Publications by authors named "Salvatore Mangiafico"

85 Publications

Different endovascular procedures for stroke with isolated M2-segment MCA occlusion: a real-world experience.

J Thromb Thrombolysis 2021 Jan 24. Epub 2021 Jan 24.

Sapienza University Hospital, Rome, Italy.

Acute ischemic stroke with isolated occlusion of the M2-segment middle cerebral artery (MCA) has not been a focus of trials on mechanical thrombectomy (MT) thus far. We aimed to assess outcomes in stroke patients treated with different endovascular procedures versus direct MT alone for isolated M2-MCA occlusion. We conducted a cohort study on data from 506 stroke patients with isolated M2-MCA occlusion who were enrolled in the Italian Registry of Endovascular Treatment in Acute Stroke cohort. We calculated odds ratio (OR) with confidence interval (CI) of different endovascular procedures (vs direct MT alone) for outcomes after adjustment for age, enrollment period, pre-stroke mRS score, NIHSS score, ASPECT score, onset-to-groin time, and procedure time. Endovascular procedures were direct MT alone (n = 156), intravenous thrombolysis (IVT) plus MT (n = 266), MT plus intra-arterial thrombolysis (IAT) (n = 43), and IAT alone (n = 41). MT plus IAT was associated with higher rates of TICI 2b/3 (OR 3.281, 95% CI 1.006-10.704), 3-month mRS 0-1 (OR 4.153, 95% CI 1.267-13.612), and 3-month mRS 0-2 (OR 4.497, 95% CI 1.485-13.617). IAT alone was associated with lower rates of TICI 3 (OR 0.348, 95% CI 0.139-0.874) and TICI 2b/3 (OR 0.369, 95% CI 0.144-0.948). IVT plus MT was associated with higher rate of asymptomatic ICH (OR 2.526, 95% CI 1.145-5.571). No significant difference was found between different endovascular procedures and direct MT alone as regards symptomatic ICH and 3-month death. In stroke patients with isolated M2-MCA occlusion, MT plus IAT was associated with better outcomes as compared with direct MT alone.
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http://dx.doi.org/10.1007/s11239-021-02378-7DOI Listing
January 2021

EXPRESS: Global Impact of the COVID-19 Pandemic on Stroke Hospitalizations and Mechanical Thrombectomy Volumes.

Authors:
Raul Nogueira Mohamad Abdalkader Muhammed M Qureshi M R Frankel Ossama Yassin Mansour Hiroshi Yamagami Zhongming Qiu Mehdi Farhoudi James E Siegler Shadi Yaghi Eytan Raz Nobuyuki Sakai Nobuyuki Ohara Michel Piotin Laura Mechtouff Omer Eker Vanessa Chalumeau Timothy Kleinig Jian-Min Liu Raoul Pop Hugh Stephen Winters Xianjin Shang Alejandro Rodriguez Vasquez Jordi Blasco Juan F Arenillas Mario Martinez-Galdamez Alex Brehm Marios Psychogios Pedro Lylyk Diogo C Haussen Alhamza Al-Bayati Mahmoud H Mohammaden Luisa Fonseca Maria Luà S Silva Francisco J Montalverne Fabricio Oliveira Lima Leonardo Renieri Salvatore Mangiafico Urs Fischer Jan Gralla Donald Frei Chandril Chugh Brijesh P Mehta Simon Nagel Markus Mà Hlenbruch Santiago Ortega Mudassir Farooqui Ameer E Hassan Allan Taylor Bertrand Lapergue Arturo Consoli Bruce Campbell Malveeka Sharma Melanie Walker Noel van Horn Jens Fiehler Huy Thang Nguyen Quoc Trung Nguyen Daisuke Watanabe Hao Zhang Huynh Vu Le Viet Quy Nguyen Ruchir Shah Thomas Devlin Priyank Khandelwal Italo Linfante Wazim Izzath Pablo Lavados Veronica V Olavarrà A Gisele Sampaio Silva Anna Verena de Carvalho Sousa Jawad Kirmani Martin Bendszus Tatsuo Amano Ryoo Yamamoto Ryosuke Doijiri Naoki Tokuda Takehiro Yamada Tadashi Terasaki Yukako Yazawa Jane G Morris Emma Griffin John Thornton Pascale Lavoie Charles Matouk Michael D Hill Andrew M Demchuk Monika Killer Fadi Nahab Dorothea Altschul Natalia Perez de la Ossa Raghid Kikano William Boisseau Gregory Walker Steve Cordina Ajit S Puri Anna Kuhn Dheeraj Gandhi Thanh Nguyen

Int J Stroke 2021 Jan 18:1747493021991652. Epub 2021 Jan 18.

Boston Medical Center, Neurology, 1 Boston Medical Center, Boston, Massachusetts, United States.

Background: The COVID-19 pandemic led to profound changes in the organization of health care systems worldwide.

Aims: We sought to measure the global impact of the COVID-19 pandemic on the volumes for mechanical thrombectomy (MT), stroke, and intracranial hemorrhage (ICH) hospitalizations over a 3-month period at the height of the pandemic (March 1 to May 31, 2020) compared with two control 3-month periods (immediately preceding and one year prior).

Methods: Retrospective, observational, international study, across 6 continents, 40 countries, and 187 comprehensive stroke centers. The diagnoses were identified by their ICD-10 codes and/or classifications in stroke databases at participating centers.

Results: The hospitalization volumes for any stroke, ICH, and MT were 26,699, 4,002, and 5,191 in the 3 months immediately before versus 21,576, 3,540, and 4,533 during the first 3 pandemic months, representing declines of 19.2% (95%CI,-19.7 to -18.7), 11.5% (95%CI,-12.6 to -10.6), and 12.7% (95%CI,-13.6 to -11.8), respectively. The decreases were noted across centers with high, mid, and low COVID-19 hospitalization burden, and also across high, mid, and low volume stroke/MT centers. High-volume COVID-19 centers (-20.5%) had greater declines in MT volumes than mid- (-10.1%) and low-volume (-8.7%) centers (p<0.0001). There was a 1.5% stroke rate across 54,366 COVID-19 hospitalizations. SARS-CoV-2 infection was noted in 3.9% (784/20,250) of all stroke admissions.

Conclusion: The COVID-19 pandemic was associated with a global decline in the volume of overall stroke hospitalizations, MT procedures, and ICH admission volumes. Despite geographic variations, these volume reductions were observed regardless of COVID-19 hospitalization burden and pre-pandemic stroke/MT volumes.
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http://dx.doi.org/10.1177/1747493021991652DOI Listing
January 2021

Mechanical Thrombectomy for Acute Intracranial Carotid Occlusion with Patent Intracranial Arteries : The Italian Registry of Endovascular Treatment in Acute Stroke.

Clin Neuroradiol 2020 Dec 10. Epub 2020 Dec 10.

Stroke Unit, University of Rome La Sapienza, Roma, Italy.

Purpose: Intracranial carotid artery occlusion represents an underinvestigated cause of acute ischemic stroke as well as an indication for mechanical thrombectomy. We investigated baseline and procedural characteristics, outcomes and predictors of outcome in patients with acute ischemic stroke secondary to intracranial carotid artery occlusion.

Methods: A retrospective analysis of the Italian Registry of Endovascular Treatment in Acute Stroke was performed. Patients with intracranial carotid artery occlusion (infraclinoid and supraclinoid) with or without cervical artery occlusion but with patent intracranial arteries were included. The 3‑month functional independence, mortality, successful reperfusion and symptomatic intracranial hemorrhage were evaluated.

Results: Intracranial carotid artery occlusion with patent intracranial arteries was diagnosed in 387 out of 4940 (7.8%) patients. The median age was 74 years and median baseline National Institute of Health Stroke Scale (NIHSS) was 18. Functional independence was achieved in 130 (34%) patients, successful reperfusion in 289 (75%) and symptomatic intracranial hemorrhage in 33 (9%), whereas mortality occurred in 111 (29%) patients. In univariate analysis functional independence was associated with lower age, lower NIHSS at presentation, higher rate of successful reperfusion and lower rate of symptomatic intracranial hemorrhage. Multivariable regression analysis found age (odds ratio, OR:1.03; P = 0.006), NIHSS at presentation (OR: 1.07; P < 0.001), diabetes (OR: 2.60; P = 0.002), successful reperfusion (OR:0.20; P < 0.001) and symptomatic intracranial hemorrhage (OR: 4.17; P < 0.001) as the best independent predictors of outcome.

Conclusion: Our study showed a not negligible rate of intracranial carotid artery occlusion with patent intracranial arteries, presenting mostly as severe stroke, with an acceptable rate of 3‑month functional independence. Age, NIHSS at presentation and successful reperfusion were the best independent predictors of outcome.
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http://dx.doi.org/10.1007/s00062-020-00980-5DOI Listing
December 2020

Complications of mechanical thrombectomy for acute ischemic stroke: Incidence, risk factors, and clinical relevance in the Italian Registry of Endovascular Treatment in acute stroke.

Int J Stroke 2020 Dec 6:1747493020976681. Epub 2020 Dec 6.

Interventional Neurovascular Unit and Stroke Unit, Ospedale Careggi-University Hospital, Firenze, Italy.

Background: There are limited data concerning procedure-related complications of endovascular thrombectomy for large vessel occlusion strokes.

Aims: We evaluated the cumulative incidence, the clinical relevance in terms of increased disability and mortality, and risk factors for complications.

Methods: From January 2011 to December 2017, 4799 patients were enrolled by 36 centers in the Italian Registry of Endovascular Stroke Treatment. Data on demographic and procedural characteristics, complications, and clinical outcome at three months were prospectively collected.

Results: The complications cumulative incidence was 201 per 1000 patients undergoing endovascular thrombectomy. Ongoing antiplatelet therapy (p < 0.01; OR 1.82, 95% CI: 1.21-2.73) and large vessel occlusion site (carotid-T, p < 0.03; OR 3.05, 95% CI: 1.13-8.19; M2-segment-MCA, p < 0.01; OR 4.54, 95% CI: 1.66-12.44) were associated with a higher risk of subarachnoid hemorrhage/arterial perforation. Thrombectomy alone (p < 0.01; OR 0.50, 95% CI: 0.31-0.83) and younger age (p < 0.04; OR 0.98, 95% CI: 0.97-0.99) revealed a lower risk of developing dissection. M2-segment-MCA occlusion (p < 0.01; OR 0.35, 95% CI: 0.19-0.64) and hypertension (p < 0.04; OR 0.77, 95% CI: 0.6-0.98) were less related to clot embolization. Higher NIHSS at onset (p < 0.01; OR 1.04, 95% CI: 1.02-1.06), longer groin-to-reperfusion time (p < 0.01; OR 1.05, 95% CI: 1.02-1.07), diabetes (p < 0.01; OR 1.67, 95% CI: 1.25-2.23), and LVO site (carotid-T, p < 0.01; OR 1.96, 95% CI: 1.26-3.05; M2-segment-MCA, p < 0.02; OR 1.62, 95% CI: 1.08-2.42) were associated with a higher risk of developing symptomatic intracerebral hemorrhage compared to no/asymptomatic intracerebral hemorrhage. The subgroup of patients treated with thrombectomy alone presented a lower risk of symptomatic intracerebral hemorrhage (p < 0.01; OR 0.70; 95% CI: 0.55-0.90). Subarachnoid hemorrhage/arterial perforation and symptomatic intracerebral hemorrhage after endovascular thrombectomy worsen both functional independence and mortality at three-month follow-up (p < 0.01). Distal embolization is associated with neurological deterioration (p < 0.01), while arterial dissection did not affect clinical outcome at follow-up.

Conclusions: Complications globally considered are not uncommon and may result in poor clinical outcome. Early recognition of risk factors might help to prevent complications and manage them appropriately in order to maximize endovascular thrombectomy benefits.
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http://dx.doi.org/10.1177/1747493020976681DOI Listing
December 2020

Mechanical thrombectomy in patients with proximal occlusions and low NIHSS: Results from a large prospective registry.

J Stroke Cerebrovasc Dis 2020 Oct 30;29(10):105091. Epub 2020 Jul 30.

Stroke Emergency Department Stroke Unit, Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy. Electronic address:

Background: Mechanical thrombectomy is now standard of care for treatment of acute ischemic stroke secondary to large vessel occlusion in the setting of high NIHSS. We analysed a large nationwide registry focusing on patients with large vessel occlusion and low NIHSS on admission to evaluate the efficacy and safety of thrombectomy in this patient population METHODS: 2826 patients treated with mechanical thrombectomy were included in a multicentre registry from January 1, 2011 to December 31, 2015. We included patients with large vessel occlusion and NIHSS ≤ 6 on admission. Baseline characteristics, imaging, clinical outcome, procedure adverse events and positive and negative outcome predictors were analysed.

Results: 134 patients were included. 90/134 had an anterior circulation and 44 a posterior circulation stroke. One patient died before treatment. Successful revascularization (mTICI 2b-3) was achieved in 73.7% (98/133) of the patients. Intraprocedural adverse event was observed in 3% (4/133) of cases. Symptomatic intracranial haemorrhage rate was 5.3% (7/133). At three months, 70.9% (95/134) of the patients had mRS score 0-2, 15.7% (21/134) mRS 3-5 and 13.4% (18/134) mRS 6. Age and successful recanalization were significant predictors of a good clinical outcome on both univariate (p= 0.005 and p=0.007) and multivariable (p=0.0018 and p=0.009 [nat log]) analysis. Absence of vessel recanalization and symptomatic intracranial hemorrhage were independent predictors of poor outcome (p=0.021) .

Conclusions: Our study suggests that patients with large vessel occlusion and low NIHSS score on admission can benefit from mechanical thrombectomy. Randomized trials are warranted.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.105091DOI Listing
October 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

Development of machine learning models to prognosticate chronic shunt-dependent hydrocephalus after aneurysmal subarachnoid hemorrhage.

Acta Neurochir (Wien) 2020 12 8;162(12):3093-3105. Epub 2020 Jul 8.

Neurosurgery Clinic, Department of Neuroscience, Psychology, Pharmacology and Child Health, Careggi University Hospital and University of Florence, Largo Piero Palagi 1, 50137, Florence, Italy.

Background: Shunt-dependent hydrocephalus significantly complicates subarachnoid hemorrhage (SAH), and reliable prognosis methods have been sought in recent years to reduce morbidity and costs associated with delayed treatment or neglected onset. Machine learning (ML) defines modern data analysis techniques allowing accurate subject-based risk stratifications. We aimed at developing and testing different ML models to predict shunt-dependent hydrocephalus after aneurysmal SAH.

Methods: We consulted electronic records of patients with aneurysmal SAH treated at our institution between January 2013 and March 2019. We selected variables for the models according to the results of the previous works on this topic. We trained and tested four ML algorithms on three datasets: one containing binary variables, one considering variables associated with shunt-dependency after an explorative analysis, and one including all variables. For each model, we calculated AUROC, specificity, sensitivity, accuracy, PPV, and also, on the validation set, the NPV and the Matthews correlation coefficient (ϕ).

Results: Three hundred eighty-six patients were included. Fifty patients (12.9%) developed shunt-dependency after a mean follow-up of 19.7 (± 12.6) months. Complete information was retrieved for 32 variables, used to train the models. The best models were selected based on the performances on the validation set and were achieved with a distributed random forest model considering 21 variables, with a ϕ = 0.59, AUC = 0.88; sensitivity and specificity of 0.73 (C.I.: 0.39-0.94) and 0.92 (C.I.: 0.84-0.97), respectively; PPV = 0.59 (0.38-0.77); and NPV = 0.96 (0.90-0.98). Accuracy was 0.90 (0.82-0.95).

Conclusions: Machine learning prognostic models allow accurate predictions with a large number of variables and a more subject-oriented prognosis. We identified a single best distributed random forest model, with an excellent prognostic capacity (ϕ = 0.58), which could be especially helpful in identifying low-risk patients for shunt-dependency.
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http://dx.doi.org/10.1007/s00701-020-04484-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593274PMC
December 2020

Endovascular Thrombectomy for Acute Ischemic Stroke Beyond 6 Hours From Onset: A Real-World Experience.

Stroke 2020 07 17;51(7):2051-2057. Epub 2020 Jun 17.

Emergency Department Stroke Unit, Sapienza University Hospital, Rome (E.N., D.T.).

Background And Purpose: To evaluate outcome and safety of endovascular treatment beyond 6 hours of onset of ischemic stroke due to large vessel occlusion in the anterior circulation, in routine clinical practice.

Methods: From the Italian Registry of Endovascular Thrombectomy, we extracted clinical and outcome data of patients treated for stroke of known onset beyond 6 hours. Additional inclusion criteria were prestroke modified Rankin Scale score ≤2 and ASPECTS score ≥6. Patients were selected on individual basis by a combination of CT perfusion mismatch (difference between total hypoperfusion and infarct core sizes) and CT collateral score. The primary outcome measure was the score on modified Rankin Scale at 90 days. Safety outcomes were 90-day mortality and the occurrence of symptomatic intracranial hemorrhage. Data were compared with those from patients treated within 6 hours.

Results: Out of 3057 patients, 327 were treated beyond 6 hours. Their mean age was 66.8±14.9 years, the median baseline National Institutes of Health Stroke Scale 16, and the median onset to groin puncture time 430 minutes. The most frequent site of occlusion was middle cerebral artery (45.1%). Functional independence (90-day modified Rankin Scale score, 0-2) was achieved by 41.3% of cases. Symptomatic intracranial hemorrhage occurred in 6.7% of patients, and 3-month case fatality rate was 17.1%. The probability of surviving with modified Rankin Scale score, 0-2 (odds ratio, 0.58 [95% CI, 0.43-0.77]) was significantly lower in patients treated beyond 6 hours as compared with patients treated earlier No differences were found regarding recanalization rates and safety outcomes between patients treated within and beyond 6 hours. There were no differences in outcome between people treated 6-12 hours from onset (278 patients) and those treated 12 to 24 hours from onset (49 patients).

Conclusions: This real-world study suggests that in patients with large vessel occlusion selected on the basis of CT perfusion and collateral circulation assessment, endovascular treatment beyond 6 hours is feasible and safe with no increase in symptomatic intracranial hemorrhage.
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http://dx.doi.org/10.1161/STROKEAHA.119.027974DOI Listing
July 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

Head or Neck First? Speed and Rates of Reperfusion in Thrombectomy for Tandem Large Vessel Occlusion Strokes.

Interv Neurol 2020 Jan 15;8(2-6):92-100. Epub 2019 Feb 15.

Department of Diagnostic and Therapeutic Neuroradiology, University Hospital of Nancy, Nancy, France.

Background: We aim to evaluate the speed and rates of reperfusion in tandem large vessel occlusion acute stroke patients undergoing upfront cervical lesion treatment (Neck-First: angioplasty and/or stent before thrombectomy) as compared to direct intracranial occlusion therapy (Head-First) in a large international multicenter cohort.

Methods: The Thrombectomy In TANdem Lesions (TITAN) collaboration pooled individual data of prospectively collected thrombectomy international databases for all consecutive anterior circulation tandem patients who underwent emergent thrombectomy. The co-primary outcome measures were rates of successful reperfusion (modified Thrombolysis in Cerebral Infarction 2b/3) and time from groin puncture to successful reperfusion.

Results: In total, 289 patients with tandem atherosclerotic etiology were included in the analysis (182 Neck-First and 107 Head-First patients). Except for differences in the Alberta Stroke Program Early CT Score (ASPECTS; median 8 [range 7-10] Neck-First vs. 7 [range 6-8] Head-First; < 0.001) and cervical internal carotid artery (ICA) lesion severity (complete occlusion in 35% of the Neck-First vs. 57% of the Head-First patients; < 0.001), patient characteristics were well balanced. After adjustments, there was no difference in successful reperfusion rates between the study groups (odds ratio associated with Neck-First: 1.18 [95% confidence interval, 0.60-2.17]). The time to successful reperfusion from groin puncture was significantly shorter in the Head-First group after adjustments (median 56 min [range 39-90] vs. 70 [range 50-102]; = 0.001). No significant differences in the rates of full reperfusion, symptomatic hemorrhage, 90-day independence, or mortality were observed. Sensitivity analysis excluding patients with complete cervical ICA occlusion yielded similar results.

Conclusions: The upfront approach of the intracranial lesion in patients with tandem large vessel occlusion strokes leads to similar reperfusion rates but faster reperfusion as compared to initial cervical revascularization followed by mechanical thrombectomy. Controlled studies are warranted.
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http://dx.doi.org/10.1159/000496292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253855PMC
January 2020

E2f8 and Dlg2 genes have independent effects on impaired insulin secretion associated with hyperglycaemia.

Diabetologia 2020 07 30;63(7):1333-1348. Epub 2020 Apr 30.

Department of Medicine (Austin Health), Austin Hospital, University of Melbourne, Level 7, Lance Townsend Building, Studley Road, Heidelberg, VIC, 3084, Australia.

Aims/hypothesis: Reduced insulin secretion results in hyperglycaemia and diabetes involving a complex aetiology that is yet to be fully elucidated. Genetic susceptibility is a key factor in beta cell dysfunction and hyperglycaemia but the responsible genes have not been defined. The Collaborative Cross (CC) is a recombinant inbred mouse panel with diverse genetic backgrounds allowing the identification of complex trait genes that are relevant to human diseases. The aim of this study was to identify and characterise genes associated with hyperglycaemia.

Methods: Using an unbiased genome-wide association study, we examined random blood glucose and insulin sensitivity in 53 genetically unique mouse strains from the CC population. The influences of hyperglycaemia susceptibility quantitative trait loci (QTLs) were investigated by examining glucose tolerance, insulin secretion, pancreatic histology and gene expression in the susceptible mice. Expression of candidate genes and their association with insulin secretion were examined in human islets. Mechanisms underlying reduced insulin secretion were studied in MIN6 cells using RNA interference.

Results: Wide variations in blood glucose levels and the related metabolic traits (insulin sensitivity and body weight) were observed in the CC population. We showed that elevated blood glucose in the CC strains was not due to insulin resistance nor obesity but resulted from reduced insulin secretion. This insulin secretory defect was demonstrated to be independent of abnormalities in islet morphology, beta cell mass and pancreatic insulin content. Gene mapping identified the E2f8 (p = 2.19 × 10) and Dlg2 loci (p = 3.83 × 10) on chromosome 7 to be significantly associated with hyperglycaemia susceptibility. Fine mapping the implicated regions using congenic mice demonstrated that these two loci have independent effects on insulin secretion in vivo. Significantly, our results revealed that increased E2F8 and DLG2 gene expression are correlated with enhanced insulin secretory function in human islets. Furthermore, loss-of-function studies in MIN6 cells demonstrated that E2f8 is involved in insulin secretion through an ATP-sensitive K channel-dependent pathway, which leads to a 30% reduction in Abcc8 expression. Similarly, knockdown of Dlg2 gene expression resulted in impaired insulin secretion in response to glucose and non-glucose stimuli.

Conclusions/interpretation: Collectively, these findings suggest that E2F transcription factor 8 (E2F8) and discs large homologue 2 (DLG2) regulate insulin secretion. The CC resource enables the identification of E2f8 and Dlg2 as novel genes associated with hyperglycaemia due to reduced insulin secretion in pancreatic beta cells. Taken together, our results provide better understanding of the molecular control of insulin secretion and further support the use of the CC resource to identify novel genes relevant to human diseases.
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http://dx.doi.org/10.1007/s00125-020-05137-0DOI Listing
July 2020

Impact of Antiplatelet Therapy During Endovascular Therapy for Tandem Occlusions: A Collaborative Pooled Analysis.

Stroke 2020 05 19;51(5):1522-1529. Epub 2020 Mar 19.

From the Department of Diagnostic and Therapeutic Neuroradiology, University Hospital of Nancy, France (F.Z., R.A., S.B., B.G.).

Background and Purpose- Antiplatelet agents could be used in the setting of endovascular therapy for tandem occlusions to reduce the risk of de novo intracranial embolic migration, reocclusion of the extracranial internal carotid artery lesion, or in-stent thrombosis in case of carotid stent placement but have to be balanced with the intracerebral hemorrhagic transformation risk. In this study, we aim to investigate the impact of acute antiplatelet therapy administration on outcomes during endovascular therapy for anterior circulation tandem occlusions. Methods- This is a retrospective analysis of a collaborative pooled analysis of 11 prospective databases from the multicenter observational TITAN registry (Thrombectomy in Tandem Lesions). Patients were divided into groups based on the number of antiplatelet administered during endovascular therapy. The primary outcome was favorable outcome, defined as a modified Rankin Scale score of 0 to 2 at 90 days. Results- This study included a total of 369 patients; 145 (39.3%) did not receive any antiplatelet agent and 224 (60.7%) received at least 1 antiplatelet agent during the procedure. Rate of favorable outcome was nonsignificantly higher in patients treated with antiplatelet therapy (58.3%) compared with those treated without antiplatelet (46.0%; adjusted odds ratio, 1.38 [95% CI, 0.78-2.43]; =0.26). Rate of 90-day mortality was significantly lower in patients treated with antiplatelet therapy (11.2% versus 18.7%; adjusted odds ratio, 0.47 [95% CI, 0.22-0.98]; =0.042), without increasing the risk of any intracerebral hemorrhage. Successful reperfusion (modified Thrombolysis in Cerebral Ischemia score 2b-3) rate was significantly better in the antiplatelet therapy group (83.9% versus 71.0%; adjusted odds ratio, 1.89 [95% CI, 1.01-3.64]; =0.045). Conclusions- Administration of antiplatelet therapy during endovascular therapy for anterior circulation tandem occlusions was safe and was associated with a lower 90-day mortality. Optimal antiplatelet therapy remains to be assessed, especially when emergent carotid artery stenting is performed. Further randomized controlled trials are needed.
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http://dx.doi.org/10.1161/STROKEAHA.119.028231DOI Listing
May 2020

Expanding Indications for Flow Diverters: Distal Aneurysms, Bifurcation Aneurysms, Small Aneurysms, Previously Coiled Aneurysms and Clipped Aneurysms, and Carotid Cavernous Fistulas.

Neurosurgery 2020 01;86(Suppl 1):S85-S94

Neurovascular Interventional Unit, Careggi University Hospital, Florence, Italy.

Flow diverter devices have gained wide acceptance for the treatment of unruptured intracranial aneurysms. Most studies are based on the treatment of large aneurysms harboring on the carotid syphon. However, during the last years the "off-label" use of these stents has widely grown up even if not supported by randomized studies. This review examines the relevant literature concerning "off-label" indications for flow diverter devices, such as for distal aneurysms, bifurcation aneurysms, small aneurysms, recurrent aneurysms, and direct carotid cavernous fistulas.
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http://dx.doi.org/10.1093/neuros/nyz334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911737PMC
January 2020

Y-Stenting Versus PulseRider-Assisted Coiling in the Treatment of Wide-Neck Bifurcation Aneurysms: Role of Anatomical Features on Midterm Results.

Neurosurgery 2020 08;87(2):329-337

Neurovascular Interventional Unit, Careggi University Hospital, Florence, Italy.

Background: Y-stenting is an effective but challenging approach for wide-neck aneurysms. PulseRider (PR) (Pulsar/Cerenovus) is a new device designed to provide scaffolding during coiling but has never been compared with other techniques.

Objective: To compare the immediate and 6-mo results of Y-stenting vs PR assisted coiling.

Methods: A total of 105 consecutive patients were retrospectively divided into 2 groups (73 Y-stenting and 32 PR). All underwent angiographic 6-mo follow-up. We evaluated if some anatomical features could influence treatment results.

Results: The groups were homogeneous. Immediate adequate occlusions as well as complication rates were similar in Y-stenting and PR group (94.5% vs 96.9% and 8.2% vs 6.2%, respectively). At 6 mo, adequate occlusion was 93.1% after Y-stenting and 84.3% after PR (P = .28), complete occlusion was significantly higher after Y-stenting: 90.3% vs 62.5% (P = .0017). Occlusion grade worsening occurred in 6.9% of Y-stenting and 18.7% of PR patients (P = .09).Neck size was associated with occlusion grade in both groups. Maximal aneurysm size was associated with occlusion grade in the PR group (P = .023) but not in the Y-stenting group (P = .06). After PR, 6-mo occlusion rate was higher in small (< 10 mm) than in large aneurysms (P = .0094); this was not observed after Y-stenting (P = .54).Location did not significantly affect the mid-term occlusion rate in both the groups. After PR, occlusion was more stable in basilar than anterior or middle cerebral artery aneurysms.

Conclusion: Y-stenting and PR are both effective with similar immediate and mid-term results. However, treatment stability seems higher after Y-stenting. Aneurysm size seems to negatively affect PR results.
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http://dx.doi.org/10.1093/neuros/nyz490DOI Listing
August 2020

[Endovascular therapy of acute ischemic stroke].

G Ital Cardiol (Rome) 2019 09;20(9 Suppl 1):50S-62S

Unità di Interventistica Neurovascolare, Dipartimento Emergenza e Accettazione, AOU Careggi, Firenze.

Endovascular treatment of acute ischemic stroke has introduced several paradigm shifts in the therapy of cerebral artery occlusion. Until recently, intravenous recombinant tissue-type plasminogen activator was the only evidence-based treatment option. Recent trials have proven the safety and efficacy of endovascular treatment and additional clinical studies are expanding the indication for this therapeutic approach. A prompt and effective revascularization is the mainstay for the treatment of acute ischemic stroke. Thrombectomy with stentrievers and/or thromboaspiration are now recommended as the standard of care for acute ischemic stroke with a proximal cerebral artery occlusion according to specific selection criteria based on patient's characteristics, clinical presentation, timing and neuroimaging. In this review, the main findings from available evidence and the state of art of endovascular therapy of acute ischemic stroke are discussed, requiring that the procedure be performed by trained neurointerventionalists to guarantee the demonstrated safety and efficacy of this treatment.
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http://dx.doi.org/10.1714/3219.31968DOI Listing
September 2019

Persistent trigeminal artery aneurysms: case report and systematic review.

J Neurointerv Surg 2019 Dec 26;11(12):1261-1265. Epub 2019 Jun 26.

NEUROMED, Pozzilli, Italy.

Background: The persistent trigeminal artery (PTA) is an adult carotid-basilar anastomosis with debated pathologic aspects, such as its association with brain aneurysms. True trigeminal artery aneurysms are rare vascular anomalies, reported in a few case reports.

Objective: To report our experience with a ruptured trigeminal artery aneurysm and to provide a systematic review of the literature in order to analyse potential links between the anatomic configuration of the PTA and PTA aneurysm (PTAA) type, and implications of each PTAA type for the diagnostic and therapeutic approach.

Methods: We reviewed the medical literature on trigeminal artery aneurysms according to the PRISMA guidelines. Population characteristics, aneurysms features, and PTA type and side were assessed.

Results: 40 previously published cases of PTAAs were included in the analysis. The mean age of subjects was 55 years, with a strong female predominance (77%). Four PTAAs were accidentally discovered, while 16 caused compressive symptoms and 20 were ruptured. Successful endovascular treatment was performed in 62% of cases.

Conclusions: PTAAs are rare vascular anomalies, underdiagnosed in the presence of a trigemino-cavernous fistula. Parent vessel occlusion seems to be the best therapeutic option for ruptured or symptomatic unruptured PTAAs in Saltzman type II and III PTAs. Patency of the parent vessel is the main target in Saltzman type I PTA.
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http://dx.doi.org/10.1136/neurintsurg-2019-015046DOI Listing
December 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

Periprocedural Heparin During Endovascular Treatment of Tandem Lesions in Patients with Acute Ischemic Stroke: A Propensity Score Analysis from TITAN Registry.

Cardiovasc Intervent Radiol 2019 Aug 31;42(8):1160-1167. Epub 2019 May 31.

Department of Diagnostic and Therapeutic Neuroradiology, IADI INSERM U1254, University Hospital of Nancy, Nancy, France.

Background And Purpose: Data on safety and efficacy of periprocedural use of heparin are limited during treatment of acute ischemic stroke patients with anterior circulation tandem occlusion. This study aimed to investigate the impact of heparin use during endovascular therapy of anterior circulation tandem occlusions on the functional and safety outcomes.

Methods: A retrospective analysis of the multicenter observational TITAN registry was performed. Patients with anterior circulation tandem occlusion and treated with endovascular therapy (EVT) were included, with or without extracranial carotid intervention. We divided patients into two groups based on periprocedural heparin use (heparin vs. non-heparin). The dose of intravenous unfractionated heparin ranged from 1500 to 2500 I.U. Primary study endpoint was 90-day Modified Rankin Scale (mRS). Secondary study endpoint included angiographic and safety endpoints such as hemorrhagic complications. A propensity-score-matched analysis was performed.

Results: Among 369 patients, heparin was used in 68 patients (18.4%). In the propensity-score-matched cohort, favorable outcome (mRS 0-2) occurred in 51.3% in heparin group and 58.0% in non-heparin group (matched OR, 0.76; 95% CI, 0.32-1.78; P = 0.52). Similar result was found in propensity-score-adjusted cohort (adjusted OR, 0.72; 95%CI, 0.39-1.32; P = 0.28). Likewise, there was no difference in the rate of successful reperfusion (mTICI 2b-3) (propensity-score-adjusted OR, 1.03; 95%CI, 0.50-2.09; P = 0.93) neither in safety endpoints between the two groups.

Conclusions: Periprocedural heparin use during EVT of anterior circulation tandem occlusions was not associated with better functional, angiographic or safety outcomes. These findings are applicable for low doses of heparin, and further studies are warranted.
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http://dx.doi.org/10.1007/s00270-019-02251-4DOI Listing
August 2019

Combined intravenous and endovascular treatment versus primary mechanical thrombectomy. The Italian Registry of Endovascular Treatment in Acute Stroke.

Int J Stroke 2019 12 24;14(9):898-907. Epub 2019 May 24.

Stroke Unit, University Hospital "Umberto I", Rome.

Background: Whether mechanical thrombectomy alone may achieve better or at least equal clinical outcome than mechanical thrombectomy combined with intravenous thrombolysis is a matter of debate.

Methods: From the Italian Registry of Endovascular Stroke Treatment, we extracted all cases treated with intravenous thrombolysis followed by mechanical thrombectomy or with primary mechanical thrombectomy for anterior circulation stroke due to proximal vessel occlusion. We included only patients who would have qualified for intravenous thrombolysis. We compared outcomes of the two groups by using multivariate regression analysis and propensity score method.

Results: We included 1148 patients, treated with combined intravenous thrombolysis and mechanical thrombectomy therapy (n = 635; 55.3%), or with mechanical thrombectomy alone (n = 513; 44.7%). Demographic and baseline clinical characteristics did not differ between the two groups, except for a shorter onset to groin puncture time (p < 0.05) in the mechanical thrombectomy group. A shift in the 90-day modified Rankin Scale distributions toward a better outcome was found in favor of the combined treatment (adjusted common odds ratio  = 1.3; 95% confidence interval: 1.04-1.66). Multivariate analyses on binary outcome show that subjects who underwent combined treatment had higher probability to survive with modified Rankin Scale 0-3 (odds ratio = 1.42; 95% confidence interval: 1.04-1.95) and lower case fatality rate (odds ratio = 0.6; 95% confidence interval: 0.44-0.9). Hemorrhagic transformation did not differ between the two groups.

Conclusion: These data seem to indicate that combined intravenous thrombolysis and mechanical thrombectomy could be associated with lower probability of death or severe dependency after three months from stroke due to large vessel occlusion, supporting the current guidelines of treating eligible patients with intravenous thrombolysis before mechanical thrombectomy.
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http://dx.doi.org/10.1177/1747493019851279DOI Listing
December 2019

Carotid Cavernous Fistulas and Dural Arteriovenous Fistulas of the Cavernous Sinus: Validation of a New Classification According to Venous Drainage.

World Neurosurg 2019 Aug 7;128:e621-e631. Epub 2019 May 7.

Neurovascular Interventional Unit, Careggi University Hospital, Florence, Italy.

Background: Multiple carotid cavernous fistula (CCF) classifications have been proposed. However, they lacked predictive factors for the clinical presentation, natural history, and hemorrhagic risk. Our aim was to externally validate a new classification according to venous drainage (i.e., the Thomas classification [TC]) to assess its relationship with symptoms, endovascular treatment, and outcomes.

Methods: We performed a multicenter retrospective review of CCFs at 2 major academic institutions. The CCFs were classified using the Barrow classification (BC) and TC systems.

Results: The data from 94 patients with a diagnosis of CCF were collected during a study period 23 years, 4 months. Of these 94 patients, 89 had undergone CCF treatment and 5 had experienced spontaneous occlusion. Complete occlusion was achieved in 89.9% of the treated patients. Complications occurred in 5.3% of the patients, including permanent deficits in 2.1%. TC type 4 was associated with cortical symptoms compared with type 2 (P = 0.003) and type 3 (P < 0.001). The BC was not able to detect significant differences among the symptom types. Significant differences were found using the TC for the transarterial-only, transvenous anterior-only, and transvenous posterior-only approaches (P < 0.001, P = 0.03, and P = 0.001, respectively). The transvenous posterior and transvenous anterior approach were significantly associated with type 2 and 3 TC, respectively. Excluding direct CCFs, the BC was not related to the treatment approach. No significant differences in the outcomes were found. However, a trend toward a lower occlusion rate for TC type 4 compared with type 3 was observed.

Conclusion: The TC provided useful information regarding the fistula anatomy and venous hemodynamics, which correlated with the clinical symptoms and treatment strategy.
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http://dx.doi.org/10.1016/j.wneu.2019.04.220DOI Listing
August 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

Effect of extracranial lesion severity on outcome of endovascular thrombectomy in patients with anterior circulation tandem occlusion: analysis of the TITAN registry.

J Neurointerv Surg 2019 Oct 6;11(10):970-974. Epub 2019 Mar 6.

Department of Diagnostic and Interventional Neuroradiology, CHRU Nancy, Nancy, France.

Introduction: Endovascular treatment (EVT) for tandem occlusion (TO) of the anterior circulation is complex but effective. The effect of extracranial internal carotid artery (EICA) lesion severity on the outcomes of EVT is unknown. In this study we investigated the effect of EICA lesion severity on the outcomes of tandem occlusion EVT.

Methods: A multicenter retrospective TITAN (Thrombectomy In TANdem lesions) study that included 18 international endovascular capable centers was performed. Patients who received EVT for atherosclerotic TO with or without EICA lesion intervention were included. Patients were divided into two groups based on the EICA lesion severity (high-grade stenosis (≥90% North American Symptomatic Carotid Endarterectomy Trial) vs complete occlusion). Outcome measures included the 90-day clinical outcome (modified Rankin Scale score (mRS)), angiographic reperfusion (modified Thrombolysis In Cerebral Ischemia (mTICI) at the end of the procedure), procedural complications, and intracranial hemorrhage at 24 hours follow-up.

Results: A total of 305 patients were included in the study, of whom 135 had complete EICA occlusion and 170 had severe EICA stenosis. The EICA occlusion group had shorter mean onset-to-groin time (259±120 min vs 305±202 min; p=0.037), more patients with diabetes, and fewer with hyperlipidemia. With respect to the outcome, mTICI 2b-3 reperfusion was lower in the EICA occlusion group (70% vs 81%; p=0.03). The favorable outcome (90-day mRS 0-2), intracerebral hemorrhage and procedural complications were similar in both groups.

Conclusion: Atherosclerotic occlusion of the EICA in acute tandem strokes was associated with a lower rate of mTICI 2b-3 reperfusion but similar functional and safety outcomes when compared with high-grade EICA stenosis.
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http://dx.doi.org/10.1136/neurintsurg-2018-014629DOI Listing
October 2019

Loss of growth hormone-mediated signal transducer and activator of transcription 5 (STAT5) signaling in mice results in insulin sensitivity with obesity.

FASEB J 2019 05 19;33(5):6412-6430. Epub 2019 Feb 19.

Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.

Growth hormone (GH) has an important function as an insulin antagonist with elevated insulin sensitivity evident in humans and mice lacking a functional GH receptor (GHR). We sought the molecular basis for this sensitivity by utilizing a panel of mice possessing specific deletions of GHR signaling pathways. Metabolic clamps and glucose homeostasis tests were undertaken in these obese adult C57BL/6 male mice, which indicated impaired hepatic gluconeogenesis. Insulin sensitivity and glucose disappearance rate were enhanced in muscle and adipose of mice lacking the ability to activate the signal transducer and activator of transcription (STAT)5 the GHR (-391) as for GHR-null () mice. These changes were associated with a striking inhibition of hepatic glucose output associated with altered glycogen metabolism and elevated hepatic glycogen content during unfed state. The enhanced hepatic insulin sensitivity was associated with increased insulin receptor β and insulin receptor substrate 1 activation along with activated downstream protein kinase B signaling cascades. Although phosphoenolpyruvate carboxykinase ()- expression was unchanged, its inhibitory acetylation was elevated because of decreased sirtuin-2 expression, thereby promoting loss of PCK1. Loss of STAT5 signaling to defined chromatin immunoprecipitation targets would further increase lipogenesis, supporting hepatosteatosis while lowering glucose output. Finally, up-regulation of IL-15 expression in muscle, with increased secretion of adiponectin and fibroblast growth factor 1 from adipose tissue, is expected to promote insulin sensitivity.-Chhabra, Y., Nelson, C. N., Plescher, M., Barclay, J. L., Smith, A. G., Andrikopoulos, S., Mangiafico, S., Waxman, D. J., Brooks, A. J., Waters, M. J. Loss of growth hormone-mediated signal transducer and activator of transcription 5 (STAT5) signaling in mice results in insulin sensitivity with obesity.
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http://dx.doi.org/10.1096/fj.201802328RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463913PMC
May 2019

Initial experience with the novel EmboTrap II clot-retrieving device for the treatment of ischaemic stroke.

Interv Neuroradiol 2019 Jun 4;25(3):271-276. Epub 2019 Feb 4.

2 Interventional Neurovascular Unit, Careggi University Hospital, Firenze, Italy.

Introduction: We report our experience with the novel stent-type clot-retrieval device EmboTrap II for the revascularization of large artery occlusions in acute ischaemic stroke.

Materials And Methods: Twenty-nine patients with acute ischaemic stroke due to large artery occlusion underwent mechanical thrombectomy with the new EmboTrap II in two Italian centres. Clinical, procedural and radiological data were collected. Angiographic results and neurological outcomes were analysed.

Results: Only large vessel occlusions were included. Intravenous thrombolysis was administered in 72% of patients. Successful reperfusion (TICI 2b-3) was obtained in 76% of patients treated exclusively with EmboTrap II. No device-related permanent complications occurred.

Conclusion: In our experience, mechanical thrombectomy with EmboTrap II is safe and effective. Reperfusion rate was comparable to that obtained with other stent retrievers.
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http://dx.doi.org/10.1177/1591019918819709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547206PMC
June 2019

Italian census on neurosciences: the ICoNe2 study.

Neurol Sci 2019 Feb 23;40(2):371-376. Epub 2018 Nov 23.

Chief Emeritus Department of Neurology, Iazzolino Hospital, Piazza Alexander Fleming 1, 89900, Vibo Valentia, Italy.

Background: The growing impact of the emergency neurology of trauma centers and of mechanical thrombectomy for the treatment of acute ischemic stroke is revolutionizing the domain of eurosciences.

Methods: A census focused on the demographic distribution of the three main cohorts of neurosciences (neurologists, neuroradiologists, and neurosurgeons) was conducted in Italy between December 2015 and February 2017, and results were compared to the estimated retirement rates and loss for other reasons.

Results: The total number of neurosciences specialists active in Italy was 4394 at the end of the period of the survey. The estimated retirement rates and losses seem not be supplied by the physicians in training in the same period.

Conclusions: A proper redistribution of the resources and the modification of the training programs seem to be mandatory to maintain acceptable standards of care for the Italian neurosciences during the next decade.
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http://dx.doi.org/10.1007/s10072-018-3649-yDOI Listing
February 2019

Left Deep Frontal Cavernous Angioma Mimicking a Glioma in an Adult Patient.

Asian J Neurosurg 2018 Oct-Dec;13(4):1233-1235

Department of Neurosurgery, Careggi University Hospital, Florence, Italy.

Cerebral cavernous angiomas are vascular malformations characterized by large adjacent vessels. Usually, these lesions are smaller than 3 cm, the mean age at presentation occurs between 20 and 40 years, and the neuroradiological findings are well described, especially for magnetic resonance imaging, where the "popcorn balls" appearance is due to the presence of locules containing blood. Among these, the giant cavernous angiomas are very rare, particularly in adults. We collected clinical and neuroradiological data from clinical file and hospital diagnostic archive. A comprehensive review of similar cases was performed. We describe the clinical, diagnostic, and surgical management of a giant cerebral cavernous angioma located in the left deep frontal lobe mimicking a high-grade glioma in an adult Chinese patient. Giant cerebral cavernous angioma may be misdiagnosed and should be considered as differential diagnosis.
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http://dx.doi.org/10.4103/ajns.AJNS_124_17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208243PMC
November 2018

Insulin regulates POMC neuronal plasticity to control glucose metabolism.

Elife 2018 09 19;7. Epub 2018 Sep 19.

Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia.

Hypothalamic neurons respond to nutritional cues by altering gene expression and neuronal excitability. The mechanisms that control such adaptive processes remain unclear. Here we define populations of POMC neurons in mice that are activated or inhibited by insulin and thereby repress or inhibit hepatic glucose production (HGP). The proportion of POMC neurons activated by insulin was dependent on the regulation of insulin receptor signaling by the phosphatase TCPTP, which is increased by fasting, degraded after feeding and elevated in diet-induced obesity. TCPTP-deficiency enhanced insulin signaling and the proportion of POMC neurons activated by insulin to repress HGP. Elevated TCPTP in POMC neurons in obesity and/or after fasting repressed insulin signaling, the activation of POMC neurons by insulin and the insulin-induced and POMC-mediated repression of HGP. Our findings define a molecular mechanism for integrating POMC neural responses with feeding to control glucose metabolism.
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http://dx.doi.org/10.7554/eLife.38704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170188PMC
September 2018

Use of Flow Diversion for the Treatment of Distal Circulation Aneurysms: A Multicohort Study.

World Neurosurg 2018 Oct 17;118:e825-e833. Epub 2018 Jul 17.

Neurosurgical Service, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. Electronic address:

Objective: The safety and efficacy of flow diversion for distal circulation aneurysms of the cerebral vasculature has not been well evaluated. The objective of this study was to assess the use of flow diversion for distal circulation aneurysms (defined as at or beyond the M1, P1, and A1 segments of the middle cerebral artery, posterior cerebral artery, and anterior cerebral artery, respectively) in an international multicenter cohort.

Methods: Clinical and radiologic records from all patients undergoing flow diversion treatment of distal circulation aneurysms at 3 academic centers (2 in the USA and 1 in Europe) from 2014 until 2017 were retrospectively reviewed.

Results: Forty-six patients (mean age, 58.2 years; 33 women) harboring 46 aneurysms who underwent treatment with either the Pipeline Embolization Device (Medtronic Inc., Dublin, Ireland) or the Flow Re-Direction Endoluminal Device (MicroVention, Tustin, California, USA) were included in these analyses. Thirty-four aneurysms (74%) were located in the anterior circulation and 12 (26%) were located in the posterior circulation. With a mean follow-up of 13.0 months, complete (100%) and near-complete (90%-99%) occlusion was noted in 36 aneurysms (78.2%). Angiographic evidence of side branch or perforator vessel coverage was present in 35 aneurysms (76.1%) but was not associated with failure to occlude at follow-up (P = 0.06). All patients had good functional outcomes after treatment (modified Rankin Scale score 0-2). There were 2 cases (4.3%) of perforator vessel stroke and no hemorrhagic complications.

Conclusions: Flow diversion for aneurysms beyond the circle of Willis has occlusion rates comparable to alternative treatments and low morbidity. The clinical significance of flow limitation through covered side branches requires further investigation.
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http://dx.doi.org/10.1016/j.wneu.2018.07.062DOI Listing
October 2018

Carotid Stenting With Antithrombotic Agents and Intracranial Thrombectomy Leads to the Highest Recanalization Rate in Patients With Acute Stroke With Tandem Lesions.

JACC Cardiovasc Interv 2018 07;11(13):1290-1299

Department of Diagnostic and Therapeutic Neuroradiology, University Hospital of Nancy, University of Lorraine, Nancy, France.

Objectives: The aim of this study was to identify the optimal endovascular approach in patients with acute stroke with tandem lesions.

Background: At present, there is no consensus about the ideal technical strategy for the endovascular treatment of patients with acute ischemic stroke with tandem lesions of the extracranial internal carotid artery (ICA) and intracranial cerebral arteries.

Methods: This was an international, multicenter registry with a total of 482 patients with acute ischemic stroke and tandem lesions. Patients were treated by intracranial thrombectomy as well as 1 of the following 4 strategies: 1) acute carotid artery stenting of the extracranial ICA with antithrombotic agents; 2) acute carotid artery stenting of the extracranial ICA without antithrombotic agents; 3) balloon angioplasty of the extracranial ICA; and 4) intracranial thrombectomy alone. The main outcome endpoints of the study were the degree of recanalization and the 90-day clinical outcome. The safety endpoints were symptomatic intracerebral hemorrhage and all causes of mortality at 90 days.

Results: Using univariate analysis, the rates of successful reperfusion (modified Thrombolysis in Cerebral Infarction grades 2B and 3) and favorable clinical outcome after 90 days were significantly higher after acute carotid stenting with antithrombotic therapy and thrombectomy compared with the group with thrombectomy alone. After adjusting for confounding variables, acute stenting with antithrombotic therapy was independently associated with successful recanalization (odds ratio: 2.4; 95% confidence interval: 1.25 to 4.59; p = 0.008). The rates of symptomatic intracerebral hemorrhage and 90-day mortality were comparable among all 4 treatment groups.

Conclusions: Acute stenting of the extracranial ICA with antithrombotic therapy in combination with intracranial thrombectomy is associated with higher recanalization rates in treatment of patients with acute stroke with tandem lesions.
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http://dx.doi.org/10.1016/j.jcin.2018.05.036DOI Listing
July 2018

Bail-out intracranial stenting with Solitaire AB device after unsuccessful thrombectomy in acute ischemic stroke of anterior circulation.

J Neuroradiol 2019 Mar 18;46(2):141-147. Epub 2018 Jun 18.

Neurovascular Interventional Unit, Careggi University Hospital, Florence. Largo P. Palagi, 1-50134 Florence, Italy. Electronic address:

Background: Recent trials established the efficacy of mechanical stent-retriever thrombectomy for treatment of stroke patients with large vessel occlusion (LVO) in the anterior circulation. However, stent-retriever thrombectomy may not accomplish successful recanalization in all patients. The aim of this study is to report the role of bail-out permanent stenting after failure of mechanical thrombectomy.

Methods: Among 430 patients included in a prospectively maintained database, we analysed 325 cases of anterior circulation LVO. Mechanical thrombectomy (mTICI 2b-3) was effective in 213/325 (65%) and failed in 112/325 (35%). Bail-out intracranial stenting was performed in 17/325 (5.2%) patients. In all cases a fully retrievable detachable stent was used (Solitaire AB, Medtronic).

Results: No intraprocedural technical complications occurred. Successful reperfusion (mTICI 2b/3) was achieved in 12/17 patients (70.6%). Three (17.6%) patients died: one extensive infarction in the internal carotid artery territory, one large intracerebral haemorrhage, and one massive pulmonary embolism. Haemorrhagic conversion, both symptomatic and asymptomatic, occurred in 2/17 (11.7%). Good clinical outcome (mRS 0-2) at 3-months was achieved in 41.2% of patients.

Conclusion: Bail-out intracranial stenting after unsuccessful thrombectomy is technically feasible and the associated haemorrhagic risk seems acceptable in selected patients. We suggest that bail-out intracranial stenting, is safe and effective in selected patients with LVO stroke who failed to respond to thrombectomy.
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http://dx.doi.org/10.1016/j.neurad.2018.05.004DOI Listing
March 2019