Publications by authors named "Bruno Bonetti"

65 Publications

Utility of Preoperative Electrodiagnosis Together with Peripheral Nerve High-Resolution Ultrasound: A Complex Case Report of Neurofibromatosis Type I.

J Neurol Surg A Cent Eur Neurosurg 2021 Apr 12. Epub 2021 Apr 12.

Department of Neurology, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Veneto, Italy.

Our case report underscores the importance of electroneuromyography (ENMG) combined with peripheral nerve high-resolution ultrasound (HRUS) in the evaluation of neurofibromatosis type 1 (NF1). A 49-year-old woman affected by NF1 came to our attention because of new-onset left arm weakness and atrophy. Debulking of a cervicothoracic C7-T1 neurofibroma had been performed 8 years earlier. On current admission, magnetic resonance imaging disclosed increased lesion volume that was thought to cause the neurologic deficits by compressing the C8 root. Findings from intraoperative neurophysiologic monitoring during repeat debulking suggested that C8 root integrity had been compromised during the first operation and that the new-onset symptoms probably stemmed from peripheral nervous system damage distal to the cervical roots. Postoperative ENMG showed chronic denervation signs in the muscles innervated by C7-C8-T1 roots, moderate carpal tunnel syndrome (CTS), and ulnar nerve conduction block at the elbow. HRUS confirmed the CTS and revealed multiple neurofibromas involving the distal tract of the radial, ulnar, and median nerves. Surgical debulking was considered unnecessary in this case. ENMG combined with nerve and plexus HRUS evaluation may help identify the cause of neurologic deficits and choose the best surgical option in such complex clinical conditions as NF1.
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http://dx.doi.org/10.1055/s-0041-1724110DOI Listing
April 2021

Stroke management during the coronavirus disease 2019 (COVID-19) pandemic: experience from three regions of the north east of Italy (Veneto, Friuli-Venezia-Giulia, Trentino-Alto-Adige).

Neurol Sci 2021 Mar 4. Epub 2021 Mar 4.

Stroke Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.

Background: Efficiency of care chain response and hospital reactivity were and are challenged for stroke acute care management during the pandemic period of coronavirus disease 2019 (COVID-19) in North-Eastern Italy (Veneto, Friuli-Venezia-Giulia, Trentino-Alto-Adige), counting 7,193,880 inhabitants (ISTAT), with consequences in acute treatment for patients with ischemic stroke.

Methods: We conducted a retrospective data collection of patients admitted to stroke units eventually treated with thrombolysis and thrombectomy, ranging from January to May 2020 from the beginning to the end of the main first pandemic period of COVID-19 in Italy. The primary endpoint was the number of patients arriving to these stroke units, and secondary endpoints were the number of thrombolysis and/or thrombectomy. Chi-square analysis was used on all patients; furthermore, patients were divided into two cohorts (pre-lockdown and lockdown periods) and the Kruskal-Wallis test was used to test differences on admission and reperfusive therapies.

Results: In total, 2536 patients were included in 22 centers. There was a significant decrease of admissions in April compared to January. Furthermore, we observed a significant decrease of thrombectomy during the lockdown period, while thrombolysis rate was unaffected in the same interval across all centers.

Conclusions: Our study confirmed a decrease in admission rate of stroke patients in a large area of northern Italy during the lockdown period, especially during the first dramatic phase. Overall, there was no decrease in thrombolysis rate, confirming an effect of emergency care system for stroke patients. Instead, the significant decrease in thrombectomy rate during lockdown addresses some considerations of local and regional stroke networks during COVID-19 pandemic evolution.
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http://dx.doi.org/10.1007/s10072-021-05066-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930104PMC
March 2021

Antibodies to MOG in CSF only: pathological findings support the diagnostic value.

Acta Neuropathol 2021 Feb 20. Epub 2021 Feb 20.

Neurology Unit, Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Policlinico GB Rossi, P.le LA Scuro 10, 37134, Verona, Italy.

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http://dx.doi.org/10.1007/s00401-021-02286-3DOI Listing
February 2021

A nomogram to predict unfavourable outcome in patients receiving oral anticoagulants for atrial fibrillation after stroke.

Eur Stroke J 2020 Dec 26;5(4):384-393. Epub 2020 Nov 26.

Neurology and Stroke Center, University Hospital Basel and University of Basel, Basel, Switzerland.

Introduction: It is unknown whether the type of treatment (direct oral anticoagulant versus vitamin K antagonist) and the time of treatment introduction (early versus late) may affect the functional outcome in stroke patients with atrial fibrillation. We aimed to develop and validate a nomogram model including direct oral anticoagulant/vitamin K antagonist and early/late oral anticoagulant introduction for predicting the probability of unfavourable outcome after stroke in atrial fibrillation-patients.

Patients And Methods: We conducted an individual patient data analysis of four prospective studies. Unfavourable functional outcome was defined as three-month modified Rankin Scale score 3 -6. To generate the nomogram, five independent predictors including age (<65 years, reference; 65--79; or 80), National Institutes of Health Stroke Scale score (0--5 points, reference; 6--15; 16--25; or >25), acute revascularisation treatments (yes, reference, or no), direct oral anticoagulant (reference) or vitamin K antagonist, and early (7 days, reference) or late (8--30) anticoagulant introduction entered into a final logistic regression model. The discriminative performance of the model was assessed by using the area under the receiver operating characteristic curve.

Results: A total of 2102 patients with complete data for generating the nomogram was randomly dichotomised into training ( = 1553) and test ( = 549) sets. The area under the receiver operating characteristic curve was 0.822 (95% confidence interval, CI: 0.800--0.844) in the training set and 0.803 (95% CI: 0.764--0.842) in the test set. The model was adequately calibrated (9.852;  = 0.276 for the Hosmer--Lemeshow test).

Discussion And Conclusion: Our nomogram is the first model including type of oral anticoagulant and time of treatment introduction to predict the probability of three-month unfavourable outcome in a large multicentre cohort of stroke patients with atrial fibrillation.
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http://dx.doi.org/10.1177/2396987320945840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856583PMC
December 2020

Timing of initiation of oral anticoagulants in patients with acute ischemic stroke and atrial fibrillation comparing posterior and anterior circulation strokes.

Authors:
Maurizio Paciaroni Giancarlo Agnelli Michela Giustozzi Georgios Tsivgoulis Shadi Yaghi Brian Mac Grory Karen L Furie Prasanna Tadi Marialuisa Zedde Azmil H Abdul-Rahim Jesse Dawson Kennedy R Lees Andrea Alberti Michele Venti Monica Acciarresi Cataldo D'Amore Maria Giulia Mosconi Valentina Bogini Manuel Cappellari Alberto Rigatelli Bruno Bonetti Jukka Putaala Liisa Tomppo Turgut Tatlisumak Fabio Bandini Simona Marcheselli Alessandro Pezzini Loris Poli Alessandro Padovani Luca Masotti Elisa Grifoni Vieri Vannucchi Sung-Il Sohn Gianni Lorenzini Rossana Tassi Francesca Guideri Maurizio Acampa Giuseppe Martini George Ntaios George Athanasakis Konstantinos Makaritsis Efstathia Karagkiozi Konstantinos Vadikolias Chrissoula Liantinioti Lina Palaiodimou Nicola Mumoli Cesare Porta Franco Galati Simona Sacco Cindy Tiseo Francesco Corea Walter Ageno Marta Bellesini Giorgio Silvestrelli Alfonso Ciccone Umberto Scoditti Licia Denti Michelangelo Mancuso Maria C Caselli Miriam Maccarrone Leonardo Ulivi Giovanni Orlandi Nicola Giannini Tiziana Tassinari Maria L De Lodovici Christina Rueckert Antonio Baldi Danilo Toni Luana Gentile Federica Letteri Martina Giuntini Enrico M Lotti Yuriy Flomin Alessio Pieroni Odysseas Kargiotis Theodore Karapanayiotides Serena Monaco Marina Mannino Mario M Baronello Laszló Csiba Lilla Szabó Alberto Chiti Elisa Giorli Massimo Del Sette Erika Schirinzi Davide Imberti Dorjan Zabzuni Boris Doronin Vera Volodina Patrik Michel Ashraf Eskandari Peter Vanacker Kristian Barlinn Jessica Barlinn Dirk Deleu Vanessa Gourbali Valeria Caso

Eur Stroke J 2020 Dec 22;5(4):374-383. Epub 2020 Jul 22.

Stroke Unit and Division of Cardiovascular Medicine, University of Perugia, Perugia, Italy.

Introduction: The aim of this study in patients with acute posterior ischaemic stroke (PS) and atrial fibrillation (AF) was to evaluate (1) the risks of recurrent ischaemic event and severe bleeding and (2) these risks in relation with oral anticoagulant therapy (OAT) and its timing.

Materials And Methods: Patients with PS were prospectively included; the outcome events of these patients were compared with those of patients with anterior stroke (AS) which were taken from previous registries. The primary outcome was the composite of stroke recurrence, transient ischaemic attack, symptomatic systemic embolism, symptomatic cerebral bleeding and major extracranial bleeding occurring within 90 days from acute stroke.

Results: A total of 2470 patients were available for the analysis: 473 (19.1%) with PS and 1997 (80.9%) with AS. Over 90 days, 213 (8.6%) primary outcome events were recorded: 175 (8.7%) in patients with AS and 38 (8.0%) in those with PS. In patients who initiated OAT within 2 days, the primary outcome occurred in 5 out of 95 patients (5.3%) with PS compared to 21 out of 373 patients (4.3%) with AS (OR 1.07; 95% CI 0.39-2.94). In patients who initiated OAT between days 3 and 7, the primary outcome occurred in 3 out of 103 patients (2.9%) with PS compared to 26 out of 490 patients (5.3%) with AS (OR 0.54; 95% CI 0.16-1.80).

Discussion: our findings suggest that, when deciding the time to initiate oral anticoagulation, the location of stroke, either anterior or posterior, does not predict the risk of outcome events.

Conclusions: Patients with PS or AS and AF appear to have similar risks of ischaemic or haemorrhagic events at 90 days with no difference concerning the timing of initiation of OAT.
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http://dx.doi.org/10.1177/2396987320937116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856592PMC
December 2020

Conditioned pain modulation affects the N2/P2 complex but not the N1 wave: A pilot study with laser-evoked potentials.

Eur J Pain 2021 Mar 28;25(3):550-557. Epub 2020 Nov 28.

Department of Neurological, Neuropsychological, Morphological and Motor Sciences, University of Verona, Verona, Italy.

Background: The 'pain-inhibits-pain' effect stems from neurophysiological mechanisms involving endogenous modulatory systems termed diffuse noxious inhibitory controls (DNIC) or conditioned pain modulation (CPM). Laser-evoked potentials (LEPs) components, the N2/P2 complex, and the N1 wave, reflect the medial and lateral pain pathway, respectively: anatomically, the lateral thalamic nuclei (LT) project mainly to the somatosensory cortex (N1 generator), while the medial thalamic nuclei (MT) are bound to the limbic cortices (N2/P2 generators).

Methods: We applied a CPM protocol in which the test stimulus was laser stimulation and the conditioning stimulus was a cold pressor test. LEPs recordings were obtained from 15 healthy subjects in three different conditions: baseline, during heterotopic noxious conditioning stimulation (HNCS) and post-HNCS.

Results: We observed a significant reduction in N2/P2 amplitude during HNCS and a return to pre-test amplitude post-HNCS, whereas the N1 wave remained unchanged during and post-HNCS.

Conclusions: Our results indicate that CPM affects only the medial pain system. The spinothalamic tract (STT) transmits to both the LT and the MT, while the spinoreticulothalamic (SRT) projects only to the MT. The reduction in the amplitude of the N2/P2 complex and the absence of change in the N1 wave suggest that DNIC inhibition on the dorsal horn neurons affects only pain transmission via the SRT, while the neurons that give rise to the STT are not involved. The N1 wave can be a reliable neurophysiological parameter for assessment of STT function in clinical practice, as it does not seem to be influenced by CPM.

Significance: No reports have described the effect of DNIC on lateral and medial pain pathways. We studied the N1 wave and the N2/P2 complex to detect changes during a CPM protocol. We found a reduction in the amplitude of the N2/P2 complex and no change in the N1 wave. This suggests that the DNIC inhibitory effect on dorsal horns neurons affects only pain transmission via the SRT, whereas the neurons that give rise to the STT are not involved.
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http://dx.doi.org/10.1002/ejp.1693DOI Listing
March 2021

Factors influencing cognitive performance after 1-year treatment with direct oral anticoagulant in patients with atrial fibrillation and previous ischemic stroke: a pilot study.

J Thromb Thrombolysis 2020 Jul 29. Epub 2020 Jul 29.

Neurology and Stroke Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.

Anticoagulant treatment as stroke prevention, particularly direct oral anticoagulant (DOAC), may reduce the risk of dementia in patients with atrial fibrillation (AF). We aimed to assess factors influencing cognitive performance after 1-year treatment with DOAC in patients with AF and previous ischemic stroke. We recruited 33 ischemic stroke patients who were discharged from Verona Stroke Unit with diagnosis of AF and prescription of treatment with DOAC. For each cognitive test, we estimated the effect of T0 (first session) variables on T1 (1-year session) cognitive performance using ordinal logistic regression fitted to a 1 point-shift from 4 to 0 on ESs. The effect of T0 clinical variables was presented as odds ratio (OR) with 95% confidence interval (CI) after adjustment for T0 total score of the corresponding cognitive test. Sustained AF (OR: 4.259, 95% CI 1.071-16.942) and ischemic heart disease (OR: 6.654, 95% CI 1.329-33.300) showed a significant effect on T1 MoCA Test; congestive heart failure on T1 RAVLT Immediate recall (OR: 9.128, 95% CI 1.055-78.995), T1 RAVLT Delayed recall (OR: 7.134, 95% CI 1.214-52.760), and T1 Trail Making Test (Part A) (OR: 16.989, 95% CI 1.765-163.565); sustained AF (OR: 5.055, 95% CI 1.224-20.878) and hyperlipidemia (OR: 4.764, 95% CI 1.175-19.310) on T1 Digit span forward Test; ischemic heart disease (aOR: 8.460, 95% CI 1.364-52.471) on T1 Stroop Color and Word Test (time); Dabigatran use (aOR: 0.084, 95% CI 0.013-0.544) on FAB; age ≥ 75 years (aOR: 0.058, 95% CI 0.006-0.563) and hyperlipidemia (aOR: 5.809, 95% CI 1.059-31.870) on T1 Phonemic word fluency Test; female sex (aOR: 6.105, 95% CI 1.146-32.519), hyperlipidemia (aOR: 21.099, 95% CI 2.773-160.564), total Modified Fazekas Scale score > 1 (aOR: 78.530, 95% CI 3.131-1969.512) on Semantic word fluency Test. Sustained AF, ischemic heart disease, congestive heart failure, hyperlipidemia, and female sex were the factors influencing cognitive performance after 1-year treatment with DOAC in patients with AF and previous ischemic stroke. Modified Fazekas Scale score in the first session was the only radiological variable that had a significant effect on cognitive performance.
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http://dx.doi.org/10.1007/s11239-020-02233-1DOI Listing
July 2020

Direct thrombectomy for stroke in the presence of absolute exclusion criteria for thrombolysis.

J Neurol 2020 Dec 25;267(12):3731-3740. Epub 2020 Jul 25.

Sapienza University Hospital, Rome, Italy.

Background: Intravenous thrombolysis (IVT)-ineligible patients undergoing direct thrombectomy tended to have poorer functional outcome as compared with IVT-eligible patients undergoing bridging therapy. We aimed to assess radiological and functional outcomes in large vessel occlusion-related stroke patients receiving direct thrombectomy in the presence of absolute exclusion criteria for IVT vs relative exclusion criteria for IVT and vs non-exclusion criteria for IVT.

Methods: A cohort study on prospectively collected data from 2282 patients enrolled in the Italian Registry of Endovascular Treatment in Acute Stroke cohort for treatment with direct thrombectomy (n = 486, absolute exclusion criteria for IVT alone; n = 384, absolute in combination with relative exclusion criteria for IVT; n = 777, relative exclusion criteria for IVT alone; n = 635, non-exclusion criteria for IVT).

Results: After adjustment for unbalanced variables (model 1), ORs for 3-month death was higher in the presence of absolute exclusion criteria for IVT alone (vs relative exclusion criteria for IVT alone) (1.595, 95% CI 1.042-2.440) and in the presence of absolute exclusion criteria for IVT alone (vs non-exclusion criteria for IVT) (1.235, 95% CI 1.014-1.504). After adjustment for predefined variables (model 2: age, sex, pre-stroke mRS ≤ 1, NIHSS, occlusion in the anterior circulation, onset-to-groin time, and procedure time), ORs for 3-month death was higher in the presence of absolute exclusion criteria for IVT alone (vs relative exclusion criteria for IVT alone) (1.235, 95% CI 1.014-1.504) and in the presence of absolute exclusion criteria for IVT alone (vs non-exclusion criteria for IVT) (1.246, 95% CI 1.039-1.495). No significant difference was found between the groups as regards any type of intracerebral hemorrhage and parenchymal hematoma within 24 h, successful and complete recanalization after procedure, and modified Rankin Scale score 0-2 at 3 months. After adjustment for predefined variables of model 2, ORs for death were higher in the presence of recent administration of IV heparin (OR: 2.077), platelet count < 100,000/mm (OR: 4.798), bacterial endocarditis (OR: 15.069), neoplasm with increased hemorrhagic risk (OR: 6.046), and severe liver disease (OR: 6.124).

Conclusions: Radiological outcomes were similar after direct thrombectomy in patients with absolute, relative, and non- exclusion criteria for IVT, while an increase of fatal outcome was observed in the presence of some absolute exclusion criterion for IVT.
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http://dx.doi.org/10.1007/s00415-020-10098-wDOI Listing
December 2020

General Anesthesia Versus Conscious Sedation and Local Anesthesia During Thrombectomy for Acute Ischemic Stroke.

Stroke 2020 07 10;51(7):2036-2044. Epub 2020 Jun 10.

NEUROFARBA Department, Careggi University Hospital, Firenze, Italy (S.N., P.N., S.M.).

Background And Purpose: As numerous questions remain about the best anesthetic strategy during thrombectomy, we assessed functional and radiological outcomes in stroke patients treated with thrombectomy in presence of general anesthesia (GA) versus conscious sedation (CS) and local anesthesia (LA).

Methods: We conducted a cohort study on prospectively collected data from 4429 patients enrolled in the Italian Registry of Endovascular Treatment in Acute Stroke.

Results: GA was used in 2013 patients, CS in 1285 patients, and LA in 1131 patients. The rates of 3-month modified Rankin Scale score of 0-1 were 32.7%, 33.7%, and 38.1% in the GA, CS, and LA groups: GA versus CS: odds ratios after adjustment for unbalanced variables (adjusted odds ratio [aOR]), 0.811 (95% CI, 0.602-1.091); and GA versus LA: aOR, 0.714 (95% CI, 0.515-0.990). The rates of modified Rankin Scale score of 0-2 were 42.5%, 46.6%, and 52.4% in the GA, CS, and LA groups: GA versus CS: aOR, 0.902 (95% CI, 0.689-1.180); and GA versus LA: aOR, 0.769 (95% CI, 0.566-0.998). The rates of 3-month death were 21.5%, 19.7%, and 14.8% in the GA, CS, and LA groups: GA versus CS: aOR, 0.872 (95% CI, 0.644-1.181); and GA versus LA: aOR, 1.235 (95% CI, 0.844-1.807). The rates of parenchymal hematoma were 9%, 12.6%, and 11.3% in the GA, CS, and LA groups: GA versus CS: aOR, 0.380 (95% CI, 0.262-0.551); and GA versus LA: aOR, 0.532 (95% CI, 0.337-0.838). After model of adjustment for predefined variables (age, sex, thrombolysis, National Institutes of Health Stroke Scale, onset-to-groin time, anterior large vessel occlusion, procedure time, prestroke modified Rankin Scale score of <1, antiplatelet, and anticoagulant), differences were found also between GA versus CS as regards modified Rankin Scale score of 0-2 (aOR, 0.659 [95% CI, 0.538-0.807]) and GA versus LA as regards death (aOR, 1.413 [95% CI, 1.095-1.823]).

Conclusions: GA during thrombectomy was associated with worse 3-month functional outcomes, especially when compared with LA. The inclusion of an LA arm in future randomized clinical trials of anesthesia strategy is recommended.
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http://dx.doi.org/10.1161/STROKEAHA.120.028963DOI Listing
July 2020

ASC-Exosomes Ameliorate the Disease Progression in SOD1(G93A) Murine Model Underlining Their Potential Therapeutic Use in Human ALS.

Int J Mol Sci 2020 May 21;21(10). Epub 2020 May 21.

Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, 37134 Verona, Italy.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motoneurons. To date, there is no effective treatment available. Exosomes are extracellular vesicles that play important roles in intercellular communication, recapitulating the effect of origin cells. In this study, we tested the potential neuroprotective effect of exosomes isolated from adipose-derived stem cells (ASC-exosomes) on the in vivo model most widely used to study ALS, the human SOD1 gene with a G93A mutation (SOD1(G93A)) mouse. Moreover, we compared the effect of two different routes of exosomes administration, intravenous and intranasal. The effect of exosomes administration on disease progression was monitored by motor tests and analysis of lumbar motoneurons and glial cells, neuromuscular junction, and muscle. Our results demonstrated that repeated administration of ASC-exosomes improved the motor performance; protected lumbar motoneurons, the neuromuscular junction, and muscle; and decreased the glial cells activation in treated SOD1(G93A) mice. Moreover, exosomes have the ability to home to lesioned ALS regions of the animal brain. These data contribute by providing additional knowledge for the promising use of ASC-exosomes as a therapy in human ALS.
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http://dx.doi.org/10.3390/ijms21103651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279464PMC
May 2020

Acute revascularization treatments for ischemic stroke in the Stroke Units of Triveneto, northeast Italy: time to treatment and functional outcomes.

J Thromb Thrombolysis 2021 Jan;51(1):159-167

Stroke Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.

It is not known whether the current territorial organization for acute revascularization treatments in ischemic stroke patients guarantees similar time to treatment and functional outcomes among different levels of institutional stroke care. We aimed to assess the impact of time to treatment on functional outcomes in ischemic stroke patients who received intravenous thrombolysis (IVT) alone, bridging (IVT plus thrombectomy), or primary thrombectomy in level 1 and level 2 Stroke Units (SUs) in Triveneto, a geographical macroarea in Northeast of Italy. We conducted an analysis of data prospectively collected from 512 consecutive ischemic stroke patients who received IVT and/or mechanical thrombectomy in 25 SUs from September 17th to December 9th 2018. The favorable outcome measures were mRS score 0-1 and 0-2 at 3 months. The unfavorable outcome measures were mRS score 3-5 and death at 3 months. We estimated separately the possible association of each variable for time to treatment (onset-to-door, door-to-needle, onset-to-needle, door-to-groin puncture, needle-to-groin puncture, and onset-to-groin puncture) with 3-month outcome measures by calculating the odds ratios (ORs) with two-sided 95% confidence intervals (CI) after adjustment for pre-defined variables and variables with a probability value ≤ 0.10 in the univariate analysis for each outcome measure. Distribution of acute revascularization treatments was different between level 1 and level 2 SUs (p < 0.001). Among 182 patients admitted to level 1 SUs (n = 16), treatments were IVT alone in 164 (90.1%), bridging in 12 (6.6%), and primary thrombectomy in 6 (3.3%) patients. Among 330 patients admitted to level 2 SUs (n = 9), treatments were IVT alone in 219 (66.4%), bridging in 74 (22.4%), and primary thrombectomy in 37 (11.2%) patients. Rates of excellent outcome (51.4% vs 45.9%), favorable outcome (60.1% vs 58.7%), unfavorable outcome (33.3% vs 33.8%), and death (9.8% vs 11.3%) at 3 months were similar between level 1 and 2 SUs. No significant association was found between time to IVT alone (onset-to-door, door-to-needle, and onset-to-needle) and functional outcomes. After adjustment, door-to-needle time ≤ 60 min (OR 4.005, 95% CI 1.232-13.016), shorter door-to-groin time (OR 0.991, 95% CI 0.983-0.999), shorter needle-to-groin time (OR 0.986, 95% CI 0.975-0.997), and shorter onset-to-groin time (OR 0.994, 95% CI 0.988-1.000) were associated with mRS 0-1. Shorter door-to-groin time (OR 0.991, 95% CI 0.984-0.998), door-to-groin time ≤ 90 min (OR 12.146, 95% CI 2.193-67.280), shorter needle-to-groin time (OR 0.983, 95% CI 0.972-0.995), and shorter onset-to-groin time (OR 0.993, 95% CI 0.987-0.999) were associated with mRS 0-2. Longer door-to-groin time (OR 1.007, 95% CI 1.001-1.014) and longer needle-to-groin time (OR 1.019, 95% CI 1.005-1.034) were associated with mRS 3-5, while door-to-groin time ≤ 90 min (OR 0.229, 95% CI 0.065-0.808) was inversely associated with mRS 3-5. Longer onset-to-needle time (OR 1.025, 95% CI 1.002-1.048) was associated with death. Times to treatment influenced the 3-month outcomes in patients treated with thrombectomy (bridging or primary). A revision of the current territorial organization for acute stroke treatments in Triveneto is needed to reduce transfer time and to increase the proportion of patients transferred from a level 1 SU to a level 2 SU to perform thrombectomy.
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http://dx.doi.org/10.1007/s11239-020-02142-3DOI Listing
January 2021

May ultrasonography be considered a useful tool for bedside screening of dysphagia in patients with acute stroke? A cohort study.

Minerva Med 2020 Apr 23. Epub 2020 Apr 23.

Neuromotor and Cognitive Rehabilitation Research Center, Physical and Rehabilitation Medicine Section, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.

Background: Dysphagia is a primary risk factor for pneumonia and affects around 50% of acute stroke patients. Systematic bedside swallowing screening of acute stroke patients is recommended before oral intake. Currently there is lack of comprehensive dysphagia assessment tools with robust good accuracy, clinical utility and cost-effectiveness. An altered hyoid bone movement may represent a major risk factor for aspiration . Ultrasonography quantitatively measures hyoid-larynx approximation, which was found reduced in stroke patients with dysphagia. Although ultrasonography was suggested for assessing stroke patients with dysphagia, there is lack of evidence about the acute phase of stroke. Thus, our aim was to investigate the use of ultrasonography for bedside screening of dysphagia in acute stroke patients.

Methods: Nineteen acute stroke patients were included. Each patient performed clinical bedside screening for dysphagia by means of the Gugging Swallow Screen and the Functional Oral Intake Scale. Furthermore, all patients underwent ultrasonography in order to measure the distance between the thyroid cartilage and hyoid bone during swallowing (water bolus of 3 mL). The hyoid-larynx approximation distance [obtained by subtracting (a - b) the shortest distance between the hyoid bone and thyroid cartilage during swallowing (b) from the initial resting distance (a) and degree {[(a - b) / a] x 100} were calculated.

Results: The Functional Oral Intake Scale showed a significant direct association with the hyoid-larynx approximation distance (P=0.011) and degree (P=0.005). Also, the Gugging Swallow Screen showed a significant direct association with the hyoid-larynx approximation distance (P=0.008) and degree (P=0.004). The hyoid-larynx approximation distance and degree were significantly reduced in dysphagic patients.

Conclusions: Our findings support the use of ultrasonography in aid of swallowing clinical (non-instrumental) evaluation for the bedside screening of dysphagia in acute stroke patients.
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http://dx.doi.org/10.23736/S0026-4806.20.06571-4DOI Listing
April 2020

Obesity paradox and stroke: a narrative review.

Eat Weight Disord 2021 Mar 2;26(2):417-423. Epub 2020 Mar 2.

Stroke Unit, Department of Neuroscience, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.

Background: Despite obesity is an established risk factor for stroke, several studies reported a better outcome after stroke in obese and overweight patients. This counterintuitive finding, which was described in the whole spectrum of cardiovascular diseases, is known as obesity paradox.

Objective: This is a narrative overview on the obesity paradox and stroke.

Methods: We used as sources MEDLINE/PubMed, CINAHL, EMBASE, and Cochrane Library from inception to 2019, and selected papers that discussed the association of obesity with outcome and mortality after stroke.

Results: The majority of studies reported lower mortality rates and better functional outcome after stroke in obese and overweight patients compared with normal weight and underweight patients, suggesting the existence of an obesity paradox in stroke. However, available studies are limited by several major methodological concerns including absence of randomized trials, retrospective nature of most studies, assessment of obesity with body mass index (BMI), non-linear relationship between BMI and outcome, short follow-up period, and differences in co-morbid conditions and stroke characteristics.

Conclusions: The existence of an obesity paradox in stroke is still controversial and further higher quality evidence is needed to clarify the relationship between obesity and stroke outcome.

Level Of Evidence: Level V, narrative review.
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http://dx.doi.org/10.1007/s40519-020-00876-wDOI Listing
March 2021

Ischemic Stroke despite Oral Anticoagulant Therapy in Patients with Atrial Fibrillation.

Ann Neurol 2020 Feb 12. Epub 2020 Feb 12.

Stroke Research Center, Department of Brain Repair and Rehabilitation, University College London Queen Square Institute of Neurology, and the National Hospital for Neurology and Neurosurgery, Queen Square, London, United Kingdom.

Objective: 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.

Methods: 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 (OAC ) with those without prior oral anticoagulation (OAC ). We further compared those who changed the type (ie, from VKA or DOAC, vice versa, or DOAC to DOAC) of anticoagulation (OAC ) with those who continued the same anticoagulation as secondary prevention (OAC ). 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).

Results: 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 CHA DS -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 OAC (n = 1,195) and OAC (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%). OAC was associated with an increased risk of AIS (HR = 1.6, 95% CI = 1.2-2.3, p = 0.005). OAC (n = 307) was not associated with decreased risk of AIS (HR = 1.2, 95% CI = 0.7-2.1, p = 0.415) compared with OAC (n = 585).

Interpretation: Patients with AF who have an ischemic stroke despite previous oral anticoagulation are at a higher risk for recurrent ischemic stroke despite a CHA DS -Vasc score similar to those without prior oral anticoagulation. Better prevention strategies are needed for this high-risk patient group. ANN NEUROL 2020.
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http://dx.doi.org/10.1002/ana.25700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383617PMC
February 2020

Increased Incidence of Ischemic Cerebrovascular Events in Cardiovascular Patients With Elevated Apolipoprotein CIII.

Stroke 2020 01 4;51(1):61-68. Epub 2019 Dec 4.

From the Department of Medicine, Unit of Internal Medicine, University of Verona, Italy (O.O., D.G., F.P., S.F., A.C., N.M.).

Background and Purpose- Apo CIII (apolipoprotein CIII), a crucial regulator of lipoprotein metabolism, has been associated with increased activity of coagulation factors and thrombin generation and, in turn, with an increased risk of thromboembolic events in both arterial and venous districts. Thus, we hypothesized that it may affect the risk of acute ischemic cerebrovascular events in cardiovascular patients. Methods- We systematically checked medical records and quantified cerebral ischemic events in a cohort of 950 subjects (median age 65 with interquartile range, 55-79 years; 30.7% females) with or without angiographically defined coronary artery disease (CAD: 774 CAD and 176 CAD-free, respectively). All the subjects, enrolled between May 1999 and December 2006, were prospectively followed until death or July 31, 2018. Assessments of complete plasma lipid and apolipoprotein profiles, including Apo A-I, B, CIII, and E, were available for all subjects at enrollment. Results- After a median follow-up of 130 months (interquartile range, 69-189), 95 subjects (10%) suffered ischemic stroke/transient ischemic attack (TIA) events. Stroke/TIA subjects had higher Apo CIII plasma concentration (11.4; interquartile range: 9.3-14.4 mg/dL) at enrollment than those without stroke/TIA (10.4, interquartile range: 8.7-13.0 mg/dL). Subjects with Apo CIII levels above the median value (10.6 mg/dL) exhibited an ≈2-fold increased risk of stroke/TIA, even after adjustment for potential confounders, including sex, age, CAD diagnosis, hypertension, atrial fibrillation, oral anticoagulant treatment, and all plasma lipid parameters (hazard ratio: 2.23 [95% CI, 1.21-4.13]). This result was confirmed in CAD and CAD-free populations, separately, and even by a propensity score matching method, in which 98 CAD and 98 CAD-free subjects were one-to-one matched for all clinical and laboratory characteristics. Conclusions- These findings suggest that a high Apo CIII plasma concentration may predict an increased risk of ischemic stroke/TIA in cardiovascular patients.
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http://dx.doi.org/10.1161/STROKEAHA.119.026811DOI Listing
January 2020

Diffuse gliomas in patients aged 55 years or over: A suggestion for IDH mutation testing.

Neuropathology 2020 Feb 22;40(1):68-74. Epub 2019 Nov 22.

Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy.

Diffuse gliomas are defined on the isocitrate dehydrogenase (IDH) gene (IDH) mutational mutational status. The most frequent IDH mutation is IDH1 R132H, which is detectable by immunohistochemistry; other IDH mutations are rare (10%). IDH mutant gliomas have better prognosis. Further, IDH wild-type low-grade (II/III) gliomas have clinical behaviors similar to those of glioblastoma (GBM) and it was suggested that they are submitted to similar post-surgical treatment. The incidence of IDH mutant gliomas (2%) and that of GBMs with non-canonical IDH mutations (< 1%) are very low in patients ≥ 55 years. For this reason, it was suggested that immunohistochemistry against IDH1 R132H is sufficient to classify GBM as IDH wild-type in this age group. However, no indication was provided for IDH mutational testing in low-grade diffuse gliomas. To address this issue, 273 diffuse gliomas were tested for IDH1 R132H immunohistochemistry. 2/4 diffuse astrocytomas (DAs), 4/9 anaplastic astrocytomas (AAs), 2/256 GBMs, and 4/4 oligodendrogliomas had positive staining. No other IDH mutations were found in immuno-negative low-grade cases by DNA sequencing. To validate our findings, we considered 311 diffuse gliomas in patients ≥ 55 years in The Cancer Genome Atlas database. Fifty-five out of 311 gliomas had IDH R132H mutations (9/16 DAs; 8/48 AAs; 3/211 GBMs; 35/36 oligodendrogliomas), one DA, and one oligodendroglioma had other IDH mutations. IDH mutant gliomas had significantly higher frequency of O-6-methylguanine-DNA methyltransferase promoter methylation (P = 0.0008) and longer overall survival (P < 0.0001). In conclusion, low-grade gliomas are a minor part of gliomas (117/584) in patients ≥ 55 years, albeit they represent most IDH mutant gliomas in this age group (64/69 cases). IDH non-canonical mutations can be found in immunonegative low-grade gliomas (2/54). In view of its significance for prognosis and therapeutic management, our results suggest that IDH mutational status is assessed in all diffuse gliomas in patients ≥ 55 years by immunohistochemistry, followed by IDH sequencing in low-grade immunonegative cases.
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http://dx.doi.org/10.1111/neup.12608DOI Listing
February 2020

Relevance of antibodies to myelin oligodendrocyte glycoprotein in CSF of seronegative cases.

Neurology 2019 11 23;93(20):e1867-e1872. Epub 2019 Oct 23.

From the Section of Neurology (S.M., A.G., M.Z., D.A., S.M., S.F.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona; Neurology Unit (L.B., R.D., G.S., S.L., M.I.P.), Department of Medical, Surgical, and Experimental Sciences, University of Sassari; Neurology Unit (B.B.), AOUI Verona, Italy; and Clinical Department of Neurology (K.S., M.R.), Medical University of Innsbruck, Austria.

Objective: To determine the diagnostic relevance of myelin oligodendrocyte glycoprotein antibodies (MOG-Abs) in CSF of seronegative cases by retrospectively analyzing consecutive time-matched CSF of 80 MOG-Ab-seronegative patients with demyelinating disease.

Methods: The cohort included 44 patients with NMOSD and related disorders and 36 patients with multiple sclerosis (MS). Two independent neurologists blinded to diagnosis analyzed MOG-Abs by live cell-based immunofluorescence assay with goat anti-human immunoglobulin (Ig) G (whole molecule) antibody. Sera were tested at dilutions of 1:20 and 1:40, and a cutoff of 1:160 was considered for serum positivity. CSF specimens were tested undiluted and at 1:2 dilution with further titrations in case of positivity. Anti-IgG-Fc and anti-IgM-µ secondary antibodies were used to confirm the exclusive presence of MOG-IgG in positive cases. CSF of 13 MOG-Abs seropositive cases and 36 patients with neurodegenerative conditions was analyzed as controls.

Results: Three seronegative cases had CSF MOG-Abs (4% of the whole cohort or 7% of cases excluding patients with MS, in which MOG-Abs seem to lack diagnostic relevance). In particular, 2 patients with neuromyelitis optica spectrum disorder (NMOSD) and 1 with acute disseminated encephalomyelitis had MOG-Abs in CSF. Analysis with anti-IgG-Fc and anti-IgM confirmed the exclusive presence of MOG-IgG in the CSF of these patients. Among the control group, MOG-Abs were detectable in the CSF of 8 of 13 MOG-Ab-seropositive cases and in none of the patients with neurodegenerative disorders.

Conclusion: Although serum is the optimal specimen for MOG-Ab testing, analyzing CSF could improve diagnostic sensitivity in seronegative patients. This observation has relevant diagnostic impact and might provide novel insight into the biological mechanisms of MOG-Ab synthesis.
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http://dx.doi.org/10.1212/WNL.0000000000008479DOI Listing
November 2019

The Anti-Apoptotic Effect of ASC-Exosomes in an In Vitro ALS Model and Their Proteomic Analysis.

Cells 2019 09 14;8(9). Epub 2019 Sep 14.

Department of Neurological, Biomedical and Movement Science, University of Verona, 37134 Verona, Italy.

Stem cell therapy represents a promising approach in the treatment of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). The beneficial effect of stem cells is exerted by paracrine mediators, as exosomes, suggesting a possible potential use of these extracellular vesicles as non-cell based therapy. We demonstrated that exosomes isolated from adipose stem cells (ASC) display a neuroprotective role in an in vitro model of ALS. Moreover, the internalization of ASC-exosomes by the cells was shown and the molecules and the mechanisms by which exosomes could exert their beneficial effect were addressed. We performed for the first time a comprehensive proteomic analysis of exosomes derived from murine ASC. We identified a total of 189 proteins and the shotgun proteomics analysis revealed that the exosomal proteins are mainly involved in cell adhesion and negative regulation of the apoptotic process. We correlated the protein content to the anti-apoptotic effect of exosomes observing a downregulation of pro-apoptotic proteins Bax and cleaved caspase-3 and upregulation of anti-apoptotic protein Bcl-2 α, in an in vitro model of ALS after cell treatment with exosomes. Overall, this study shows the neuroprotective effect of ASC-exosomes after their internalization and their global protein profile, that could be useful to understand how exosomes act, demonstrating that they can be employed as therapy in neurodegenerative diseases.
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http://dx.doi.org/10.3390/cells8091087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770878PMC
September 2019

Causes and Risk Factors of Cerebral Ischemic Events in Patients With Atrial Fibrillation Treated With Non-Vitamin K Antagonist Oral Anticoagulants for Stroke Prevention.

Authors:
Maurizio Paciaroni Giancarlo Agnelli Valeria Caso Giorgio Silvestrelli David Julian Seiffge Stefan Engelter Gian Marco De Marchis Alexandros Polymeris Maria Luisa Zedde Shadi Yaghi Patrik Michel Ashraf Eskandari Kateryna Antonenko Sung-Il Sohn Manuel Cappellari Tiziana Tassinari Rossana Tassi Luca Masotti Aristeidis H Katsanos Sotirios Giannopoulos Monica Acciarresi Andrea Alberti Michele Venti Maria Giulia Mosconi Maria Cristina Vedovati Patrizia Pierini Michela Giustozzi Enrico Maria Lotti George Ntaios Odysseas Kargiotis Serena Monaco Piergiorgio Lochner Fabio Bandini Chrysoula Liantinioti Lina Palaiodimou Azmil H Abdul-Rahim Kennedy Lees Michelangelo Mancuso Leonardo Pantoni Silvia Rosa Pierluigi Bertora Silvia Galliazzo Walter Ageno Elisabetta Toso Filippo Angelini Alberto Chiti Giovanni Orlandi Licia Denti Yuriy Flomin Simona Marcheselli Nicola Mumoli Alexandra Rimoldi Elena Verrengia Erika Schirinzi Massimo Del Sette Panagiotis Papamichalis Apostolos Komnos Nemanja Popovic Marija Zarkov Alessandro Rocco Marina Diomedi Elisa Giorli Alfonso Ciccone Brian C Mac Grory Karen L Furie Bruno Bonetti Valentina Saia Francesca Guideri Maurizio Acampa Giuseppe Martini Elisa Grifoni Marina Padroni Efstathia Karagkiozi Kalliopi Perlepe Konstantinos Makaritsis Marina Mannino Miriam Maccarrone Leonardo Ulivi Nicola Giannini Elena Ferrari Alessandro Pezzini Boris Doronin Vera Volodina Antonio Baldi Cataldo D'Amore Dirk Deleu Francesco Corea Jukka Putaala Paola Santalucia Katiuscia Nardi Angela Risitano Danilo Toni Georgios Tsivgoulis

Stroke 2019 08 25;50(8):2168-2174. Epub 2019 Jun 25.

Second Department of Neurology, Attikon Hospital, National and Kapodistrian University of Athens, School of Medicine, Greece (C.L., L.P., G.T.).

Background and Purpose- Despite treatment with oral anticoagulants, patients with nonvalvular atrial fibrillation (AF) may experience ischemic cerebrovascular events. The aims of this case-control study in patients with AF were to identify the pathogenesis of and the risk factors for cerebrovascular ischemic events occurring during non-vitamin K antagonist oral anticoagulants (NOACs) therapy for stroke prevention. Methods- Cases were consecutive patients with AF who had acute cerebrovascular ischemic events during NOAC treatment. Controls were consecutive patients with AF who did not have cerebrovascular events during NOACs treatment. Results- Overall, 713 cases (641 ischemic strokes and 72 transient ischemic attacks; median age, 80.0 years; interquartile range, 12; median National Institutes of Health Stroke Scale on admission, 6.0; interquartile range, 10) and 700 controls (median age, 72.0 years; interquartile range, 8) were included in the study. Recurrent stroke was classified as cardioembolic in 455 cases (63.9%) according to the A-S-C-O-D (A, atherosclerosis; S, small vessel disease; C, cardiac pathology; O, other causes; D, dissection) classification. On multivariable analysis, off-label low dose of NOACs (odds ratio [OR], 3.18; 95% CI, 1.95-5.85), atrial enlargement (OR, 6.64; 95% CI, 4.63-9.52), hyperlipidemia (OR, 2.40; 95% CI, 1.83-3.16), and CHADS-VASc score (OR, 1.72 for each point increase; 95% CI, 1.58-1.88) were associated with ischemic events. Among the CHADS-VASc components, age was older and presence of diabetes mellitus, congestive heart failure, and history of stroke or transient ischemic attack more common in patients who had acute cerebrovascular ischemic events. Paroxysmal AF was inversely associated with ischemic events (OR, 0.45; 95% CI, 0.33-0.61). Conclusions- In patients with AF treated with NOACs who had a cerebrovascular event, mostly but not exclusively of cardioembolic pathogenesis, off-label low dose, atrial enlargement, hyperlipidemia, and high CHADS-VASc score were associated with increased risk of cerebrovascular events.
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http://dx.doi.org/10.1161/STROKEAHA.119.025350DOI Listing
August 2019

IER-SICH Nomogram to Predict Symptomatic Intracerebral Hemorrhage After Thrombectomy for Stroke.

Stroke 2019 04 14;50(4):909-916. Epub 2019 Mar 14.

Stroke Unit (M.D.M., D.T.), Sapienza University Hospital, Roma, Italy.

Background and Purpose- As a reliable scoring system to detect the risk of symptomatic intracerebral hemorrhage after thrombectomy for ischemic stroke is not yet available, we developed a nomogram for predicting symptomatic intracerebral hemorrhage in patients with large vessel occlusion in the anterior circulation who received bridging of thrombectomy with intravenous thrombolysis (training set), and to validate the model by using a cohort of patients treated with direct thrombectomy (test set). Methods- We conducted a cohort study on prospectively collected data from 3714 patients enrolled in the IER (Italian Registry of Endovascular Stroke Treatment in Acute Stroke). Symptomatic intracerebral hemorrhage was defined as any type of intracerebral hemorrhage with increase of ≥4 National Institutes of Health Stroke Scale score points from baseline ≤24 hours or death. Based on multivariate logistic models, the nomogram was generated. We assessed the discriminative performance by using the area under the receiver operating characteristic curve. Results- National Institutes of Health Stroke Scale score, onset-to-end procedure time, age, unsuccessful recanalization, and Careggi collateral score composed the IER-SICH nomogram. After removing Careggi collateral score from the first model, a second model including Alberta Stroke Program Early CT Score was developed. The area under the receiver operating characteristic curve of the IER-SICH nomogram was 0.778 in the training set (n=492) and 0.709 in the test set (n=399). The area under the receiver operating characteristic curve of the second model was 0.733 in the training set (n=988) and 0.685 in the test set (n=779). Conclusions- The IER-SICH nomogram is the first model developed and validated for predicting symptomatic intracerebral hemorrhage after thrombectomy. It may provide indications on early identification of patients for more or less postprocedural intensive management.
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http://dx.doi.org/10.1161/STROKEAHA.118.023316DOI Listing
April 2019

Direct oral anticoagulants versus vitamin K antagonists after recent ischemic stroke in patients with atrial fibrillation.

Ann Neurol 2019 06 30;85(6):823-834. Epub 2019 Apr 30.

Neurology and Stroke Center, University Hospital Basel and University of Basel, Basel, Switzerland.

Objective: We compared outcomes after treatment with direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) and a recent cerebral ischemia.

Methods: We conducted an individual patient data analysis of seven prospective cohort studies. We included patients with AF and a recent cerebral ischemia (<3 months before starting oral anticoagulation) and a minimum follow-up of 3 months. We analyzed the association between type of anticoagulation (DOAC versus VKA) with the composite primary endpoint (recurrent ischemic stroke [AIS], intracerebral hemorrhage [ICH], or mortality) using mixed-effects Cox proportional hazards regression models; we calculated adjusted hazard ratios (HRs) with 95% confidence intervals (95% CIs).

Results: We included 4,912 patients (median age, 78 years [interquartile range {IQR}, 71-84]; 2,331 [47.5%] women; median National Institute of Health Stroke Severity Scale at onset, 5 [IQR, 2-12]); 2,256 (45.9%) patients received VKAs and 2,656 (54.1%) DOACs. Median time from index event to starting oral anticoagulation was 5 days (IQR, 2-14) for VKAs and 5 days (IQR, 2-11) for DOACs (p = 0.53). There were 262 acute ischemic strokes (AISs; 4.4%/year), 71 intracranial hemorrrhages (ICHs; 1.2%/year), and 439 deaths (7.4%/year) during the total follow-up of 5,970 patient-years. Compared to VKAs, DOAC treatment was associated with reduced risks of the composite endpoint (HR, 0.82; 95% CI, 0.67-1.00; p = 0.05) and ICH (HR, 0.42; 95% CI, 0.24-0.71; p < 0.01); we found no differences for the risk of recurrent AIS (HR, 0.91; 95% CI, 0.70-1.19; p = 0.5) and mortality (HR, 0.83; 95% CI, 0.68-1.03; p = 0.09).

Interpretation: DOAC treatment commenced early after recent cerebral ischemia related to AF was associated with reduced risk of poor clinical outcomes compared to VKA, mainly attributed to lower risks of ICH. ANN NEUROL 2019;85:823-834.
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http://dx.doi.org/10.1002/ana.25489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563449PMC
June 2019

IER-START nomogram for prediction of three-month unfavorable outcome after thrombectomy for stroke.

Int J Stroke 2020 Jun 25;15(4):412-420. Epub 2019 Mar 25.

Sapienza University Hospital, Roma, Italy.

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 <6 h of stroke onset.

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 ( = 1219) and test ( = 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.
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http://dx.doi.org/10.1177/1747493019837756DOI Listing
June 2020

Lymphomatosis cerebri and anti-NMDAR antibodies: A unique constellation.

J Neurol Sci 2019 Mar 14;398:19-21. Epub 2019 Jan 14.

Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Italy.

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http://dx.doi.org/10.1016/j.jns.2019.01.014DOI Listing
March 2019

Intravenous thrombolysis for ischemic stroke in the Veneto region: the gap between eligibility and reality.

J Thromb Thrombolysis 2019 Jan;47(1):113-120

Stroke Unit, Azienda Ospedaliera Universitaria Integrata Verona, Piazzale Aristide Stefani, 1, 37126, Verona, Italy.

Intravenous thrombolysis (IVT) is the treatment of choice for most patients with acute ischemic stroke. According to the recently updated guidelines, IVT should be administered in absence of absolute exclusion criteria. We aimed to assess the proportion of ischemic strokes potentially eligible and actually treated with IVT, and to explore the reasons for not administering IVT. We prospectively collected and analyzed data from 1184 consecutive ischemic stroke patients admitted to the 22 Stroke Units (SUs) of the Veneto region from September 18th to December 10th 2017. Patients were treated with IVT according to the current Italian guidelines. For untreated patients, the reasons for not administering IVT were reported by each center in a predefined model including absolute and/or relative exclusion criteria and other possible reasons. Out of 841 (71%) patients who presented within 4.5 h of stroke onset, 704 (59%) had no other absolute exclusion criteria and were therefore potentially eligible for IVT according to the current guidelines. However, only 323 (27%) patients were eventually treated with IVT. Among 861 (73%) untreated patients, 480 had at least one absolute exclusion criterion, 283 only relative exclusion criteria, 56 only other reasons, and 42 a combination of relative exclusion criteria and other reasons. Our study showed that only 46% (323/704) of the potentially eligible patients were actually treated with IVT in the SUs of the Veneto region. All healthcare professionals involved in the acute stroke pathway should make an effort to bridge this gap between eligibility and reality.
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http://dx.doi.org/10.1007/s11239-018-1753-8DOI Listing
January 2019

Number of ischemic strokes potentially eligible for revascularization treatments in an Italian Comprehensive Stroke Center: a modeling study.

J Thromb Thrombolysis 2018 Oct;46(3):427-430

Neurology and Stroke Unit, Department of Neuroscience, Azienda Ospedaliera Universitaria Integrata Verona, Piazzale Aristide Stefani 1, 37126, Verona, Italy.

To rationally plan acute services, the proportion of ischemic strokes that may be eligible for revascularization treatments should be estimated. We aimed to estimate the proportion of patients directly admitted to an Italian Comprehensive Stroke Center who may be eligible for intravenous thrombolysis (IVT), combined IVT and endovascular thrombectomy (ET), or direct ET according to the current guidelines. We conducted a retrospective analysis based on data prospectively collected from 876 consecutive adult ischemic stroke patients who were directly admitted to the Stroke Unit of the University Hospital of Verona within 12 h of stroke onset. A theoretical model was created to calculate the proportion of patients potentially eligible for revascularization treatments. In our cohort, 289 (33%) patients would be eligible for IVT alone, 193 (22%) for combined IVT and ET, and 39 (4%) for direct ET with level of evidence IA according to the current guidelines. According to our theoretical model, more than half of the ischemic stroke patients directly admitted to Verona Stroke Unit within 12 h of stroke onset would be eligible for IVT and more than a quarter for ET. Systems of care should promptly organize to offer each patient the best treatment.
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http://dx.doi.org/10.1007/s11239-018-1712-4DOI Listing
October 2018

The dispersion of myocardial repolarization in ischemic stroke and intracranial hemorrhage.

J Electrocardiol 2018 Jul - Aug;51(4):691-695. Epub 2018 May 17.

Department of Neurosciences, Stroke Unit, Verona Hospital, Piazzale A. Stefani 1 -, 37126 Verona, Italy.

Background: Markers of dispersion of myocardial repolarization have been proposed to identify the patients at higher risk of malignant arrhythmic events. The aim of the present study is to assess a possible association of the electrocardiografic (ECG) markers of the dispersion of repolarization with the type of stroke, involvement of insula, neurological severity (National Institutes of Health Stroke Scale, NIHSS score), and disability (modified Rankin Scale, mRS score) in patients with a cerebrovascular event.

Methods: We conducted a retrospective analysis based on data prospectively collected from consecutive patients with a cerebrovascular event who underwent 12‑lead ECG at admission to the Verona Stroke Unit.

Results: Of the 63 patients included in the study, 55 had ischemic stroke and 8 intracranial hemorrhage. TpTe (time between the peak and the end of the T wave) and TpTe/QTc (TpTe/corrected time between the start of the Q wave and the end of the T wave) in lead V5 were higher in intracranial hemorrhage than in ischemic stroke (p = 0.03 and p = 0.04, respectively) and QT max (the longest QT calculated in the 12 leads) was higher in patients with involvement of insula (p ≤ 0.01). A correlation was found between QTc max and NIHSS score at admission (p = 0.02), QT max and NIHSS score at discharge (p = 0.05), and QT max and mRS score at discharge (p = 0.02).

Conclusions: TpTe and TpTe/QTc in V5 lead were associated with intracranial hemorrhage and QT max was associated with involvement of insula. The prolongation of QT was correlated with neurological severity and disability.
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http://dx.doi.org/10.1016/j.jelectrocard.2018.05.007DOI Listing
May 2019

Pain Modulation after Oromucosal Cannabinoid Spray (SATIVEX) in Patients with Multiple Sclerosis: A Study with Quantitative Sensory Testing and Laser-Evoked Potentials.

Medicines (Basel) 2018 Jun 21;5(3). Epub 2018 Jun 21.

Neurology Unit, Department of Neuroscience, AOUI Verona, 37126 Verona, Italy.

Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) (nabiximols or Sativex) is an oromucosal spray formulation containing THC and CBD at an approximately 1:1 fixed ratio. Its administration for the treatment of pain in patients with multiple sclerosis (MS) has been established. MS patients generally complain of different kinds of pain, including spasticity-related and neuropathic pain. In this study, we compared and evaluated pain modulation and thermal/pain threshold of MS patients before and after THC/CBD administration. 19 MS patients underwent clinical examination, numerical rating scale (NRS), quantitative sensory testing (QST), and laser-evoked potentials (LEPs) before and after 1 month of therapy. Psychophysiological and neurophysiological data were compared to sex- and age-matched controls. Patients reported a significant reduction in pain. We found statistically significant differences in LEP parameters between patients and controls but no significant change in LEP measures after THC/CBD therapy. Cold and heat detection thresholds were altered in patients but did not change after THC/CBD therapy. There was a significant increase in cold pain threshold by hand stimulation and a significant reduction in abnormal cold perception thresholds. Our results indicate that Sativex therapy provides pain relief in MS patients and suggest that it might modulate peripheral cold-sensitive TRP channels.
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http://dx.doi.org/10.3390/medicines5030059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6163235PMC
June 2018

Introduction of direct oral anticoagulant within 7 days of stroke onset: a nomogram to predict the probability of 3-month modified Rankin Scale score > 2.

J Thromb Thrombolysis 2018 Oct;46(3):292-298

Department of Neuroscience, Azienda Ospedaliera Universitaria Integrata, Piazzale A. Stefani 1, 37126, Verona, Italy.

In clinical practice, direct oral anticoagulants (DOACs) are often started earlier (≤ 7 days) than in randomized clinical trials after stroke. We aimed to develop a nomogram model incorporating time of DOAC introduction ≤ 7 days of stroke onset in combination with different degrees of stroke radiological/neurological severity at the time of treatment to predict the probability of unfavorable outcome. We conducted a multicenter prospective study including 344 patients who started DOAC 1-7 days after atrial fibrillation-related stroke onset. Computed tomography scan 24-36 h after stroke onset was performed in all patients before starting DOAC. Unfavorable outcome was defined as modified Rankin Scale (mRS) score > 2 at 3 months. Based on multivariate logistic model, the nomogram was generated. We assessed the discriminative performance by using the area under the receiver operating characteristic curve (AUC-ROC) and calibration of risk prediction model by using the Hosmer-Lemeshow test. Onset-to-treatment time for DOAC (OR: 1.21, p = 0.030), NIH Stroke Scale (NIHSS) score at the time of treatment (OR: 1.00 for NIHSS = 0-5; OR: 2.67, p = 0.016 for NIHSS = 6-9; OR: 26.70, p < 0.001 for NIHSS = 10-14; OR: 57.48, p < 0.001 for NIHSS ≥ 15), size infarct (OR: 1.00 for small infarct; OR: 2.26, p = 0.023 for medium infarct; OR: 3.40, p = 0.005 for large infarct), and age ≥ 80 years (OR: 1.96, p = 0.028) remained independent predictors of unfavorable outcome to compose the nomogram. The AUC-ROC of nomogram was 0.858. Calibration was good (p = 2.889 for the Hosmer-Lemeshow test). The combination of onset-to-treatment time of DOAC with stroke radiological/neurological severity at the time of treatment and old age may predict the probability of unfavorable outcome.
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http://dx.doi.org/10.1007/s11239-018-1700-8DOI Listing
October 2018

Association of Short- and Medium-Term Particulate Matter Exposure with Risk of Mortality after Spontaneous Intracerebral Hemorrhage.

J Stroke Cerebrovasc Dis 2018 Sep 24;27(9):2519-2523. Epub 2018 May 24.

Department of Neuroscience, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy.

Objective: We investigated the association of short- and medium-term particulate matter (PM) exposure with risk of mortality in patients with spontaneous intracerebral hemorrhage (ICH) identified according to strict etiologic criteria.

Methods: We conducted a retrospective analysis of prospectively collected data from consecutive patients with spontaneous ICH admitted to the emergency department of the University Hospital of Verona from March 2011 to December 2014. Outcome measures were mortality within 1 month after ICH and significant hematoma expansion (HE) defined as an absolute growth of more than 12.5 mL or a relative increase of more than 50% from baseline to follow-up computed tomography scan.

Results: A final number of 308 patients were included. In the adjusted model, higher PM and PM values in the last 3 days (odds ratio [OR] 1.827, 95% confidence interval [CI] 1.057-3.159, P = .031 and OR 1.949, 95% CI 1.025-3.704, P = .042, respectively) and in the last 4 weeks (OR 4.975, 95% CI 2.174-11.381, P < .001 and OR 9.781, 95% CI 3.425-27.932, P < .001, respectively) before ICH were associated with higher mortality rate. No association was found between PM exposure and significant HE.

Conclusions: PM exposure in the short- and medium-term before spontaneous ICH was associated with risk of 1-month mortality, independent of predictors such as age, sex, stroke severity, intraventricular hemorrhage, ICH volume, ICH location, ICH etiologic subtype, significant HE, antithrombotic therapy, atrial fibrillation, and blood glucose levels.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2018.05.007DOI Listing
September 2018