.

Background and Purpose- Bridging therapy with low-molecular-weight heparin reportedly leads to a worse outcome for acute cardioembolic stroke patients because of a higher incidence of intracerebral bleeding. However, this practice is common in clinical settings. This observational study aimed to compare (1) the clinical profiles of patients receiving and not receiving bridging therapy, (2) overall group outcomes, and (3) outcomes according to the type of anticoagulant prescribed. Methods- We analyzed data of patients from the prospective RAF and RAF-NOACs studies. The primary outcome was defined as the composite of ischemic stroke, transient ischemic attack, systemic embolism, symptomatic cerebral bleeding, and major extracerebral bleeding observed at 90 days after the acute stroke. Results- Of 1810 patients who initiated oral anticoagulant therapy, 371 (20%) underwent bridging therapy with full-dose low-molecular-weight heparin. Older age and the presence of leukoaraiosis were inversely correlated with the use of bridging therapy. Forty-two bridged patients (11.3%) reached the combined outcome versus 72 (5.0%) of the nonbridged patients (P=0.0001). At multivariable analysis, bridging therapy was associated with the composite end point (odds ratio, 2.3; 95% CI, 1.4-3.7; P0.0001), as well as ischemic (odds ratio, 2.2; 95% CI, 1.3-3.9; P=0.005) and hemorrhagic (odds ratio, 2.4; 95% CI, 1.2-4.9; P=0.01) end points separately. Conclusions- Our findings suggest that patients receiving low-molecular-weight heparin have a higher risk of early ischemic recurrence and hemorrhagic transformation compared with nonbridged patients.

Patrizia Ripa,1 Raffaele Ornello,1 Diana Degan,1 Cindy Tiseo,1 Janet Stewart,2 Francesca Pistoia,1 Antonio Carolei,1 Simona Sacco1 1Department of Applied Clinical Sciences and Biotechnology, Institute of Neurology, University ofL’Aquila, L’Aquila, Italy; 2Psychology Division, School of Natural Sciences, University of Stirling, Scotland, UK Abstract: Evidence suggests that migraine activity is influenced by hormonal factors, and particularly by estrogen levels, but relatively few studies have investigated the prevalence and characteristics of migraine according to the menopausal status. Overall, population-based studies have shown an improvement of migraine after menopause, with a possible increase in perimenopause. On the contrary, the studies performed on patients referring to headache centers have shown no improvement or even worsening of migraine. Menopause etiology may play a role in migraine evolution during the menopausal period, with migraine improvement more likely occurring after spontaneous rather than after surgical menopause. Postmenopausal hormone replacement therapy has been found to be associated with migraine worsening in observational population-based studies. The effects of several therapeutic regimens on migraine has also been investigated, leading to nonconclusive results. To date, no specific preventive measures are recommended for menopausal women with migraine. There is a need for further research in order to clarify the relationship between migraine and hormonal changes in women, and to quantify the real burden of migraine after the menopause. Hormonal manipulation for the treatment of refractory postmenopausal migraine is still a matter of debate. Keywords: headache, female, menstrual cycle, sex hormones

The aim of this study was to identify the impact of comorbidities on outcomes of patients with vegetative state (VS) or minimally conscious state (MCS). All patients in VS or MCS consecutively admitted to two postacute care units within a 1-year period were evaluated at baseline and at 6 months through the Coma Recovery Scale-Revised Version and the Disability Rating Scale (DRS). Comorbidities were also recorded for each patient along the same period. Six-month outcomes included death, full recovery of consciousness, and functional improvement. One hundred and thirty-nine patients (88 male and 51 female; median age, 59 years) were included. Ninety-seven patients were in VS (70%) and 42 in MCS (30%). At 6 months, 33 patients were dead (24%), 39 had a full recovery of consciousness (28%), and 67 remained in VS or MCS (48%). According to DRS scores, 40% of patients (n=55) showed a functional improvement in the level of disability. One hundred and thirty patients (94%) showed at least one comorbidity. Severity of comorbidities (hazard ratio [HR]=2.8; 95% confidence interval [CI], 1.71-4.68; p0.001) and the presence of ischemic or organic heart diseases (HR=2.6; 95% CI, 1.21-5.43; p=0.014) were the strongest predictors of death, together with increasing age (HR=1.0; 95% CI, 1.0-1.06; p=0.033). Respiratory diseases and arrhythmias without organic heart diseases were negative predictors of full recovery of consciousness (odds ratio [OR]=0.3; 95% CI, 0.12-0.7; p=0.006; OR=0.2; 95% CI, 0.07-0.43; p0.001) and functional improvement (OR=0.4; 95% CI, 0.15-0.85, p=0.020; OR=0.2; 95% CI, 0.08-0.45; p0.001). Our data show that comorbidities are common in these patients and some of them influence recovery of consciousness and outcomes.

Background and purpose Several studies have assessed the risk of ischaemic heart diseases in migraineurs, drawing different conclusions. To define and update the issue, a systematic review and meta-analysis of the available observational studies was performed. Methods PubMed and EMBASE were systematically searched up to April 2014 for observational studies dealing with the risk of any form of ischaemic heart disease in migraineurs. Studies assessing migraine as exposure and several types of ischaemic heart disease as outcomes were included in the analysis. A random effects model was used to pool the effect sizes. Results Out of 3348 records, 15 studies (one case−control, one cross-sectional and 13 cohort studies) were identified and were included in the meta-analysis. The pooled analysis indicated an increased risk of myocardial infarction (pooled adjusted effect estimate 1.33, 95% confidence interval 1.08–1.64; P = 0.007) and of angina (pooled adjusted effect estimate 1.29, 95% confidence interval 1.17–1.43; P

Disorders of consciousness and locked-in syndrome are two completely different neurological conditions which share unresponsiveness or minimal responsiveness at an observable behavioral level. The key element of disorders of consciousness is the loss of self- and environmental awareness, while the main feature of locked-in syndrome is extreme motor entrapment despite preserved awareness. In both cases accurate diagnosis may come late and patients are at risk of being wrongly diagnosed and missing out on appropriate rehabilitative opportunities. Clinical assessment alone often does not suffice in establishing the correct diagnosis and prognosis. The contribution of advanced neuroimaging techniques is essential in order to properly recognize patients’ conditions and formulate a tailored rehabilitative approach. Neuroimaging findings are also crucial in identifying the neuropathological substrate of the disorders: they contribute to elucidating the dynamics of cortical-subcortical networks in disorders of consciousness and the neural correlates of recently reported non-motor symptoms in locked-in syndrome.

Previous evidence suggests that hallucinations and delusions may be detected in patients with the most severe forms of motor disability including locked-in syndrome (LIS). However, such phenomena are rarely described in LIS and their presence may be underestimated as a result of the severe communication impairment experienced by the patients. In this study, we retrospectively reviewed the clinical history and the neuroimaging data of a cohort of patients with LIS in order to recognize the presence of hallucinations and delusions and to correlate it with the pontine damage and the presence of any cortical volumetric changes. Ten patients with LIS were included (5 men and 5 women, mean age 50.1 ± 14.6). According to the presence of indicators of symptoms, these patients were categorized as hallucinators (n = 5) or non-hallucinators (n = 5). MRI images of patients were analyzed using Freesurfer 6.0 software to evaluate volume differences between the two groups. Hallucinators showed a selective cortical volume loss involving the fusiform (p = 0.001) and the parahippocampal (p = 0.0008) gyrus and the orbital part of the inferior frontal gyrus (p = 0.001) in the right hemisphere together with the lingual (p = 0.01) and the fusiform gyrus (p = 0.01) in the left hemisphere. Moreover, a volumetric decrease of bilateral anterior portions of the precuneus was recognized in the hallucinators (right p = 0.01; left p = 0.001) as compared to non-hallucinators. We suggested that the presence of hallucinations and delusions in some LIS patients could be accounted for by the combination of a damage of the corticopontocerebellar pathways with cortical changes following the primary brainstem injury. The above areas are embedded within cortico-cortical and cortico-subcortical loops involved in self-monitoring and have been related to the presence of hallucinations in other diseases. The two main limitations of our study are the small sample of included patients and the lack of a control group of healthy individuals. Further studies would be of help to expand this field of research in order to integrate existing theories about the mechanisms underlying the generation of hallucinations and delusions in neurological patients.

Traditionally neurological diseases have been classified, on the basis of their pathogenesis, into vascular, degenerative, inflammatory and traumatic diseases. Examples of the main inflammatory neurological diseases include multiple sclerosis, which is characterized by an immune-mediated response against myelin proteins, and meningoencephalitis, where the inflammatory response is triggered by infectious agents. However, recent evidence suggests a potential role of inflammatory mechanisms also in neurological conditions not usually categorized as inflammatory, such as Alzheimer’s disease, Parkinson’s disease, Huntington’ disease, amyotrophic lateral sclerosis, stroke and traumatic brain injuries. The activation of glial cells and of complement-mediated pathways, the synthesis of inflammation mediators, and the recruitment of leukocytes are the key elements of secondary inflammatory injury following a wide spectrum of primary brain injuries. A better understanding of the role that inflammatory processes play in the natural history of diseases is essential in order to identify potential therapeutic targets and to develop integrated pharmacological approaches acting at different levels and stages of the diseases.

Background. Posterior reversible encephalopathy syndrome (PRES) is characterized by a variable association of symptoms including headache, consciousness impairment, visual disturbances, seizures, and focal neurological signs. Treating the underlying cause usually leads to partial or complete resolution of symptoms within days or weeks. Brain MRI findings include hyperintensities on T2-weighted sequences and their reversibility on follow-up exams. We describe two patients, one with an atypical clinical presentation characterized by a severe and prolonged impairment of consciousness and the other with atypical neuroimaging findings. Case Presentation. The first patient was a 42-year-old woman, with a negative medical history, presenting with seizures, lethargy, and left hemiparesis, 60 hours after uncomplicated delivery. Brain MRI showed an atypical pattern of alterations, with patchy asymmetric distribution in all lobes. Symptoms completely resolved after twelve days. The second patient was a 59-year-old woman with a history of hypertension, presenting with severe impairment of consciousness, vision loss, and seizures. Symptoms partially resolved after three weeks. Conclusion. PRES is characterized by reversible symptoms and radiological findings. Brain MRI usually shows widespread oedema in white matter with typical patterns. The cases we described suggest that PRES may presents with atypical symptoms and radiological manifestations, mimicking other neurological conditions.

Objective. The aim of this prospective observational multicenter postmarketing study was to evaluate fingolimod efficacy in a real world clinical setting.Methods. One hundred forty-two subjects with relapsing-remitting multiple sclerosis (RRMS) were enrolled in three multiple sclerosis centers throughout Central and Southern Italy between January 2011 and September 2013. After enrollment, regular visits and EDSS assessment were scheduled every 3 months, and MRI scan was obtained every 12 months. Patients were followed up from 1 to 33 months (mean 14.95 ± 9.15 months). The main efficacy endpoints included the proportion of patients free from clinical relapses, from disability progression, from magnetic resonance imaging activity, and from any disease activity.Results. Out of 142 patients enrolled in the study, 88.1% were free from clinical relapse and 69.0% were free from disability progression; 68.5% of patients remained free from new or newly enlarging T2 lesions and 81.7% of patients were free from gadolinium enhancing lesions. Overall the proportion of patients free from any disease activity was 41.9%.Conclusions. Our data in a real world cohort are consistent with previous findings that yield convincing evidence for the efficacy of fingolimod in patients with RRMS.

ObjectiveTo examine factors contributing to the sex differences in functional outcomes and participation restriction after stroke.MethodsIndividual participant data on long-term functional outcome or participation restriction (i.e., handicap) were obtained from 11 stroke incidence studies (1993–2014). Multivariable log-binomial regression was used to estimate the female:male relative risk (RR) of poor functional outcome (modified Rankin Scale score >2 or Barthel Index score ResultsIn unadjusted analyses, women experienced worse functional outcomes after stroke than men (1 year: pooled RRunadjusted 1.32, 95% confidence interval [CI] 1.18–1.48; 5 years: RRunadjusted 1.31, 95% CI 1.16–1.47). However, this difference was greatly attenuated after adjustment for age, prestroke dependency, and stroke severity (1 year: RRadjusted 1.08, 95% CI 0.97–1.20; 5 years: RRadjusted 1.05, 95% CI 0.94–1.18). Women also had greater participation restriction than men (pooled MDunadjusted −5.55, 95% CI −8.47 to −2.63), but this difference was again attenuated after adjustment for the aforementioned factors (MDadjusted −2.48, 95% CI −4.99 to 0.03).ConclusionsWorse outcomes after stroke among women were explained mostly by age, stroke severity, and prestroke dependency, suggesting these potential targets to improve the outcomes after stroke in women.

Progress in medical science and technology drastically improved physicians’ ability to interact with patient’s physical body. Nevertheless, medicine still addresses the human body from a Hippocratic point of view, considering the organism and its processes just as a matter of mechanics and fluids. However, the interaction between the cognitive neuroscience of bodily self-consciousness (BSC), fundamentally rooted in the integration of multisensory bodily inputs, with virtual reality (VR), haptic technologies and robotics is giving a new meaning to the classic Juvenal’s latin dictum “Mens sana in corpore sano” (a healthy mind in a healthy body). This vision provides the basis for a new research field, “Embodied Medicine”: the use of advanced technologies for altering the experience of being in a body with the goal of improving health and well-being. Up to now, most of the research efforts in the field have been focused upon how external bodily information is processed and integrated. Despite the important results, we believe that existing bodily illusions still need to be improved to enhance their capability to effectively correct pathological dysfunctions. First, they do not follow the suggestions provided by the free-energy and predictive coding approaches. More, they lacked to consider a peculiar feature of the human body, the multisensory integration of internal inputs (interoceptive, proprioceptive and vestibular) that constitute our inner body dimension. So, a future challenge is the integration of simulation/stimulation technologies also able to measure and modulate this internal/inner experience of the body. Finally, we also proposed the concept of “Sonoception” as an extension of this approach. The core idea is to exploit recent technological advances in the acoustic field to use sound and vibrations to modify the internal/inner body experience.