Publications by authors named "Valeria De Giuli"

26 Publications

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SARS-CoV-2 infection and acute ischemic stroke in Lombardy, Italy.

J Neurol 2021 May 24. Epub 2021 May 24.

Department of Neurology and Stroke Unit, Carlo Poma Hospital, ASST Mantova, Mantova, Italy.

Objective: To characterize patients with acute ischemic stroke related to SARS-CoV-2 infection and assess the classification performance of clinical and laboratory parameters in predicting in-hospital outcome of these patients.

Methods: In the setting of the STROKOVID study including patients with acute ischemic stroke consecutively admitted to the ten hub hospitals in Lombardy, Italy, between March 8 and April 30, 2020, we compared clinical features of patients with confirmed infection and non-infected patients by logistic regression models and survival analysis. Then, we trained and tested a random forest (RF) binary classifier for the prediction of in-hospital death among patients with COVID-19.

Results: Among 1013 patients, 160 (15.8%) had SARS-CoV-2 infection. Male sex (OR 1.53; 95% CI 1.06-2.27) and atrial fibrillation (OR 1.60; 95% CI 1.05-2.43) were independently associated with COVID-19 status. Patients with COVID-19 had increased stroke severity at admission [median NIHSS score, 9 (25th to75th percentile, 13) vs 6 (25th to75th percentile, 9)] and increased risk of in-hospital death (38.1% deaths vs 7.2%; HR 3.30; 95% CI 2.17-5.02). The RF model based on six clinical and laboratory parameters exhibited high cross-validated classification accuracy (0.86) and precision (0.87), good recall (0.72) and F1-score (0.79) in predicting in-hospital death.

Conclusions: Ischemic strokes in COVID-19 patients have distinctive risk factor profile and etiology, increased clinical severity and higher in-hospital mortality rate compared to non-COVID-19 patients. A simple model based on clinical and routine laboratory parameters may be useful in identifying ischemic stroke patients with SARS-CoV-2 infection who are unlikely to survive the acute phase.
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http://dx.doi.org/10.1007/s00415-021-10620-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142879PMC
May 2021

Hematoma Expansion in Intracerebral Hemorrhage With Unclear Onset.

Neurology 2021 05 1;96(19):e2363-e2371. Epub 2021 Apr 1.

From UO Neurologia (A.M.), Azienda Socio-Sanitaria Territoriale (ASST) Valcamonica, Esine, Italy; Neuroradiology Department (G. Boulouis), Centre Hospitalier Sainte-Anne, Paris, France; J.P. Kistler Stroke Research Center, Department of Neurology (A. Charidimou, Q.L., A.D.W., C.D.A., M.E.G., A.B., A.V., S.M.G., J.R., J.N.G.), Massachusetts General Hospital Stroke Research Center, Harvard Medical School, Boston; Dipartimento di Scienze Cliniche e Sperimentali, Clinica Neurologica (L.P., A. Pezzini, A. Padovani), Università degli Studi di Brescia; UO di Neurologia (P.C.), Istituto Clinico Fondazione Poliambulanza, Brescia; UOC Neurologia (V.D.G.), ASST Cremona; UC Malattie Cerebrovascolari e Stroke Unit (E.L., F.M., A. Cavallini) and UC Neurologia d'Urgenza (E.L., F.M., G.M.), IRCCS Fondazione Mondino, Pavia; Dipartimento di Dipartimento di Scienze Biomediche, Sperimentali e Cliniche, Neuroradiologia, Università degliStudi di Firenze (G. Busto, E.F.), and Stroke Unit (F.A., A.Z.), Ospedale Universitario Careggi, Firenze; UOC Neurologia e Rete Stroke, Metropolitana (L.B., S.G.), and Unità di Neuroradiologia (L.S.), IRCCS Istituto delle Scienze Neurologiche di Bologna, Ospedale Maggiore; Clinica Neurologica, Dipartimento di Scienze Biomediche e Chirurgico Specialistiche (M.L., I.C.), Università degli studi diFerrara, Ospedale Universitario S. Anna, Ferrara; Neurologia e Stroke Unit (E.C.), Ospedale di Circolo, ASST Settelaghi, Varese; Stroke Unit (M.G., M.M.), Neurologia Vascolare, ASST Spedali Civili, Brescia, Italy; Division of Neurocritical Care and Emergency Neurology, Department of Neurology (C.D.A., J.R., J.N.G.), Harvard Medical School, Henry and Allison McCance Center for Brain Health (C.D.A., J.R., J.N.G.), and Department of Emergency Medicine (J.N.G.), Massachusetts General Hospital, Boston.

Objective: To investigate the prevalence, predictors, and prognostic effect of hematoma expansion (HE) in patients with intracerebral hemorrhage (ICH) with unclear symptom onset (USO).

Methods: We performed a retrospective analysis of patients with primary spontaneous ICH admitted at 5 academic medical centers in the United States and Italy. HE (volume increase >6 mL or >33% from baseline to follow-up noncontrast CT [NCCT]) and mortality at 30 days were the outcomes of interest. Baseline NCCT was also analyzed for presence of hypodensities (any hypodense region within the hematoma margins). Predictors of HE and mortality were explored with multivariable logistic regression.

Results: We enrolled 2,165 participants, 1,022 in the development cohort and 1,143 in the replication cohort, of whom 352 (34.4%) and 407 (35.6%) had ICH with USO, respectively. When compared with participants having a clear symptom onset, patients with USO had a similar frequency of HE (25.0% vs 21.9%, = 0.269 and 29.9% vs 31.5%, = 0.423). Among patients with USO, HE was independently associated with mortality after adjustment for confounders (odds ratio [OR] 2.64, 95% confidence interval [CI] 1.43-4.89, = 0.002). This finding was similar in the replication cohort (OR 3.46, 95% CI 1.86-6.44, < 0.001). The presence of NCCT hypodensities in patients with USO was an independent predictor of HE in the development (OR 2.59, 95% CI 1.27-5.28, = 0.009) and replication (OR 2.43, 95% CI 1.42-4.17, = 0.001) population.

Conclusion: HE is common in patients with USO and independently associated with worse outcome. These findings suggest that patients with USO may be enrolled in clinical trials of medical treatments targeting HE.
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http://dx.doi.org/10.1212/WNL.0000000000011895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166446PMC
May 2021

Impact of SARS-CoV-2 on reperfusion therapies for acute ischemic stroke in Lombardy, Italy: the STROKOVID network.

J Neurol 2021 Oct 8;268(10):3561-3568. Epub 2021 Mar 8.

Department of Neurology and Stroke Unit, Carlo Poma Hospital, ASST Mantova, Mantua, Italy.

Whether and how SARS-CoV-2 outbreak affected in-hospital acute stroke care system is still matter of debate. In the setting of the STROKOVID network, a collaborative project between the ten centers designed as hubs for the treatment of acute stroke during SARS-CoV-2 outbreak in Lombardy, Italy, we retrospectively compared clinical features and process measures of patients with confirmed infection (COVID-19) and non-infected patients (non-COVID-19) who underwent reperfusion therapies for acute ischemic stroke. Between March 8 and April 30, 2020, 296 consecutive patients [median age, 74 years (interquartile range (IQR), 62-80.75); males, 154 (52.0%); 34 (11.5%) COVID-19] qualified for the analysis. Time from symptoms onset to treatment was longer in the COVID-19 group [230 (IQR 200.5-270) minutes vs. 190 (IQR 150-245) minutes; p = 0.007], especially in the first half of the study period. Patients with COVID-19 who underwent endovascular thrombectomy had more frequently absent collaterals or collaterals filling ≤ 50% of the occluded territory (50.0% vs. 16.6%; OR 5.05; 95% CI 1.82-13.80) and a lower rate of good/complete recanalization of the primary arterial occlusive lesion (55.6% vs. 81.0%; OR 0.29; 95% CI 0.10-0.80). Post-procedural intracranial hemorrhages were more frequent (35.3% vs. 19.5%; OR 2.24; 95% CI 1.04-4.83) and outcome was worse among COVID-19 patients (in-hospital death, 38.2% vs. 8.8%; OR 6.43; 95% CI 2.85-14.50). Our findings showed longer delays in the intra-hospital management of acute ischemic stroke in COVID-19 patients, especially in the early phase of the outbreak, that likely impacted patients outcome and should be the target of future interventions.
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http://dx.doi.org/10.1007/s00415-021-10497-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937781PMC
October 2021

SARS-CoV-2 encephalitis is a cytokine release syndrome: evidences from cerebrospinal fluid analyses.

Clin Infect Dis 2021 Jan 4. Epub 2021 Jan 4.

Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Italy.

Background: Recent findings indicated that SARS-CoV-2 related neurological manifestations involve cytokine release syndrome along with endothelial activation, blood brain barrier dysfunction, and immune-mediated mechanisms. Very few studies have fully investigated the CSF correlates of SARS-CoV-2 encephalitis.

Methods: Patients with PCR-confirmed SARS-CoV-2 infection and encephalitis (COV-Enc), encephalitis without SARS-CoV-2 infection (ENC) and healthy controls (HC) underwent an extended panel of CSF neuronal (NfL, T-tau), glial (GFAP, TREM2, YKL-40) and inflammatory biomarkers (IL-1β, IL-6, Il-8, TNF- α, CXCL-13 and β2-microglobulin).

Results: Thirteen COV-Enc, 21 ENC and 18 HC entered the study. In COV-Enc cases, CSF was negative for SARS-CoV-2 real-time PCR but exhibited increased IL-8 levels independently from presence of pleocytosis/hyperproteinorracchia. COV-Enc patients showed increased IL-6, TNF- α, and β2-microglobulin and glial markers (GFAP, sTREM-2, YKL-40) levels similar to ENC but normal CXCL13 levels. Neuronal markers NfL and T-Tau were abnormal only in severe cases.

Conclusions: SARS-CoV-2-related encephalitis were associated with prominent glial activation and neuroinflammatory markers, whereas neuronal markers were increased in severe cases only. The pattern of CSF alterations suggested a cytokine-release syndrome as the main inflammatory mechanism of SARS-CoV-2 related encephalitis.
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http://dx.doi.org/10.1093/cid/ciaa1933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799260PMC
January 2021

Canakinumab as treatment for COVID-19-related pneumonia: A prospective case-control study.

Int J Infect Dis 2021 Mar 29;104:433-440. Epub 2020 Dec 29.

COVID Unit, Azienda Socio Sanitaria Territoriale di Cremona, Cremona, Italy.

Objectives: Canakinumab is an IL-1β antibody that neutralises the activity of IL-1β. This study examined the efficacy and safety of canakinumab in patients with moderate COVID-19-related pneumonia.

Design: This study aimed to evaluate the reduction in duration of hospitalisation with adequate oxygen status. Forty-eight patients with moderate COVID-19-related pneumonia were asked to participate in the prospective case-control study: 33 patients (cases) signed informed consent and received canakinumab (Cohort 1) and 15 patients (Controls) refused to receive the experimental drug and received institutional standard of care (Cohort 2).

Results: Hospital discharge within 21 days was seen in 63% of patients in Cohort 1 vs. 0% in Cohort 2 (median 14 vs. 26 days, respectively; p < 0.001). There was significant clinical improvement in ventilation regimes following administration of canakinumab compared with Cohort 2 (Stuart-Maxwell test for paired data, p < 0.001). Patients treated with canakinumab experienced a significant increase in PaO:FiO (p < 0.001) and reduction in lung damage by CT (p = 0.01), along with significant decreases in immune/inflammation markers that were not observed in Cohort 2. Only mild side-effects were seen in patients treated with canakinumab; survival at 60 days was 90.0% (95% CI 71.9-96.7) in patients treated with canakinumab and 73.3% (95% CI 43.6-89.1) for Cohort 2.

Conclusions: Treatment with canakinumab in patients with COVID-19-related pneumonia rapidly restored normal oxygen status, decreased the need for invasive mechanical ventilation, and was associated with earlier hospital discharge and favourable prognosis versus standard of care.
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http://dx.doi.org/10.1016/j.ijid.2020.12.073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771302PMC
March 2021

Clinical Presentation and Outcomes of Severe Acute Respiratory Syndrome Coronavirus 2-Related Encephalitis: The ENCOVID Multicenter Study.

J Infect Dis 2021 01;223(1):28-37

Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

Background: Several preclinical and clinical investigations have argued for nervous system involvement in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Some sparse case reports have described various forms of encephalitis in coronavirus disease 2019 (COVID-19) disease, but very few data have focused on clinical presentations, clinical course, response to treatment, and outcomes.

Methods: The SARS-CoV-2 related encephalopaties (ENCOVID) multicenter study included patients with encephalitis with full infectious screening, cerebrospinal fluid (CSF), electroencephalography (EEG), and magnetic resonance imaging (MRI) data and confirmed SARS-CoV-2 infection recruited from 13 centers in northern Italy. Clinical presentation and laboratory markers, severity of COVID-19 disease, response to treatment, and outcomes were recorded.

Results: Twenty-five cases of encephalitis positive for SARS-CoV-2 infection were included. CSF showed hyperproteinorrachia and/or pleocytosis in 68% of cases whereas SARS-CoV-2 RNA by reverse-transcription polymerase chain reaction resulted negative. Based on MRI, cases were classified as acute demyelinating encephalomyelitis (ADEM; n = 3), limbic encephalitis (LE; n = 2), encephalitis with normal imaging (n = 13), and encephalitis with MRI alterations (n = 7). ADEM and LE cases showed a delayed onset compared to the other encephalitis cases (P = .001) and were associated with previous, more severe COVID-19 respiratory involvement. Patients with MRI alterations exhibited worse response to treatment and final outcomes compared to those with other encephalitis.

Conclusions: SARS-CoV-2 infection is associated with a wide spectrum of encephalitis characterized by different clinical presentation, response to treatment, and outcomes.
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http://dx.doi.org/10.1093/infdis/jiaa609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543535PMC
January 2021

Subarachnoid Extension Predicts Lobar Intracerebral Hemorrhage Expansion.

Stroke 2020 05 23;51(5):1470-1476. Epub 2020 Mar 23.

Dipartimento di Dipartimento di Scienze Biomediche, Sperimentali e Cliniche, Neuroradiologia, Università degli Studi di Firenze, Ospedale Universitario Careggi, Firenze, Italia (G.B., E.F.).

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 (=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%; <0.001). When controlling for confounders in logistic regression, SAHE was an independent predictor of lobar HE (odds ratio, 6.00 [95% CI, 2.16-16.64]; =0.001) whereas there was no association with HE in nonlobar ICH (odds ratio, 0.55 [95% CI, 0.17-1.84]; =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]; =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.
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http://dx.doi.org/10.1161/STROKEAHA.119.028338DOI Listing
May 2020

History of Migraine and Volume of Brain Infarcts: The Italian Project on Stroke at Young Age (IPSYS).

J Stroke 2019 09 30;21(3):324-331. Epub 2019 Sep 30.

Department of Clinical and Experimental Sciences, Neurological Clinic, University of Brescia, Brescia, Italy.

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<0.001), and the largest volumes were observed in patients with migraine with aura (median, 9.0 cm3 [IQR, 3.4 to 16.6]). In a linear regression model, migraine was an independent predictor of increased log (acute infarct volumes) (median ratio [MR], 1.64; 95% confidence interval [CI], 1.22 to 2.20), an effect that was more prominent for migraine with aura (MR, 2.92; 95% CI, 1.88 to 4.54).

Conclusion: s These findings reinforce the experimental observation of larger acute cerebral infarcts in migraineurs, extend animal data to human disease, and support the hypothesis of increased vulnerability to ischemic brain injury in people suffering migraine.
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http://dx.doi.org/10.5853/jos.2019.00332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780016PMC
September 2019

Validation and Comparison of Noncontrast CT Scores to Predict Intracerebral Hemorrhage Expansion.

Neurocrit Care 2020 06;32(3):804-811

Stroke Unit, IRCCS Fondazione Istituto Neurologico Nazionale C. Mondino, Pavia, Italy.

Background And Purpose: 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.

Methods: 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 χ 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.

Results: 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).

Conclusions: 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.
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http://dx.doi.org/10.1007/s12028-019-00797-2DOI Listing
June 2020

Intravenous fibrinolysis plus endovascular thrombectomy versus direct endovascular thrombectomy for anterior circulation acute ischemic stroke: clinical and infarct volume results.

BMC Neurol 2019 May 29;19(1):103. Epub 2019 May 29.

Stroke Unit, Neurologia Vascolare, ASST Spedali Civili di Brescia, Piazzale Spedali Civili 1, Brescia 25123, Brescia, Italy.

Background: endovascular therapy (ET) is the standard of care for anterior circulation acute ischemic stroke (AIS) caused by large vessel occlusion (LVO). The role of adjunctive intravenous thrombolysis (IVT) in these patients remains unclear. The present study aims to investigate whether IVT followed by ET (CoT, combined therapy) provides additional benefits over direct ET for anterior circulation AIS with LVO.

Methods: we achieved a single center retrospective study of patients with AIS caused by anterior circulation LVO, referred to our center between January 2014 and January 2017 and treated with ET. Functional recovery (modified Rankin at 3-months follow-up), recanalization rate (thrombolysis in cerebral infarction [TICI] score) and time, early follow-up brain CT scan infarct volume (EFIV) (for recanalized patients only), symptomatic intracerebral hemorrhage (sICH) and 3-month mortality were the outcomes of interests. Independent predictors of the outcomes were explored with multivariable logistic regression.

Results: 145 subjects were included in the study, of whom 70 underwent direct ET and 75 were treated with CoT. Functional independence at 3-months was more frequent in CoT subjects compared to patients who received direct ET (mRS score 0-1: 48.5% vs 18.6%; P < 0.001. mRS score 0-2: 67.1% vs 37.3%; P < 0.001); CoT patients had also higher first-pass success rate (62.7% vs 38.6%, P < 0.05), higher recanalization rate (84.3% vs 65.3%; P = 0.009) and, in recanalized subjects, smaller EFIV (16.4 ml vs 62.3 ml; P = 0.003). Mortality and intracranial bleeding did not differ between the two groups. In multivariable regression analysis, low baseline NIHSS score (P < 0.05), vessel recanalization (P = 0.05) and CoT (P = 0.03) were independent predictors of favorable outcome at three months.

Conclusions: CoT appears more effective than ET alone for anterior circulation AIS with LVO, with similar safety profile.
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http://dx.doi.org/10.1186/s12883-019-1341-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540520PMC
May 2019

The clinical spectrum of reversible cerebral vasoconstriction syndrome: The Italian Project on Stroke at Young Age (IPSYS).

Cephalalgia 2019 Sep 6;39(10):1267-1276. Epub 2019 May 6.

28 Neurologia d'Urgenza and Stroke Unit, Humanitas Clinical and Research Center, IRCCS, Rozzano-Milano, Italy.

Introduction: To describe clinical, neuroimaging, and laboratory features of a large cohort of Italian patients with reversible cerebral vasoconstriction syndrome.

Methods: In the setting of the multicenter Italian Project on Stroke at Young Age (IPSYS), we retrospectively enrolled patients with a diagnosis of definite reversible cerebral vasoconstriction syndrome according to the International Classification of Headache Disorders (ICHD)-3 beta criteria (6.7.3 Headache attributed to reversible cerebral vasoconstriction syndrome, imaging-proven). Clinical manifestations, neuroimaging, treatment, and clinical outcomes were evaluated in all patients. Characteristics of reversible cerebral vasoconstriction syndrome without typical causes ("idiopathic reversible cerebral vasoconstriction syndrome") were compared with those of reversible cerebral vasoconstriction syndrome related to putative causative factors ("secondary reversible cerebral vasoconstriction syndrome").

Results: A total of 102 patients (mean age, 47.2 ± 13.9 years; females, 85 [83.3%]) qualified for the analysis. Thunderclap headache at presentation was reported in 69 (67.6%) patients, and it typically recurred in 42 (60.9%). Compared to reversible cerebral vasoconstriction syndrome cases related to putative etiologic conditions (n = 21 [20.6%]), patients with idiopathic reversible cerebral vasoconstriction syndrome (n = 81 [79.4%]) were significantly older (49.2 ± 13.9 vs. 39.5 ± 11.4 years), had more frequently typical thunderclap headache (77.8% vs. 28.6%) and less frequently neurological complications (epileptic seizures, 11.1% vs. 38.1%; cerebral infarction, 6.1% vs. 33.3%), as well as concomitant reversible brain edema (25.9% vs. 47.6%).

Conclusions: Clinical manifestations and putative etiologies of reversible cerebral vasoconstriction syndrome in our series are slightly different from those observed in previous cohorts. This variability might be partly related to the coexistence of precipitating conditions with a putative etiologic role on disease occurrence.
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http://dx.doi.org/10.1177/0333102419849013DOI Listing
September 2019

Migraine improvement after spontaneous cervical artery dissection the Italian Project on Stroke in Young Adults (IPSYS).

Neurol Sci 2019 Jan 21;40(1):59-66. Epub 2018 Sep 21.

Dipartimento di Scienze Cliniche e Sperimentali, Clinica Neurologica, Università degli Studi di Brescia, P.le Spedali Civili, 1,, 25123, Brescia, Italy.

Objective: Whether migraine modifies after spontaneous cervical artery dissection (sCeAD) more than after other stroke etiologic subtypes has never been adequately investigated.

Methods: In the setting of the Italian Project on Stroke in Young Adults (IPSYS), we compared the course of migraine before and after acute brain infarct in a group of migraine patients with sCeAD and a group of migraine patients whose ischemia was due to a cause other than CeAD (non-CeAD IS), matched by sex, age (± 3 years), and migraine subtype.We applied linear mixed models to evaluate pre-event vs post-event changes and differences between sCeAD and non-CeAD IS patients.

Results: Eighty-seven patients per group (migraine without aura/migraine with aura, 67/20) qualified for the analysis. After the acute event, migraine headaches disappeared in 14.0% of CeAD patients vs 0.0% of non-CeAD IS patients (p ≤ 0.001). Migraine frequency (patients suffering at least 1 attack, from 93.1 to 80.5%, p = 0.001), pain intensity (from 6.7 ± 1.7 to 4.6 ± 2.6 in a 0 to 10 pain scale, p ≤ 0.001), and use of acute anti-migraine medications (patients taking at least 1 preparation, from 81.6 to 64.4%, p = 0.007) also improved significantly after CeAD as opposed to that observed after non-CeAD IS.

Conclusion: The spontaneous improvement of migraine after sCeAD reinforces the hypothesis of a pathogenic link between the two conditions.
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http://dx.doi.org/10.1007/s10072-018-3578-9DOI Listing
January 2019

Alcohol intake and the risk of intracerebral hemorrhage in the elderly: The MUCH-Italy.

Neurology 2018 07 13;91(3):e227-e235. Epub 2018 Jun 13.

From U.O. Neurologia (P.C.), Istituto Ospedaliero Poliambulanza, Brescia; Dipartimento di Scienze Cliniche e Sperimentali (A. Pezzini, L.P., V.D.G., F.C., A. Padovani), Clinica Neurologica, Università degli Studi di Brescia; Dipartimento di Scienze del Sistema Nervoso e del Comportamento (M. Grassi), Unità di Statistica Medica e Genomica, Università di Pavia; Laboratorio di Epidemiologia Molecolare e Nutrizionale (L.I., A.D.C., G.d.G.), Dipartimento di Epidemiologia e Prevenzione, IRCCS Istituto Neurologico Mediterraneo, NEUROMED, Pozzilli; S.C. Neurologia (M.Z.), Arcispedale Santa Maria Nuova, IRCCS, Reggio Emilia; Neurologia d'Urgenza and Stroke Unit (S.M.), IRCCS Istituto Clinico Humanitas, Rozzano-Milano; Stroke Unit (G.S.), Dipartimento di Neuroscienze, Ospedale Carlo Poma, Mantova; Unità di Neurologia (M.L.D.), Ospedale di Circolo, Università dell'Insubria, Varese; U.O. Neurologia (M.S.), Istituti Ospedalieri di Cremona, Cremona; Stroke Unit (A.Z.), Clinica Neurologica, Nuovo Ospedale Civile, "S. Agostino Estense," AUSL Modena; Stroke Unit and Divisione di Medicina Cardiovascolare (M.P., G.A.), Università di Perugia; Stroke Unit (C.A., A.D.V.), Divisione di Neurologia, Dipartimento di Neuroscienze e Riabilitazione, Azienda Ospedaliero-Universitaria di Ferrara; Stroke Unit (M. Gamba), Neurologia Vascolare, Spedali Civili di Brescia; Unità di Neurologia (M.D.S.), E.O. Ospedali Galliera, Genova; U.O.C. Neurologia (A.T., N.P.), A.O. Universitaria "San Giovanni di Dio e Ruggi d'Aragona," Salerno; Dipartimento di Neuroscienze (C.G.), Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili, Università di Genova; U.O. Neurologia (D.M.B.), Azienda Ospedaliera "Cà Foncello," Treviso; Stroke Unit (R.T., G.M.), AOU Senese, Siena; Stroke Unit (A. Cavallini, A.M.), IRCCS Fondazione Istituto Neurologico Nazionale "C. Mondino," Pavia; Neurologia (A. Chiti), Azienda Ospedaliero Universitaria Pisana, Pisa; Istituto di Ricovero e Cura a Carattere Scientifico (R.S.C.), Centro Neurolesi Bonino-Pulejo, Messina; Dipartimento di Neuroscienze (F.G.), Scienze Psichiatriche e Anestesiologiche Clinica Neurologica, Università di Messina; USD Stroke Unit (P.B., G.T.), DAI di Neuroscienze, Azienda Ospedaliera Universitaria Integrata Verona; Centro Trombosi (C.L.), IRCCS Istituto Clinico Humanitas, Rozzano-Milano; Divisione di Biologia e Genetica (M.R., M.C.), Dipartimento di Medicina Molecolare e Traslazionale, Università degli Studi di Brescia; and Dipartimento di Specialità Medico-Chirurgiche (C.C.), Scienze Radiologiche e Sanità Pubblica, Clinica Neurochirurgica, Università degli Studi di Brescia, Italy.

Objective: To investigate the role of alcohol as a causal factor for intracerebral hemorrhage (ICH) and whether its effects might vary according to the pathogenic mechanisms underlying cerebral bleeding.

Methods: We performed a case-control analysis, comparing a cohort of consecutive white patients with ICH aged 55 years and older with a group of age- and sex-matched stroke-free controls, enrolled in the setting of the Multicenter Study on Cerebral Haemorrhage in Italy (MUCH-Italy) between 2002 and 2014. Participants were dichotomized into excessive drinkers (>45 g of alcohol) and light to moderate drinkers or nondrinkers. To isolate the unconfounded effect of alcohol on ICH, we used causal directed acyclic graphs and the back-door criterion to select a minimal sufficient adjustment set(s) of variables for multivariable analyses. Analyses were performed on the whole group as well as separately for lobar and deep ICH.

Results: We analyzed 3,173 patients (1,471 lobar ICH and 1,702 deep ICH) and 3,155 controls. After adjusting for the preselected variables in the minimal sufficient adjustments, heavy alcohol intake was associated with deep ICH risk (odds ratio [OR], 1.68; 95% confidence interval [CI], 1.36-2.09) as well as with the overall risk of ICH (OR, 1.38; 95% CI, 1.17-1.63), whereas no effect was found for lobar ICH (OR, 1.01; 95% CI, 0.77-1.32).

Conclusions: In white people aged 55 years and older, high alcohol intake might exert a causal effect on ICH, with a prominent role in the vascular pathologies underlying deep ICH.
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http://dx.doi.org/10.1212/WNL.0000000000005814DOI Listing
July 2018

Vulnerability to Infarction During Cerebral Ischemia in Migraine Sufferers.

Stroke 2018 03 19;49(3):573-578. Epub 2018 Feb 19.

From the Dipartimento di Scienze Cliniche e Sperimentali, Clinica Neurologica (A.P., L.P., F.C., V.D.G., A.P.) and Sezione di Neuroradiologia, Dipartimento di Specialità Medico-Chirurgiche, Scienze Radiologiche e Sanità Pubblica (R.G.), Università degli Studi di Brescia, Italia; Dipartimento di Scienze Biomediche, Sperimentali e Cliniche, Struttura Operativa Dipartimentale di Radiodiagnostica 2 (G.B., S.C.) and Dipartimento di Scienze Biomediche, Sperimentali e Cliniche, Struttura Operativa Dipartimentale di Neuroradiologia (E.F.), Università degli Studi di Firenze, Azienda Ospedaliero-Universitaria Careggi, Italia; Unità di Neurologia, Stroke Unit (M.Z.) and Unità di Neuroradiologia (R.P.), Arcispedale Santa Maria Nuova - IRCCS, Reggio Emilia, Italia; Stroke Unit, Neurologia Vascolare, Spedali Civili di Brescia, Italia (M.G.); Stroke Unit, Clinica Neurologica, Nuovo Ospedale Civile S. Agostino Estense, AUSL Modena, Italia (A.Z., A.M.S.); and Unità di Neurologia, Dipartimento di Scienze Biologiche, Psichiatriche e Psicologiche, Università di Ferrara, Italia (M.P.).

Background And Purpose: Cerebral hyperexcitability in migraine experiencers might sensitize brain tissue to ischemia. We investigated whether a personal history of migraine is associated with vulnerability to brain ischemia in humans.

Methods: Multicenter cohort study of patients with acute ischemic stroke who underwent a brain computed tomography perfusion and were scheduled to undergo reperfusion therapy. In a case-control design, we compared the proportion of subjects with no-mismatch, the volume of penumbra salvaged, as well as the final infarct size in a group of patients with migraine and a group of patients with no history of migraine.

Results: We included 61 patients with migraine (34 [55.7%] men; mean age, 52.2±15.1 years; migraine without aura/migraine with aura, 44/17) and 61 patients with no history of migraine. The proportion of no-mismatch among migraineurs was significantly higher than among nonmigraineurs (17 [27.9%] versus 7 [11.5%]; =0.039) and was more prominent among patients with migraine with aura (6 [35.3%]; =0.030) while it was nonsignificantly increased in patients with migraine without aura (11 [25.0%]; =0.114). Migraine, especially migraine with aura, was independently associated with a no-mismatch pattern (odds ratio, 2.65; 95% CI, 0.95-7.41 for migraine; odds ratio, 5.54; 95% CI, 1.28-23.99 for migraine with aura), and there was a linear decrease of the proportion of patients with migraine with aura with increasing quartiles of mismatch volumes. Patients with migraine with aura had also smaller volumes of salvaged penumbra (9.8±41.2 mL) compared with patients with migraine without aura (36.4±54.1 mL) and patients with no migraine (45.1±55.0 mL; =0.056). Conversely, there was no difference in final infarct size among the 3 migraine subgroups (=0.312).

Conclusions: Migraine is likely to increase individual vulnerability to ischemic stroke during the process of acute brain ischemia and might represent, therefore, a potential new therapeutic target against occurrence and progression of the ischemic damage.
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http://dx.doi.org/10.1161/STROKEAHA.118.020554DOI Listing
March 2018

Anticoagulants Resumption after Warfarin-Related Intracerebral Haemorrhage: The Multicenter Study on Cerebral Hemorrhage in Italy (MUCH-Italy).

Thromb Haemost 2018 03 12;118(3):572-580. Epub 2018 Feb 12.

S.C. Neurologia, IRCCS - Arcispedale Santa Maria Nuova, Reggio Emilia, Italy.

Whether to resume antithrombotic treatment after oral anticoagulant-related intracerebral haemorrhage (OAC-ICH) is debatable. In this study, we aimed at investigating long-term outcome associated with OAC resumption after warfarin-related ICH, in comparison with secondary prevention strategies with platelet inhibitors or antithrombotic discontinuation. Participants were patients who sustained an incident ICH during warfarin treatment (2002-2014) included in the Multicenter Study on Cerebral Hemorrhage in Italy. Primary end-point was a composite of ischemic stroke/systemic embolism (SE) and all-cause mortality. Secondary end-points were ischemic stroke/SE, all-cause mortality and major recurrent bleeding. We computed individual propensity score (PS) as the probability that a patient resumes OACs or other agents given his pre-treatment variables, and performed Cox multivariable analysis using Inverse Probability of Treatment Weighting (IPTW) procedure. A total of 244 patients qualified for the analysis. Unlike antiplatelet agents, OAC resumption was associated with a lower rate of the primary end-point (weighted hazard ratio [HR], 0.21; 95% confidence interval [CI], 0.09-0.45), as well as of overall mortality (weighted HR, 0.17; 95% CI, 0.06-0.45) and ischemic stroke/SE (weighted HR, 0.19; 95% CI, 0.06-0.60) with no significant increase of major bleeding in comparison with patients receiving no antithrombotics. In the subgroup of patients with atrial fibrillation, OACs resumption was also associated with a reduction of the primary end-point (weighted HR, 0.22; 95% CI, 0.09-0.54), and the secondary end-point ischemic stroke/SE (weighted HR, 0.09; 95% CI, 0.02-0.40). In conclusion, in patients who have an ICH while receiving warfarin, resuming anticoagulation results in a favorable trade-off between bleeding susceptibility and thromboembolic risk.
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http://dx.doi.org/10.1055/s-0038-1627454DOI Listing
March 2018

Arterial tortuosity in patients with spontaneous cervical artery dissection.

Neuroradiology 2017 Jun 11;59(6):571-575. Epub 2017 May 11.

Dipartimento di Scienze Cliniche e Sperimentali, Clinica Neurologica, Università degli Studi di Brescia, Brescia, Italy.

Purpose: The aim of this study was to test the hypothesis that patients with spontaneous cervical artery dissection (CeAD) have increased arterial tortuosity, and the objective quantification of such a tortuosity may aid in the identification of subjects at increased risk of disease.

Methods: In the setting of a hospital-based, case-control study, we used the vertebral tortuosity index (VTI) measured on magnetic resonance angiography, a validated method for the assessment and quantification of arterial tortuosity, to compare the degree of tortuosity in a series of consecutive patients with spontaneous CeAD and of age- and sex-matched patients with ischemic stroke unrelated to CeAD (non-CeAD IS) and stroke-free subjects.

Results: The study group was composed of 102 patients with CeAD (mean age, 44.5 ± 7.8 years; 66.7% men), 102 with non-CEAD IS, and 102 stroke-free subjects. The VTI was higher in the group of patients with CeAD (median, 7.3; 25th-75th percentile, 10.2) compared with that of non-CeAD IS (median, 3.4; 25th-75th percentile, 4.4) and of stroke-free subjects (median, 4.0; 25th-75th percentile, 2.9; p ≤ 0.001), and was independently associated to the risk of CeAD (OR, 1.18; 95% CI, 1.09-1.29) in multivariable regression analysis. The degree of tortuosity also tended to be higher in CeAD patients who experienced short-term recurrence (5.8%; median, 20.2; 25th-75th percentile, 31.2) than in those without recurrent events (median, 7.2; 25th-75th percentile, 9.4; p = 0.074).

Conclusion: CeAD patients exhibit increased arterial tortuosity. This might have potential implications for better understanding of the pathophysiology of the disease as well as clinical utility in evaluation, prognostication, and decision-making of affected individuals.
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http://dx.doi.org/10.1007/s00234-017-1836-9DOI Listing
June 2017

Association Between Migraine and Cervical Artery Dissection: The Italian Project on Stroke in Young Adults.

JAMA Neurol 2017 05;74(5):512-518

Dipartimento di Scienze Cliniche e Sperimentali, Clinica Neurologica, Università degli Studi di Brescia, Brescia, Italia.

Importance: Although sparse observational studies have suggested a link between migraine and cervical artery dissection (CEAD), any association between the 2 disorders is still unconfirmed. This lack of a definitive conclusion might have implications in understanding the pathogenesis of both conditions and the complex relationship between migraine and ischemic stroke (IS).

Objective: To investigate whether a history of migraine and its subtypes is associated with the occurrence of CEAD.

Design, Setting, And Participants: A prospective cohort study of consecutive patients aged 18 to 45 years with first-ever acute ischemic stroke enrolled in the multicenter Italian Project on Stroke in Young Adults was conducted between January 1, 2000, and June 30, 2015. In a case-control design, the study assessed whether the frequency of migraine and its subtypes (presence or absence of an aura) differs between patients whose IS was due to CEAD (CEAD IS) and those whose IS was due to a cause other than CEAD (non-CEAD IS) and compared the characteristics of patients with CEAD IS with and without migraine.

Main Outcomes And Measures: Frequency of migraine and its subtypes in patients with CEAD IS vs non-CEAD IS.

Results: Of the 2485 patients (mean [SD] age, 36.8 [7.1] years; women, 1163 [46.8%]) included in the registry, 334 (13.4%) had CEAD IS and 2151 (86.6%) had non-CEAD IS. Migraine was more common in the CEAD IS group (103 [30.8%] vs 525 [24.4%], P = .01), and the difference was mainly due to migraine without aura (80 [24.0%] vs 335 [15.6%], P < .001). Compared with migraine with aura, migraine without aura was independently associated with CEAD IS (OR, 1.74; 95% CI, 1.30-2.33). The strength of this association was higher in men (OR, 1.99; 95% CI, 1.31-3.04) and in patients 39.0 years or younger (OR, 1.82; 95% CI, 1.22-2.71). The risk factor profile was similar in migrainous and non-migrainous patients with CEAD IS (eg, hypertension, 20 [19.4%] vs 57 [24.7%], P = .29; diabetes, 1 [1.0%] vs 3 [1.3%], P > .99).

Conclusions And Relevance: In patients with IS aged 18 to 45 years, migraine, especially migraine without aura, is consistently associated with CEAD. This finding suggests common features and warrants further analyses to elucidate the underlying biologic mechanisms.
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http://dx.doi.org/10.1001/jamaneurol.2016.5704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5822194PMC
May 2017

Propensity Score-Based Analysis of Percutaneous Closure Versus Medical Therapy in Patients With Cryptogenic Stroke and Patent Foramen Ovale: The IPSYS Registry (Italian Project on Stroke in Young Adults).

Circ Cardiovasc Interv 2016 09;9(9)

From the Dipartimento di Scienze Cliniche e Sperimentali, Clinica Neurologica, Università degli Studi di Brescia, Italia (A.Pezzini, P. Costa, L.P. A.M., V.D.G., S.B., A. Padovani); Dipartimento di Scienze del Sistema Nervoso e del Comportamento, Unità di Statistica Medica e Genomica, Università di Pavia, Italia (M. Grassi, D.G.); Centro Trombosi, IRCCS Istituto Clinico Humanitas, Rozzano-Milano, Italia (C.L., P.F.); Stroke Unit, Azienda Ospedaliera Sant'Andrea, Università "La Sapienza," Roma, Italia (R.P., A.S., M.R., S.L.S.); Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili, Università di Genova, Italia (C.G., D.M.); Stroke Unit, Clinica Neurologica, Nuovo Ospedale Civile "S. Agostino Estense," AUSL Modena, Italia (A.Z., A.M.S.); Unità di Neurologia, Ospedale di Circolo, Università dell'Insubria, Varese, Italia (M.L.D.); Stroke Unit, Divisione di Medicina Cardiovascolare, Università di Perugia, Perugia, Italia (M.P., C.D.); Unità di Neurologia, Ospedale Galliera, Genova, Italia (M.D.S.); U.O.C. Neurologia, A.O Universitaria "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italia (A.T.); Dipartimento di Neuroscienze, Scienze Psichiatriche e Anestesiologiche, Clinica Neurologica, Università di Messina, Italia (R.M.); IRCCS, Centro Neurolesi Bonino-Pulejo, Messina, Italia (R.S.C.); UO Neurologia, Azienda Ospedaliera-Universitaria Borgo Trento, Verona, Italia (P.B., G.T.); Stroke Center, Dipartimento di Neurologia, Ospedale Sacro Cuore Negrar, Verona, Italia (A.A.); Stroke Unit, Dipartimento di Neuroscienze, Azienda Ospedaliera Carlo Poma, Mantova, Italia (G.S.); U.O Neurologia, Istituti Ospitalieri, Cremona, Italia (M.S.); Stroke Unit, IRCCS Fondazione Istituto "C. Mondino," Pavia, Italia (A. Cavallini); Neurologia d'Urgenza e Stroke Unit, IRCCS Istituto Clinico Humanitas, Rozzano-Milano, Italia (S.M.); Stroke Unit, U.O Neurologia, Ospedale "S. Chiara," Trento, Italia (D.M.B.); U.O.C Neurologia, Ospedale Vald

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.
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http://dx.doi.org/10.1161/CIRCINTERVENTIONS.115.003470DOI Listing
September 2016

Risk Profile of Symptomatic Lacunar Stroke Versus Nonlobar Intracerebral Hemorrhage.

Stroke 2016 08 21;47(8):2141-3. Epub 2016 Jun 21.

From the Dipartimento di Scienze Cliniche e Sperimentali, Clinica Neurologica (A.M., P.C., L.P., V.D.G., A. Padovani, A. Pezzini) and Sezione di Biologia e Genetica, Dipartimento di Medicina Molecolare e Traslazionale (M.R., M.C.), Università degli Studi di Brescia, Brescia, Italy; Stroke Unit, Divisione di Medicina Cardiovascolare, Università di Perugia, Perugia, Italy (M.P., V.C., G.A.); Stroke Unit, Clinica Neurologica, Nuovo Ospedale Civile "S. Agostino Estense", AUSL Modena, Modena, Italy (A.Z., A.M.S., M.L.D.A.); S.C. di Neurologia e S.S. di Stroke Unit, ASST di Mantova, Mantova, Italy (G.S., A.L., A.C.); U.O. di Recupero e Rieducazione Funzionale, IRCCS Fondazione Don Gnocchi, Rovato, Italy (E.D.Z.); Stroke Unit, Neurologia Vascolare, Spedali Civili di Brescia, Brescia, Italy (M.G.); Laboratorio di Epidemiologia Molecolare e Nutrizionale, Dipartimento di Epidemiologia e Prevenzione, IRCCS Istituto Neurologico Mediterraneo, NEUROMED, Pozzilli, Italy (A.D.C., L.I., G.d.G.); and Dipartimento di Scienze del Sistema Nervoso e del Comportamento, Unità di Statistica Medica e Genomica, Università di Pavia, Pavia, Italy (M.G.).

Background And Purpose: Although lacunar stroke (LS) and deep intracerebral hemorrhage (dICH) represent acute manifestations of the same pathological process involving cerebral small vessels (small vessel disease), it remains unclear what factors predispose to one phenotype rather than the other at individual level.

Methods: Consecutive patients with either acute symptomatic LS or dICH were prospectively enrolled as part of a multicenter Italian study. We compared the risk factor profile of the 2 subgroups using multivariable logistic regression.

Results: During a time course of 9.5 years, 1931 subjects (1434 LS and 497 dICH; mean age, 71.3±13.3 years; males, 55.5%) qualified for the analysis. Current smoking was associated with LS (odds ratio [OR], 2.17; P<0.001). Conversely, dICH cases were more likely to be hypertensive (OR, 1.87; P<0.001), excessive alcohol consumers (OR, 1.70; P=0.001), and more frequently under treatment with warfarin (OR, 2.05; P=0.010) and statins (OR, 3.10; P<0.001). Hypercholesterolemia, diabetes mellitus, and antiplatelet treatment were not associated with a specific small vessel disease manifestation.

Conclusions: The risk factor profile of dICH differs from that associated with LS. This might be used for disease risk stratification at individual level.
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http://dx.doi.org/10.1161/STROKEAHA.116.013722DOI Listing
August 2016

Serum cholesterol levels, HMG-CoA reductase inhibitors and the risk of intracerebral haemorrhage. The Multicenter Study on Cerebral Haemorrhage in Italy (MUCH-Italy).

J Neurol Neurosurg Psychiatry 2016 09 21;87(9):924-9. Epub 2016 Mar 21.

Stroke Unit, AOU Senese, Siena, Italia.

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.
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http://dx.doi.org/10.1136/jnnp-2015-312736DOI Listing
September 2016

Determinants of premature familial arterial thrombosis in patients with juvenile ischaemic stroke. The Italian Project on Stroke in Young Adults (IPSYS).

Thromb Haemost 2015 Mar 20;113(3):641-8. Epub 2014 Nov 20.

Alessandro Pezzini, Dipartimento di Scienze Cliniche e Sperimentali, Clinica Neurologica, Università degli Studi di Brescia, P.le Spedali Civili, 1, 25123 Brescia, Italia, Tel: +39.030.3384086, Fax: +39.030. 3384086, E-mail:

Factors predicting family history (FH) of premature arterial thrombosis in young patients with ischaemic stroke (IS) have not been extensively investigated, and whether they might influence the risk of post-stroke recurrence is still unknown. In the present study we analysed 1,881 consecutive first-ever IS patients aged 18-45 years recruited from January 2000 to January 2012 as part of the Italian Project on Stroke in Young Adults (IPSYS). FH of premature arterial thrombosis was any thrombotic event [IS, myocardial infarction or other arterial events event] < 45 years in proband's first-degree relatives. Compared with patients without FH of premature arterial thrombosis, those with FH (n = 85) were more often smokers (odds ratio [OR], 1.94; 95 % confidence interval [CI], 1.21-3.09) and carriers of procoagulant abnormalities (OR, 3.66; 95 % CI, 2.21-6.06). Smoking (OR, 2.48; 95 % CI, 1.20-5.15), the A1691 mutation in factor V gene (OR, 3.64; 95 % CI, 1.31-10.10), and the A20210 mutation in the prothrombin gene (OR, 8.40; 95 % CI 3.35-21.05) were associated with FH of premature stroke (n = 33), while circulating anti-phospholipids to FH of premature myocardial infarction (n = 45; OR, 3.48; 95 % CI, 1.61-7.51). Mean follow-up time was 46.6 ± 38.6 months. Recurrent events occurred more frequently in the subgroup of patients with FH of premature stroke [19.4 %); p = 0.051] compared to patients without such a FH. In conclusion, young IS patients with FH of premature arterial thrombosis exhibit a distinct risk-factor profile, an underlying procoagulant state and have worse vascular prognosis than those with no FH of juvenile thrombotic events.
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http://dx.doi.org/10.1160/TH14-06-0566DOI Listing
March 2015

Percheron artery occlusion: an uncommon cause of decreased arousal.

Int J Stroke 2014 Dec;9(8):E42-3

Dipartimento di Scienze Neurologiche e Della Visione, Clinica Neurologica, Università degli Studi di Brescia, Brescia, Italy.

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http://dx.doi.org/10.1111/ijs.12395DOI Listing
December 2014

Connective tissue anomalies in patients with spontaneous cervical artery dissection.

Neurology 2014 Nov 29;83(22):2032-7. Epub 2014 Oct 29.

From the U.O. Neurologia (A.G.), Istituto Clinico S. Anna, Brescia; Dipartimento di Scienze Cliniche e Sperimentali (P.C., A.M., L.P., I.V., V.D.G., A. Padovani, A. Pezzini), Clinica Neurologica, Università degli Studi di Brescia; U.O. di Recupero e Rieducazione Funzionale (E.D.Z.), IRCCS Fondazione Don Gnocchi, Milano; Stroke Unit (M.G.), Neurologia Vascolare, Spedali Civili di Brescia; U.O. Neurologia (P.B., G.T., M. Carletti), Azienda Ospedaliera-Universitaria Borgo Trento, Verona; U.O.C. Neurologia (N. Checcarelli), Ospedale Valduce, Como; Dipartimento di Neuroscienze (G.M.), Università di Padova; U.O.C. Neurologia (M.M.), Ospedale di Arzignano; S.O.C. Neurologia (M. Chinaglia), Ospedale di Rovigo; and Sezione di Biologia e Genetica (M.R., N. Chiarelli, M. Colombi), Dipartimento di Medicina Molecolare e Traslazionale, Università degli Studi di Brescia, Italia.

Objective: To investigate the prevalence of connective tissue abnormalities in patients with spontaneous cervical artery dissections (sCeAD).

Methods: We systematically assessed clinically detectable signs of connective tissue aberration in a series of consecutive patients with sCeAD and of age- and sex-matched patients with ischemic stroke unrelated to CeAD (non-CeAD IS) by a standard examination protocol including 68 items, and performed extensive molecular investigation for hereditary connective tissue disorders in all patients with sCeAD.

Results: The study group included 84 patients with sCeAD (mean age, 44.5 ± 7.8 years; 66.7% men) and 84 patients with non-CeAD IS. None of the patients with sCeAD met clinical or molecular diagnostic criteria for established hereditary connective tissue disorder. Connective tissue abnormalities were detected more frequently in the group of patients with sCeAD than in the group of those with non-CeAD IS (mean number of pathologic findings, 4.5 ± 3.5 vs 1.9 ± 2.3; p < 0.001). Eighty-one patients (96.4%) in the sCeAD group had at least one detectable sign compared with 55 patients (66.7%) in the group with non-CeAD IS (p < 0.001). Skeletal, ocular, and skin abnormalities, as well as craniofacial dysmorphisms, were the clinical signs more strongly associated with sCeAD. Signs suggesting connective tissue abnormality were also more frequently represented in patients with sCeAD than in patients with traumatic CeAD (28.6%, p < 0.001; mean number of pathologic findings, 1.7 ± 3.7, p = 0.045).

Conclusions: Connective tissue abnormalities are frequent in patients with sCeAD. This reinforces the hypothesis that systemic aberrations of the connective tissue might be implicated in the pathogenesis of the disease.
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http://dx.doi.org/10.1212/WNL.0000000000001030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248452PMC
November 2014

Predictors of long-term recurrent vascular events after ischemic stroke at young age: the Italian Project on Stroke in Young Adults.

Circulation 2014 Apr 7;129(16):1668-76. Epub 2014 Feb 7.

Dipartimento di Scienze Mediche e Chirurgiche, Clinica Neurologica, Università degli Studi di Brescia, Brescia, Italia (A. Pezzini, P.C., L.P., A.M., V.D.G., A. Padovani; Dipartimento di Scienze del Sistema Nervoso e del Comportamento, Unità di Statistica Medica e Genomica, Università di Pavia, Pavia, Italia (M.G.); Centro Trombosi, IRCCS Istituto Clinico Humanitas, Rozzano-Milano, Italia (C.L., P.F.); Stroke Unit, Azienda Ospedaliera Sant'Andrea, Roma, Italia (R.P., A.S., M.R.); Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili, Università di Genova, Genova, Italia (C.G., D.M.); Stroke Unit, Clinica Neurologica, Nuovo Ospedale Civile "S. Agostino Estense", AUSL Modena, Italia (A.Z., A.M.S.); Unità di Neurologia, Ospedale di Circolo, Università dell'Insubria, Varese, Italia (M.L.D.); Stroke Unit, Divisione di Medicina Cardiovascolare, Università di Perugia, Perugia, Italia (M.P.); Unità di Neurologia, Ospedale S. Andrea, La Spezia, Italia (M.D.S.); U.O.C. Neurologia, A.O Universitaria "San Giovanni di Dio e Ruggi d'Aragona", Salerno, Italia (A.T.); Dipartimento di Neuroscienze, Scienze Psichiatriche e Anestesiologiche, Clinica Neurologica, Università di Messina, Messina, Italia (R.M.); Istituto di Ricovero e Cura a Carattere Scientifico, Centro Neurolesi Bonino-Pulejo, Messina, Italia (R.S.C.); UO Neurologia, Azienda Ospedaliera-Universitaria Borgo Trento, Verona, Italia (P.B.); Stroke Center, Dipartimento di Neurologia, Ospedale Sacro Cuore Negrar, Verona, Italia (A.A.); Stroke Unit, U.O Neurologia, Azienda Ospedaliera "C. Poma", Mantova, Italia (G.S.); Stroke Unit, U.O Neurologia, IRCCS Ospedale S. Raffaele, Milano, Italia (M.S., G.G.); U.C Malattie Cerebrovascolari e Stroke Unit (A.C.) and U.C Neurologia d'Urgenza (G.M.), IRCCS Fondazione Istituto Neurologico Nazionale "C. Mondino," Pavia, Italia; Neurologia d'Urgenza and Stroke Unit, IRCCS Istituto Clinico Humanitas, Rozzano-Milano, Italia (S.M.); Stroke Un

Background: Data on long-term risk and predictors of recurrent thrombotic events after ischemic stroke at a young age are limited.

Methods And Results: We followed 1867 patients with first-ever ischemic stroke who were 18 to 45 years of age (mean age, 36.8±7.1 years; women, 49.0%), as part of the Italian Project on Stroke in Young Adults (IPSYS). Median follow-up was 40 months (25th to 75th percentile, 53). The primary end point was a composite of ischemic stroke, transient ischemic attack, myocardial infarction, or other arterial events. One hundred sixty-three patients had recurrent thrombotic events (average rate, 2.26 per 100 person-years at risk). At 10 years, cumulative risk was 14.7% (95% confidence interval, 12.2%-17.9%) for primary end point, 14.0% (95% confidence interval, 11.4%-17.1%) for brain ischemia, and 0.7% (95% confidence interval, 0.4%-1.3%) for myocardial infarction or other arterial events. Familial history of stroke, migraine with aura, circulating antiphospholipid antibodies, discontinuation of antiplatelet and antihypertensive medications, and any increase of 1 traditional vascular risk factor were independent predictors of the composite end point in multivariable Cox proportional hazards analysis. A point-scoring system for each variable was generated by their β-coefficients, and a predictive score (IPSYS score) was calculated as the sum of the weighted scores. The area under the receiver operating characteristic curve of the 0- to 5-year score was 0.66 (95% confidence interval, 0.61-0.71; mean, 10-fold internally cross-validated area under the receiver operating characteristic curve, 0.65).

Conclusions: Among patients with ischemic stroke aged 18 to 45 years, the long-term risk of recurrent thrombotic events is associated with modifiable, age-specific risk factors. The IPSYS score may serve as a simple tool for risk estimation.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.113.005663DOI Listing
April 2014

Measured and perceived environmental comfort: field monitoring in an Italian school.

Appl Ergon 2014 Jul 23;45(4):1035-47. Epub 2014 Jan 23.

Department of Management and Engineering, Università degli Studi di Padova, Stradella San Nicola, 3, Vicenza, Italy.

Microclimatic conditions were recorded in an Italian school and Fanger's indexes PMV and PPD were calculated under different conditions. Students' sensations were investigated four times by means of two surveys, one related to actual microclimatic conditions and one on overall satisfaction, interaction occupant-building and reactions to discomfort. Pupils' classroom position was considered to look for possible influence on thermal comfort: a difference emerged from PMV and the survey, but the results obtained from the two approaches differ for both the entity of discomfort and its distribution within each classroom. Innovative multivariate nonparametric statistical techniques were applied to compare and rank the classrooms in accordance with students' subjective perceptions; a global ranking has been also calculated, considering thermal and visual comfort and air quality. Comparing pupil-sensation-based ranking with environmental parameters no clear correspondence was found, except for mid-season, where PMV, CO2 concentration and desk illuminance were similar in all the classrooms.
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http://dx.doi.org/10.1016/j.apergo.2014.01.004DOI Listing
July 2014

Antithrombotic medications and the etiology of intracerebral hemorrhage: MUCH-Italy.

Neurology 2014 Feb 15;82(6):529-35. Epub 2014 Jan 15.

From the Dipartimento di Scienze Cliniche e Sperimentali, Clinica Neurologica (A. Pezzini, P.C., L.P., A.M., V.D.G., A. Padovani), and Divisione di Biologia e Genetica, Dipartimento di Medicina Molecolare e Traslazionale (M.R., M.C.), Università degli Studi di Brescia; Dipartimento di Scienze del Sistema Nervoso e del Comportamento (M. Grassi, D.P.), Unità di Statistica Medica e Genomica, Università di Pavia; Stroke Unit and Divisione di Medicina Cardiovascolare (M.P., V.C., G.A.), Università di Perugia; Stroke Unit (A.Z., M.L.D., A.M.S.), Clinica Neurologica, Nuovo Ospedale Civile "S. Agostino Estense," AUSL Modena; U.O di Neurologia (G.S., A.L., A.C.), Ospedale "C. Poma," Mantova; U.O. di Recupero e Rieducazione Funzionale (E.D.Z.), IRCCS Fondazione Don Gnocchi, Rovato; U.O Neurologia (A.G., I.V.), Istituto Clinico "S. Anna," Brescia; and Stroke Unit (M. Gamba), Neurologia Vascolare, Spedali Civili di Brescia, Brescia, Italy.

Objective: To test the hypothesis that the effect of antithrombotic medications on the risk of intracerebral hemorrhage (ICH) varies according to the location of the hematoma.

Methods: Consecutive patients with ICH were enrolled as part of the Multicenter Study on Cerebral Hemorrhage in Italy (MUCH-Italy). Multivariable logistic regression models served to examine whether risk factors for ICH and location of the hematoma (deep vs lobar) predict treatment-specific ICH subgroups (antiplatelets-related ICH and oral anticoagulants [OACs]-related ICH).

Results: A total of 870 (313 lobar ICH, 557 deep ICH) subjects were included. Of these, 223 (25.6%) were taking antiplatelets and 77 (8.8%) OACs at the time of stroke. The odds of antiplatelet-related ICH increased with aging (odds ratio [OR] 1.05; 95% confidence interval [CI] 1.03-1.07) and hypertension (OR 1.86; 95% CI 1.22-2.85) but had no relation with the anatomical location of ICH. Conversely, lobar location of the hematoma was associated with the subgroup of OAC-related ICH (OR 1.70; 95% CI 1.03-2.81) when compared to the subgroup of patients taking no antithrombotic medications. Within the subgroup of patients taking OACs, international normalized ratio (INR) values were higher in those with lobar ICH as compared to those with deep ICH (2.8 ± 1.1 vs 2.2 ± 0.8; p = 0.011). The proportion of patients with lobar hematoma increased with increasing intensity of anticoagulation, with a ~2-fold increased odds of lobar compared to deep ICH (odds 2.17; p = 0.03) in those exposed to overanticoagulation (INR values >3.0).

Conclusions: OACs, as opposed to antiplatelets, predispose to lobar location of brain hematomas according to a dose-response relationship.
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http://dx.doi.org/10.1212/WNL.0000000000000108DOI Listing
February 2014
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