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There is great interest about the therapeutic potentialities of transcutaneous vagus nerve stimulation (tVNS) applied to neuropsychiatric disorders. However, the mechanisms of action of tVNS and its impact on cortical excitability are unclear. To this regard, transcranial magnetic stimulation (TMS) can be useful because it is able of evaluating non-invasively excitatory and inhibitory circuitry of the human cortex. Aim of the present study is to investigate the effects of tVNS on cerebral cortex excitability in healthy volunteers by means of TMS. Ten healthy subjects participated in this randomized placebo-controlled double-blind study. Real tVNS was administered at left external acoustic meatus, while sham stimulation was performed at left ear lobe, both of them for 60 min. We evaluated motor thresholds, motor evoked potential amplitude, recruitment curves, and short-interval intracortical inhibition (SICI) in right and left motor cortex. Such parameters were evaluated before and 60 min after the exposure to tVNS, for both the real and the sham stimulation. Cardiovascular parameters were monitored during the stimulation. A generalized linear model for repeated measures was implemented to assess the effect of time and stimulation type on cardiovascular and neurophysiological variables. SICI, a double-pulse TMS paradigm informative of GABA-A activity, was significantly increased in right motor cortex after real tVNS. Other neurophysiological parameters, as well as cardiovascular variables, remained unchanged. Our findings confirm that tVNS is a safe and effective way to stimulate vagus nerve and provide innovative data about the possible mechanisms of action that supports the potential therapeutic application of this technique.

Comparison studies on recovery outcomes in ischemic (IS) and hemorrhagic strokes (HS) have yielded mixed results. In this retrospective observational study of consecutive IS and HS patients, we aimed at evaluating functional outcomes at discharge from an intensive rehabilitation hospital, comparing IS vs. HS, analyzing possible predictors. Modified Rankin Scale (mRS) at discharge was the main outcome. Out of the 229 patients included (mean age 72.9 ± 13.9 years, 48% males), 81 had HS (35%). Compared with IS (n = 148), HS patients were significantly younger (75 ± 12.5 vs. 68.8 ± 15.4 years, p = 0.002), required longer hospitalizations both in acute (23.9 ± 36.7 vs. 35.2 ± 29.9 days, p = 0.019) and rehabilitation hospitals (41.5 ± 31.8 vs. 77.2 ± 51.6 days, p = 0.001), and had more severe initial clinical deficit (mean number of neurological impairments: 2.0 ± 1.1 vs. 2.6 ± 1.4, p = 0.001) and mRS scores at admission (p = 0.046). At discharge, functional status change, expressed as mRS, was not significantly different between IS and HS (F = 0.01, p = 0.902), nor was the discharge destination (p = 0.428). Age and clinical severity were predictors of functional outcome in both stroke types. On admission in an intensive rehabilitation hospital, HS patients presented a worse functional and clinical status compared to IS. Despite this initial gap, the two stroke types showed an overlapped trajectory of functional recovery, with age and initial stroke severity as the main prognostic factors.

Background: Atrial fibrillation (AF) is one of the most common heart rhythm disorders encountered in clinical practice. Emerging evidence suggests a significant role of inflammation in the pathogenesis of AF, but certain questions still remain unanswered, in particular whether AF-related inflammation is a cause or a consequence of the arrhythmia, and whether inflammation reflects underlying disease or AF itself. At the current state of the art, scientific evidence on the role of oral anticoagulants (OAC) in modulating pro-inflammatory cytokines implicated in the pathogenesis of AF remains scarce. The aim of our study was to evaluate, in a population of AF patients undergoing OAC, the different roles of anticoagulant therapy [Vitamin K antagonists (VKAs) and direct oral anti-coagulants (DOACs)] in modulating the levels of inflammatory biomarkers in AF. Methods: The Strat-AF study is an observational, prospective, single center, hospital-based study enrolling elderly patients with AF. Results refer to 170 subjects with complete clinical and biohumoral assessment. Results: At multivariate logistic regression analysis, adjusted for several covariates, VKA treatment was an independent protective predictor for having a high grade of inflammation not balanced by anti-inflammatory cytokine levels [OR = 0.26 (0.10–0.69), p = 0.007]. Conclusions: These results from the Strat-AF study are “generators of hypotheses” and provide preliminary evidence for the differential effects of VKAs and DOACs on inflammatory biomarkers (e.g., IL-6, TNF-α) in AF patients. These findings suggest that inflammatory biomarkers could enhance stroke risk prediction models, potentially improving a tailored AF management.

In anticoagulated atrial fibrillation (AF) patients, the validity of models recommended for the stratification of the risk ratio between benefits and hemorrhage risk is limited. We hypothesize that both circulating and neuroimaging-based markers might improve the prediction of bleeding and thrombotic risk in anticoagulated AF patients. The Strat-AF study is an observational, prospective, single-center study enrolling 170 patients with AF; recruited patients are evaluated by means of a comprehensive protocol, with clinical, cerebral magnetic resonance imaging and circulating biomarkers assessment. The main outcome is the evaluation of cerebral microangiopathy related to the levels of circulating biomarkers of inflammation and extracellular matrix (ECM) remodeling. At multivariate logistic regression analysis adjusted for age, sex, CHA2DS2-VASc, HAS-BLED and type of anticoagulant, matrix metalloproteinases (MMP)-2 levels were significantly and positively associated with the presence of cerebral microbleeds (CMBs). A significant association between MMP-2, tissue inhibitor of metalloproteinases (TIMP)-1,-2,-4 levels and white matter hyperintensity was also found. Concerning the small vessel disease (SVD) score, MMP-2 and TIMP-1,-2 levels were associated with the presence of two and three or more signs of SVD, whereas TIMP-4 levels were associated with the presence of three signs of SVD with respect to patients with no instrumental signs of SVD. As regarding the presence of enlarged perivascular spaces (EPVS), a significant association was found for high levels of interleukin (IL)-8 and TIMP 1-2-3. These results demonstrate that patients with AF have evidence of impaired ECM degradation, which is an independent risk factor for thrombotic complications of AF patients on oral anticoagulant therapy. The incorporation of these markers in the prognostic schemes might improve their clinical capability in predicting stroke risk and thrombotic complications.

Background: Sporadic CAA is recognized as a major cause of sICH and sABI. Even if intensive rehabilitation is recommended to maximize functional recovery after sICH, no data are available on whether CAA may affect rehabilitation outcomes. In this observational prospective study, to explore the impact of CAA on rehabilitation results, functional outcomes after intensive rehabilitation have been compared between patients affected by sICH with and without a diagnosis of CAA. Methods: All adults affected by sABI due to sICH and admitted to the IRU of IRCCS-Don-Gnocchi-Foundation were consecutively enrolled for 12 months. Demographic and clinical data were recorded upon admission and discharge. Results: Among 102 sICH patients (age: 66 (IQR = 16), 53% female), 13% were diagnosed as probable/possible-CAA. TPO and functional assessment were comparable upon admission, but CAA patients were significantly older (p = 0.001). After a comparable LOS, CAA patients presented higher care burden (ERBI: p = 0.025), poorer functional recovery (FIM: p = 0.02) and lower levels of global independence (GOSE > 4: p = 0.03). In multivariate analysis, CAA was significantly correlated with a lower FIM (p = 0.019) and a lower likelihood of reaching GOS-E > 4, (p = 0.041) at discharge, independently from age. Conclusions: CAA seems to be independently associated with poorer rehabilitation outcomes, suggesting the importance of improving knowledge about CAA to better predict rehabilitation outcomes.

Background and Objectives: In anticoagulated atrial fibrillation (AF) patients, the validity of models recommended for the stratification of the risk ratio between benefits and hemorrhage risk is limited. Cerebral small vessel disease (SVD) represents the pathologic substrate for primary intracerebral hemorrhage and ischemic stroke. We hypothesize that biological markers—both circulating and imaging-based—and their possible interaction, might improve the prediction of bleeding risk in AF patients under treatment with any type of oral anticoagulant. Materials and Methods: The Strat-AF study is an observational, prospective, single-center hospital-based study enrolling patients with AF, aged 65 years or older, and with no contraindications to magnetic resonance imaging (MRI), referring to Center of Thrombosis outpatient clinic of our University Hospital for the management of oral anticoagulation therapy. Recruited patients are evaluated by means of a comprehensive protocol, with clinical, cerebral MRI, and circulating biomarkers assessment at baseline and after 18 months. The main outcome is SVD progression—particularly microbleeds—as a selective surrogate marker of hemorrhagic complication. Stroke occurrence (ischemic or hemorrhagic) and the progression of functional, cognitive, and motor status will be evaluated as secondary outcomes. Circulating biomarkers may further improve predictive potentials. Results: Starting from September 2017, 194 patients (mean age 78.1 ± 6.7, range 65–97; 61% males) were enrolled. The type of AF was paroxysmal in 93 patients (48%), and persistent or permanent in the remaining patients. Concerning the type of oral anticoagulant, 57 patients (29%) were on vitamin K antagonists, and 137 (71%) were on direct oral anticoagulants. Follow-up clinical evaluation and brain MRI are ongoing. Conclusions: The Strat-AF study may be an essential step towards the exploration of the role of a combined clinical biomarker or multiple biomarker models in predicting stroke risk in AF, and might sustain the incorporation of such new markers in the existing stroke prediction schemes by the demonstration of a greater incremental value in predicting stroke risk and improvement in clinical outcomes in a cost-effective fashion.

Cerebral microbleeds are a neuroimaging biomarker of stroke risk. A crucial clinical question is whether cerebral microbleeds indicate patients with recent ischaemic stroke or transient ischaemic attack in whom the rate of future intracranial haemorrhage is likely to exceed that of recurrent ischaemic stroke when treated with antithrombotic drugs. We therefore aimed to establish whether a large burden of cerebral microbleeds or particular anatomical patterns of cerebral microbleeds can identify ischaemic stroke or transient ischaemic attack patients at higher absolute risk of intracranial haemorrhage than ischaemic stroke. We did a pooled analysis of individual patient data from cohort studies in adults with recent ischaemic stroke or transient ischaemic attack. Cohorts were eligible for inclusion if they prospectively recruited adult participants with ischaemic stroke or transient ischaemic attack; included at least 50 participants; collected data on stroke events over at least 3 months follow-up; used an appropriate MRI sequence that is sensitive to magnetic susceptibility; and documented the number and anatomical distribution of cerebral microbleeds reliably using consensus criteria and validated scales. Our prespecified primary outcomes were a composite of any symptomatic intracranial haemorrhage or ischaemic stroke, symptomatic intracranial haemorrhage, and symptomatic ischaemic stroke. We registered this study with the PROSPERO international prospective register of systematic reviews, number CRD42016036602. Between Jan 1, 1996, and Dec 1, 2018, we identified 344 studies. After exclusions for ineligibility or declined requests for inclusion, 20 322 patients from 38 cohorts (over 35 225 patient-years of follow-up; median 1·34 years [IQR 0·19–2·44]) were included in our analyses. The adjusted hazard ratio [aHR] comparing patients with cerebral microbleeds to those without was 1·35 (95% CI 1·20–1·50) for the composite outcome of intracranial haemorrhage and ischaemic stroke; 2·45 (1·82–3·29) for intracranial haemorrhage and 1·23 (1·08–1·40) for ischaemic stroke. The aHR increased with increasing cerebral microbleed burden for intracranial haemorrhage but this effect was less marked for ischaemic stroke (for five or more cerebral microbleeds, aHR 4·55 [95% CI 3·08–6·72] for intracranial haemorrhage vs 1·47 [1·19–1·80] for ischaemic stroke; for ten or more cerebral microbleeds, aHR 5·52 [3·36–9·05] vs 1·43 [1·07–1·91]; and for ≥20 cerebral microbleeds, aHR 8·61 [4·69–15·81] vs 1·86 [1·23–2·82]). However, irrespective of cerebral microbleed anatomical distribution or burden, the rate of ischaemic stroke exceeded that of intracranial haemorrhage (for ten or more cerebral microbleeds, 64 ischaemic strokes [95% CI 48–84] per 1000 patient-years vs 27 intracranial haemorrhages [17–41] per 1000 patient-years; and for ≥20 cerebral microbleeds, 73 ischaemic strokes [46–108] per 1000 patient-years vs 39 intracranial haemorrhages [21–67] per 1000 patient-years). In patients with recent ischaemic stroke or transient ischaemic attack, cerebral microbleeds are associated with a greater relative hazard (aHR) for subsequent intracranial haemorrhage than for ischaemic stroke, but the absolute risk of ischaemic stroke is higher than that of intracranial haemorrhage, regardless of cerebral microbleed presence, antomical distribution, or burden. British Heart Foundation and UK Stroke Association.

Balancing the risks of recurrent ischaemic stroke and intracranial haemorrhage is important for patients treated with antithrombotic therapy after ischaemic stroke or transient ischaemic attack. However, existing predictive models offer insufficient performance, particularly for assessing the risk of intracranial haemorrhage. We aimed to develop new risk scores incorporating clinical variables and cerebral microbleeds, an MRI biomarker of intracranial haemorrhage and ischaemic stroke risk. We did a pooled analysis of individual-patient data from the Microbleeds International Collaborative Network (MICON), which includes 38 hospital-based prospective cohort studies from 18 countries. All studies recruited participants with previous ischaemic stroke or transient ischaemic attack, acquired baseline MRI allowing quantification of cerebral microbleeds, and followed-up participants for ischaemic stroke and intracranial haemorrhage. Participants not taking antithrombotic drugs were excluded. We developed Cox regression models to predict the 5-year risks of intracranial haemorrhage and ischaemic stroke, selecting candidate predictors on biological relevance and simplifying models using backward elimination. We derived integer risk scores for clinical use. We assessed model performance in internal validation, adjusted for optimism using bootstrapping. The study is registered on PROSPERO, CRD42016036602. The included studies recruited participants between Aug 28, 2001, and Feb 4, 2018. 15 766 participants had follow-up for intracranial haemorrhage, and 15 784 for ischaemic stroke. Over a median follow-up of 2 years, 184 intracranial haemorrhages and 1048 ischaemic strokes were reported. The risk models we developed included cerebral microbleed burden and simple clinical variables. Optimism-adjusted c indices were 0·73 (95% CI 0·69–0·77) with a calibration slope of 0·94 (0·81–1·06) for the intracranial haemorrhage model and 0·63 (0·62–0·65) with a calibration slope of 0·97 (0·87–1·07) for the ischaemic stroke model. There was good agreement between predicted and observed risk for both models. The MICON risk scores, incorporating clinical variables and cerebral microbleeds, offer predictive value for the long-term risks of intracranial haemorrhage and ischaemic stroke in patients prescribed antithrombotic therapy for secondary stroke prevention; external validation is warranted. British Heart Foundation and Stroke Association.

PurposeParticipation needs to be assessed objectively, to state accurate rehabilitation objectives. The Frenchay Activities Index (FAI) is a widely used tool to measure participation in stroke patients. To date, no cross-culturally validated Italian version of FAI is available. This study provides a translation and cross-cultural adaptation of FAI into Italian, assessing its validity and reliability in sub-acute stroke patients.MethodsAccording to international guidelines, a multistep translation and cultural adaptation protocol of forward and backward translations was conducted by qualified linguists and independent native English translators and revised by a healthcare committee. Patients admitted to intensive inpatient rehabilitation after stroke were recruited. Structural validity, reliability (internal consistency, inter- and intra-rater reliability and measurement error), and construct validity were studied.ResultsOne hundred and seventy-three patients were included in this study. No significant observations in terms of comprehensibility and conceptual equivalence of the FAI Italian version emerged. The exploratory factorial analysis revealed the presence of two subscales (i.e., domestic chores and work/leisure). The internal consistency resulted good for the first and second subscale (α = 0.821 and 0.716, respectively). Intra- and inter-reliability showed an ICC > 0.90 for both subscales. SEM = 5.75% and 2.33% and MDC = 15.85% and 6.48% were found for the first and second subscale, respectively. Construct validity of first subscale was satisfactory, as 100.0% a priori hypotheses were met, while for the second subscale it was moderate, as 66.6% a priori hypotheses were respected.ConclusionFAI-I provides a tool for professionals to measure participation in Italian stroke patients in health and social care settings.