Publications by authors named "Anna Bersano"

92 Publications

Safety and Outcomes of Intravenous Thrombolytic Therapy in Ischemic Stroke Patients with COVID-19: CASCADE Initiative.

J Stroke Cerebrovasc Dis 2021 Sep 20;30(12):106121. Epub 2021 Sep 20.

Doctor of Medical Science, Professor Doctor of Medical Science, Professor, Department of Medicine, Al-Farabi Kazakh National University. Almaty, Kazakhstan.

Background: There is little information regarding the safety of intravenous tissue plasminogen activator (IV-tPA) in patients with stroke and COVID-19.

Methods: This multicenter study included consecutive stroke patients with and without COVID-19 treated with IV-tPA between February 18, 2019, to December 31, 2020, at 9 centers participating in the CASCADE initiative. Clinical outcomes included modified Rankin Scale (mRS) at hospital discharge, in-hospital mortality, the rate of hemorrhagic transformation. Using Bayesian multiple regression and after adjusting for variables with significant value in univariable analysis, we reported the posterior adjusted odds ratio (OR, with 95% Credible Intervals [CrI]) of the main outcomes.

Results: A total of 545 stroke patients, including 101 patients with COVID-19 were evaluated. Patients with COVID-19 had a more severe stroke at admission. In the study cohort, 85 (15.9%) patients had a hemorrhagic transformation, and 72 (13.1%) died in the hospital. After adjustment for confounding variables, discharge mRS score ≥2 (OR: 0.73, 95% CrI: 0.16, 3.05), in-hospital mortality (OR: 2.06, 95% CrI: 0.76, 5.53), and hemorrhagic transformation (OR: 1.514, 95% CrI: 0.66, 3.31) were similar in COVID-19 and non COVID-19 patients. High-sensitivity C reactive protein level was a predictor of hemorrhagic transformation in all cases (OR:1.01, 95%CI: 1.0026, 1.018), including those with COVID-19 (OR:1.024, 95%CI:1.002, 1.054).

Conclusion: IV-tPA treatment in patients with acute ischemic stroke and COVID-19 was not associated with an increased risk of disability, mortality, and hemorrhagic transformation compared to those without COVID-19. IV-tPA should continue to be considered as the standard of care in patients with hyper acute stroke and COVID-19.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.106121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450304PMC
September 2021

Clinical Management of Moyamoya Patients.

J Clin Med 2021 Aug 17;10(16). Epub 2021 Aug 17.

Cerebrovascular Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.

Moyamoya angiopathy (MMA) is a peculiar cerebrovascular condition characterized by progressive steno-occlusion of the terminal part of the internal carotid arteries (ICAs) and their proximal branches, associated with the development of a network of fragile collateral vessels at the base of the brain. The diagnosis is essentially made by radiological angiographic techniques. MMA is often idiopathic (moyamoya disease-MMD); conversely, it can be associated with acquired or hereditary conditions (moyamoya Syndrome-MMS); however, the pathophysiology underlying either MMD or MMS has not been fully elucidated to date, and this poor knowledge reflects uncertainties and heterogeneity in patient management. MMD and MMS also have similar clinical expressions, including, above all, ischemic and hemorrhagic strokes, then headaches, seizures, cognitive impairment, and movement disorders. The available treatment strategies are currently shared between idiopathic MMD and MMS, including pharmacological and surgical stroke prevention treatments and symptomatic drugs. No pharmacological treatment able to reverse the progressive disappearance of the ICAs has been found to date in both idiopathic and syndromic cases. Antithrombotic agents are usually prescribed in ischemic MMA, although the coexisting hemorrhagic risk should be considered. Surgical revascularization techniques, which are currently the best available treatment in symptomatic MMA, are associated with good long-term outcomes and reduced ischemic and hemorrhagic risks. Given the lack of dedicated randomized clinical trials, current treatment is mainly based on observational studies and physicians' and surgeons' expertise.
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http://dx.doi.org/10.3390/jcm10163628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397113PMC
August 2021

Characteristics of Moyamoya Disease in the Older Population: Is It Possible to Define a Typical Presentation and Optimal Therapeutical Management?

J Clin Med 2021 May 25;10(11). Epub 2021 May 25.

Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.

Whereas several studies have been so far presented about the surgical outcomes in terms of mortality and perioperative complications for elderly patients submitted to neurosurgical treatments, the management of elderly moyamoya patients is unclear. This review aims to explore the available data about the clinical manifestation, characteristics, and outcome after surgery of older patients with moyamoya arteriopathy (MA). We found only two articles strictly concerning elderly patients with MA. We have also evaluated other reported adult series of moyamoya patients, including elderly cases in their analysis. Patients with MA above 50 years old may be considered a peculiar subset in which patients are often presenting with ischemic symptoms and a higher Suzuki grade. Conservative treatment may be proposed in asymptomatic or stable cases due to their fragility and possible increase of post-operative complications, while the best surgical options in symptomatic cases are still under investigation, although we believe that a minimal invasive superficial temporal artery-middle cerebral artery bypass could be considered the treatment of choice for the immediate effect on brain perfusion with a limited rate of post-operative complications.
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http://dx.doi.org/10.3390/jcm10112287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197522PMC
May 2021

Neuro-telehealth for fragile patients in a tertiary referral neurological institute during the COVID-19 pandemic in Milan, Lombardy.

Neurol Sci 2021 Jul 30;42(7):2637-2644. Epub 2021 Apr 30.

Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Background: Lombardy was severely hit by the COVID-19 pandemic since February 2020 and the Health System underwent rapid reorganization. Outpatient clinics were stopped for non-urgent patients: it became a priority to manage hundreds of fragile neurological patients who suddenly had less reference points. In Italy, before the pandemic, Televisits were neither recognized nor priced.

Methods: At the Fondazione IRCCS Istituto Neurologico C. Besta, we reorganized outpatient clinics to deliver Neuro-telemedicine services, including Televisits and Teleneurorehabilitation, since March 2020. A dedicated Working Group prepared the procedure, tested the system, and designed satisfaction questionnaires for adults and children.

Results: After a pilot phase, we prepared a procedure for Telemedicine outpatient clinics which was approved by hospital directions. It included prescription, booking, consenting, privacy and data protection, secure connection with patients (Teams Microsoft 365), electronic report preparation and delivery, reporting, and accountability of the services. During the March-September 2020 period, we delivered 3167 Telemedicine services, including 1618 Televisits, to 1694 patients (972 adults, 722 children) with a wide range of chronic neurological disorders. We successfully administered different clinical assessment and scales. Satisfaction among patients and caregivers was very high.

Conclusions: During the dramatic emergency, we were able to take care of more than 1600 patients by organizing Neuro-telehealth in a few weeks, lessening the impact of the pandemic on fragile patients with chronic neurological disorders; this strategy is now stably embedded in our care pathways. In Italy, Telehealth is at present recognized and priced and is becoming a stable pillar of the health system.
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http://dx.doi.org/10.1007/s10072-021-05252-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086222PMC
July 2021

Authors' reply to Bugiani O: More focus on SENECA with CAA.

Authors:
Anna Bersano

Neurol Sci 2021 06 1;42(6):2589-2590. Epub 2021 Feb 1.

Cerebrovascular Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

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http://dx.doi.org/10.1007/s10072-021-05092-7DOI Listing
June 2021

Clinical Features of Patients With Cervical Artery Dissection and Fibromuscular Dysplasia.

Stroke 2021 Mar 28;52(3):821-829. Epub 2021 Jan 28.

UO Neurologia, Ospedale Villa Sofia, Palermo, Italy (V.T.).

Background And Purpose: Observational studies have suggested a link between fibromuscular dysplasia and spontaneous cervical artery dissection (sCeAD). However, whether patients with coexistence of the two conditions have distinctive clinical characteristics has not been extensively investigated.

Methods: In a cohort of consecutive patients with first-ever sCeAD, enrolled in the setting of the multicenter IPSYS CeAD study (Italian Project on Stroke in Young Adults Cervical Artery Dissection) between January 2000 and June 2019, we compared demographic and clinical characteristics, risk factor profile, vascular pathology, and midterm outcome of patients with coexistent cerebrovascular fibromuscular dysplasia (cFMD; cFMD+) with those of patients without cFMD (cFMD-).

Results: A total of 1283 sCeAD patients (mean age, 47.8±11.4 years; women, 545 [42.5%]) qualified for the analysis, of whom 103 (8.0%) were diagnosed with cFMD+. In multivariable analysis, history of migraine (odds ratio, 1.78 [95% CI, 1.13-2.79]), the presence of intracranial aneurysms (odds ratio, 8.71 [95% CI, 4.06-18.68]), and the occurrence of minor traumas before the event (odds ratio, 0.48 [95% CI, 0.26-0.89]) were associated with cFMD. After a median follow-up of 34.0 months (25th to 75th percentile, 60.0), 39 (3.3%) patients had recurrent sCeAD events. cFMD+ and history of migraine predicted independently the risk of recurrent sCeAD (hazard ratio, 3.40 [95% CI, 1.58-7.31] and 2.07 [95% CI, 1.06-4.03], respectively) in multivariable Cox proportional hazards analysis.

Conclusions: Risk factor profile of sCeAD patients with cFMD differs from that of patients without cFMD. cFMD and migraine are independent predictors of midterm risk of sCeAD recurrence.
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http://dx.doi.org/10.1161/STROKEAHA.120.031579DOI Listing
March 2021

Cutaneous manifestations in Moyamoya angiopathy: A review.

Eur J Neurol 2021 05 1;28(5):1784-1793. Epub 2021 Mar 1.

Department of Neurology, Alfried Krupp von Bohlen und Halbach Hospital, Essen, Germany.

Background And Purpose: Moyamoya angiopathy (MA) is a progressive cerebrovascular disease with a poorly understood pathophysiology. It is mainly characterized by progressive bilateral stenosis of the terminal intracranial part of the supraclinoid internal carotid arteries and the proximal parts of the middle and anterior cerebral arteries. This results in early-onset ischemic or hemorrhagic strokes. The disease may be idiopathic (known as Moyamoya disease) or associated with other heritable or acquired conditions, including type 1 neurofibromatosis or other RASopathies, sickle cell disease, Down syndrome, or autoimmune disorders (known as Moyamoya syndrome). Apart from the brain, other organ manifestations including cutaneous ones have also been described in MA patients.

Materials And Methods: A literature research on PubMed was performed for articles mentioning the cutaneous association in MA and published between 1994 and October 2020.

Conclusion: The present review summarizes the cutaneous associations as well as the coincidental dermatological findings seen in MA patients. Those include changes in the epidermis, dermis, or skin appendages for example café-au-lait spots, hypomelanosis of Ito, livedo racemosa, hemangiomas, premature graying of hair, chilblains etc.
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http://dx.doi.org/10.1111/ene.14754DOI Listing
May 2021

Visual fixation in disorders of consciousness: Development of predictive models to support differential diagnosis.

Physiol Behav 2021 03 4;230:113310. Epub 2021 Jan 4.

Neurology, Public Health, Disability Unit - Coma Research Centre; Scientific Directorate, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, Milan, 20133, Italy. Electronic address:

The visual fixation represents a doubtful behavioral sign to discriminate Vegetative from Minimally Conscious State (MCS). To disentangle its meaning, we fitted univariate and multivariable logistic regression models matching different neurophysiological and neuroimaging data of 54 patients with Disorders of Consciousness to select the best model predicting which visual performance (visual blink or pursuit) was shown by patients and the best predictors set. The best models found highlighted the importance of the structural MRI and the visual evoked potentials data in predicting visual pursuit. Then, a qualitative pilot test was made on four patients showing visual fixation revealing that the obtained models correctly predict whether the patients' visual performance could support/correlate to a cognitively mediated behavior. The present pilot models could help clinicians to evaluate if the visual fixation response can support the MCS diagnosis.
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http://dx.doi.org/10.1016/j.physbeh.2021.113310DOI Listing
March 2021

Stroke care in Italy at the time of the COVID-19 pandemic: a lesson to learn.

J Neurol 2021 Jul 20;268(7):2307-2313. Epub 2020 Sep 20.

Stroke and Dementia Lab, "Luigi Sacco" Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.

From March to May 2020, the Italian health care system, as many others, was almost entirely devoted to the fight against the COVID-19 pandemic. In this context, a number of questions arose, from the increased stroke risk due to COVID-19 infection to the quality of stroke patient care. The overwhelming need of COVID-19 patient management made mandatory a complete re-organization of the stroke pathways: many health professionals were reallocated and a number of stroke units was turned into COVID-19 wards. As a result, acute stroke care suffered from a shortage of services and delays in time-dependent treatments and diagnostic work-up. In-patient and out-patient care and rehabilitation facilities for stroke survivors were also reduced or slowed down, to direct resources to COVID-19 patients care and to reduce contagion risks. Overall, this is likely to result in a significant future increased burden of complications and disabilities that will impact the health care systems in the coming months. Thus, while still fighting against COVID-19 disease, authorities need to promptly implement robust action plans, including an increase of workforce, without forgetting the assurance of a high level of stroke care. The medical community and the health care administrators should always keep in mind that stroke was before, and will be after the pandemic, a, sometimes, life-threatening condition, and almost always a disease with a severe impact on the quality of life.
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http://dx.doi.org/10.1007/s00415-020-10200-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502274PMC
July 2021

Migraine and rare neurological disorders.

Neurol Sci 2020 Dec;41(Suppl 2):439-446

Cerebrovascular Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, 20133, Milan, Italy.

Although migraine is generally considered an idiopathic and isolated neurological condition, it may also represent the presenting symptom of several uncommon heritable and acquired neurological diseases contributing to the recognition of such conditions. Migraine may indeed present with atypical characteristics or prolonged duration and may be associated with specific neuroradiological findings that may help in identifying the underlying condition. However, features of migraine in rare diseases are usually little known because of the lack of systematic studies. The aim of this paper is to provide clinicians with an updated review on specific clinical and neuroradiological features of migraine in uncommon neurological diseases that may be helpful to their diagnosis and treatment. Therefore, the early diagnosis of these uncommon diseases is crucial for patients' clinical management and for the implementation of therapeutic approaches aimed at targeting the underlying disease pathogenic mechanisms. Thus, when investigating patients affected by migraine, physicians should always be aware about rare causes of migraine that if misdiagnosed could seriously impact patients' outcome. Given these relevant implications, future studies specifically assessing features of migraine in uncommon diseases are mandatory.
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http://dx.doi.org/10.1007/s10072-020-04645-6DOI Listing
December 2020

Call to Action: SARS-CoV-2 and CerebrovAscular DisordErs (CASCADE).

J Stroke Cerebrovasc Dis 2020 Sep 8;29(9):104938. Epub 2020 May 8.

Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia.

Background And Purpose: The novel severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), now named coronavirus disease 2019 (COVID-19), may change the risk of stroke through an enhanced systemic inflammatory response, hypercoagulable state, and endothelial damage in the cerebrovascular system. Moreover, due to the current pandemic, some countries have prioritized health resources towards COVID-19 management, making it more challenging to appropriately care for other potentially disabling and fatal diseases such as stroke. The aim of this study is to identify and describe changes in stroke epidemiological trends before, during, and after the COVID-19 pandemic.

Methods: This is an international, multicenter, hospital-based study on stroke incidence and outcomes during the COVID-19 pandemic. We will describe patterns in stroke management, stroke hospitalization rate, and stroke severity, subtype (ischemic/hemorrhagic), and outcomes (including in-hospital mortality) in 2020 during COVID-19 pandemic, comparing them with the corresponding data from 2018 and 2019, and subsequently 2021. We will also use an interrupted time series (ITS) analysis to assess the change in stroke hospitalization rates before, during, and after COVID-19, in each participating center.

Conclusion: The proposed study will potentially enable us to better understand the changes in stroke care protocols, differential hospitalization rate, and severity of stroke, as it pertains to the COVID-19 pandemic. Ultimately, this will help guide clinical-based policies surrounding COVID-19 and other similar global pandemics to ensure that management of cerebrovascular comorbidity is appropriately prioritized during the global crisis. It will also guide public health guidelines for at-risk populations to reduce risks of complications from such comorbidities.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.104938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205703PMC
September 2020

Vascular Remodeling in Moyamoya Angiopathy: From Peripheral Blood Mononuclear Cells to Endothelial Cells.

Int J Mol Sci 2020 Aug 11;21(16). Epub 2020 Aug 11.

Laboratory of Cellular Neurobiology, Neurology IX Unit, UCV, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.

The pathophysiological mechanisms of Moyamoya angiopathy (MA), which is a rare cerebrovascular condition characterized by recurrent ischemic/hemorrhagic strokes, are still largely unknown. An imbalance of vasculogenic/angiogenic mechanisms has been proposed as one possible disease aspect. Circulating endothelial progenitor cells (cEPCs) have been hypothesized to contribute to vascular remodeling of MA, but it remains unclear whether they might be considered a disease effect or have a role in disease pathogenesis. The aim of the present study was to provide a morphological, phenotypical, and functional characterization of the cEPCs from MA patients to uncover their role in the disease pathophysiology. cEPCs were identified from whole blood as CD45CD34CD133 mononuclear cells. Morphological, biochemical, and functional assays were performed to characterize cEPCs. A significant reduced level of cEPCs was found in blood samples collected from a homogeneous group of adult (mean age 46.86 ± 11.7; 86.36% females), Caucasian, non-operated MA patients with respect to healthy donors (HD; = 0.032). Since no difference in cEPC characteristics and functionality was observed between MA patients and HD, a defective recruitment mechanism could be involved in the disease pathophysiology. Collectively, our results suggest that cEPC level more than endothelial progenitor cell (EPC) functionality seems to be a potential marker of MA. The validation of our results on a larger population and the correlation with clinical data as well as the use of more complex cellular model could help our understanding of EPC role in MA pathophysiology.
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http://dx.doi.org/10.3390/ijms21165763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460840PMC
August 2020

Moyamoya disease.

Pract Neurol 2020 Dec 3;20(6):507-508. Epub 2020 Jul 3.

Interventional Neuroradiology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy

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http://dx.doi.org/10.1136/practneurol-2020-002602DOI Listing
December 2020

Visual behaviors in disorders of consciousness: Disentangling conscious visual processing by a multimodal approach.

Eur J Neurosci 2020 11 12;52(10):4345-4355. Epub 2020 Jul 12.

Neurology, Public health, Disability Unit / Coma Research Centre, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

One of the major challenges for clinicians who treat patients with Disorders of Consciousness (DoCs) concerns the detection of signs of consciousness that distinguish patients in Vegetative State from those in Minimally Conscious State. Recent studies showed how visual responses to tailored stimuli are one of the first evidence revealing that one patient is changing from one state to another. This study aimed to explore the integrity of the neural structures being part of the visual system in patients with DoCs manifesting a reflexive behavior (visual blink) and in those manifesting a cognitively and cortically mediated behavior (visual pursuit). We collected instrumental data using specialized equipment (EEG following the rules of the International 10-20 system, 3T Magnetic Resonance, and Positron Emission Tomography) in 54 DoC patients. Our results indicated that visual pursuit group showed a better fVEPs response than the visual blink group, because of a greater area under the N2/P2 component of fVEPs (AUC could be seen as an indicator of the residual activity of visual areas). Considering neuroimaging data, the main structural differences between groups were found in the retrochiasmatic areas, specifically in the right optic radiation and visual cortex (V1), areas statistically less impaired in patients able to perform a visual pursuit. FDG-PET analysis confirmed difference between groups at the level of the right calcarine cortex and neighboring right lingual gyrus. In conclusion, although there are methodological and theoretical limitations that should be considered, our study suggests a new perspective to consider for a future diagnostic protocol.
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http://dx.doi.org/10.1111/ejn.14875DOI Listing
November 2020

Understanding the Pathophysiology of Cerebral Amyloid Angiopathy.

Int J Mol Sci 2020 May 13;21(10). Epub 2020 May 13.

Cerebrovascular Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.

Cerebral amyloid angiopathy (CAA), one of the main types of cerebral small vessel disease, is a major cause of spontaneous intracerebral haemorrhage and an important contributor to cognitive decline in elderly patients. Despite the number of experimental in vitro studies and animal models, the pathophysiology of CAA is still largely unknown. Although several pathogenic mechanisms including an unbalance between production and clearance of amyloid beta (Aβ) protein as well as 'the prion hypothesis' have been invoked as possible disease triggers, they do not explain completely the disease pathogenesis. This incomplete disease knowledge limits the implementation of treatments able to prevent or halt the clinical progression. The continuous increase of CAA patients makes imperative the development of suitable experimental in vitro or animal models to identify disease biomarkers and new pharmacological treatments that could be administered in the early disease stages to prevent irreversible changes and disease progression.
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http://dx.doi.org/10.3390/ijms21103435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279405PMC
May 2020

Long-term outcome of cervical artery dissection : IPSYS CeAD: study protocol, rationale, and baseline data of an Italian multicenter research collaboration.

Neurol Sci 2020 Nov 12;41(11):3265-3272. Epub 2020 May 12.

UO Neurologia, Ospedale Villa Sofia, Palermo, Italy.

Long-term consequences of cervical artery dissection (CeAD), a major cause of ischemic stroke in young people, have been poorly investigated. The Italian Project on Stroke at Young Age - Cervical Artery Dissection (IPSYS CeAD) project is a multicenter, hospital-based, consecutively recruiting, observational, cohort study aimed to address clinically important questions about long-term outcome of CeAD patients, which are not covered by other large-scale registries. Patients with radiologically diagnosed CeAD were consecutively included in the registry. Baseline demographic and clinical variables, as well as information on risk factors, were systematically collected for each eligible patient. Follow-up evaluations were conducted between 3 and 6 months after the initial event (t) and then annually (t at 1 year, t at 2 years , and so on), in order to assess outcome events (long-term recurrent CeAD, any fatal/nonfatal ischemic stroke, transient ischemic attack (TIA), or other arterial thrombotic event, and death from any cause). Between 2000 and 2019, data from 1530 patients (age at diagnosis, 47.2 ± 11.5 years; women, 660 [43.1%]) have been collected at 39 Italian neurological centers. Dissection involved a single vessel in 1308 (85.5%) cases and caused brain ischemia in 1303 (85.1%) (190 TIA/1113 ischemic stroke). Longitudinal data are available for 1414 (92.4%) patients (median follow-up time in patients who did not experience recurrent events, 36.0 months [25th to 75th percentile, 63.0]). The collaborative IPSYS CeAD effort will provide novel information on the long-term outcome of CeAD patients. This could allow for tailored treatment approaches based on patients' individual characteristics.
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http://dx.doi.org/10.1007/s10072-020-04464-9DOI Listing
November 2020

On being a neurologist in Italy at the time of the COVID-19 outbreak.

Neurology 2020 05 3;94(21):905-906. Epub 2020 Apr 3.

From the UO Malattie Cerebrovascolari (A.B.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy; and "Luigi Sacco" Department of Biomedical and Clinical Sciences (L.P.), University of Milan, Milan, Italy.

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http://dx.doi.org/10.1212/WNL.0000000000009508DOI Listing
May 2020

Discovering the Italian phenotype of cerebral amyloid angiopathy (CAA): the SENECA project.

Neurol Sci 2020 Aug 12;41(8):2193-2200. Epub 2020 Mar 12.

Hemorrhagic Stroke Research Program, J. Philip Kistler Stroke Research Center, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Cerebral amyloid angiopathy (CAA) is one of the major types of cerebral small vessel disease, and a leading cause of spontaneous intracerebral hemorrhage and cognitive decline in elderly patients. Although increasingly detected, a number of aspects including the pathophysiology, the clinical and neuroradiological phenotype, and the disease course are still under investigation. The incomplete knowledge of the disease limits the implementation of evidence-based guidelines on patient's clinical management and the development of treatments able to prevent or reduce disease progression. The SENECA (SEarchiNg biomarkErs of Cerebral Angiopathy) project is the first Italian multicenter cohort study aimed at better defining the disease natural history and identifying clinical and neuroradiological markers of disease progression. By a multidisciplinary approach and the collection of a large and well-phenotyped series and biorepository of CAA patients, the study is ultimately expected to improve the diagnosis and the knowledge of CAA pathophysiological mechanisms.
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http://dx.doi.org/10.1007/s10072-020-04306-8DOI Listing
August 2020

PGE Is Crucial for the Generation of FAST Whole- Tumor-Antigens Loaded Dendritic Cells Suitable for Immunotherapy in Glioblastoma.

Pharmaceutics 2020 Mar 2;12(3). Epub 2020 Mar 2.

Cell Therapy Production Unit-UPTC and Cerebrovascular Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.

Dendritic cells (DC) are the most potent antigen-presenting cells, strongly inducers of T cell-mediated immune responses and, as such, broadly used as vaccine adjuvant in experimental clinical settings. DC are widely generated from human monocytes following in vitro protocols which require 5-7 days of differentiation with GM-CSF and IL-4 followed by 2-3 days of activation/maturation. In attempts to shorten the vaccine's production, Fast-DC protocols have been developed. Here we reported a Fast-DC method in compliance with good manufacturing practices for the production of autologous mature dendritic cells loaded with antigens derived from whole tumor lysate, suitable for the immunotherapy in glioblastoma patients. The feasibility of generating Fast-DC pulsed with whole tumor lysate was assessed using a series of small-scale cultures performed in parallel with clinical grade large scale standard method preparations. Our results demonstrate that this Fast protocol is effective only in the presence of PGE in the maturation cocktail to guarantee that Fast-DC cells exhibit a mature phenotype and fulfill all requirements for in vivo use in immunotherapy approaches. Fast-DC generated following this protocol were equally potent to standard DC in inducing Ag-specific T cell proliferation in vitro. Generation of Fast-DC not only reduces labor, cost, and time required for in vitro clinical grade DC development, but can also minimizes inter-preparations variability and the risk of contamination.
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http://dx.doi.org/10.3390/pharmaceutics12030215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150800PMC
March 2020

CADASIL as Multiple Sclerosis Mimic: A 48-year-old man with severe leukoencephalopathy and spinal cord involvement.

Mult Scler Relat Disord 2020 Jun 19;41:102014. Epub 2020 Feb 19.

Unit of Neurology, Neurophysiology, Neurobiology, Department of Medicine, Università Campus Bio-Medico di Roma, Rome, Italy.

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a common cause of inherited stroke in young adults. CADASIL causes extensive white matter T2 hyperintensities at brain MRI, in particular involving anterior-temporal lobes and external capsules; usually, there is no spinal cord involvement. Since CADASIL clinical spectrum is heterogeneous and MRI findings are sometimes not specific, Multiple Sclerosis (MS) represents a frequent CADASIL misdiagnosis. Herein, we describe the case of a 48-year-old man affected by CADASIL and referred to our clinic with an initial diagnosis of secondary progressive MS because of diffuse leukoencephalopathy and spinal cord lesions at MRI.
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http://dx.doi.org/10.1016/j.msard.2020.102014DOI Listing
June 2020

Artery occlusion independently predicts unfavorable outcome in cervical artery dissection.

Neurology 2020 01 22;94(2):e170-e180. Epub 2019 Nov 22.

From the Department of Neurology and Stroke Center (C.T., G.M.D.M., A. Polymeris, H.G., L.H.B., S.T.E., P.L.), University Hospital Basel and University of Basel; Neurorehabilitation Unit (C.T., H.G., S.T.E.), University of Basel and University Center for Medicine of Aging and Rehabilitation, Felix Platter Hospital, Basel, Switzerland; Departments of Neurology (C.G.-G., M.K.) and Vascular and Endovascular Surgery (C.G.-G.), Heidelberg University Hospital, Germany; Department of Neurology (B.G.S., U.F., H.S., M.A.), University Hospital Bern; Ospedale San Giovanni (B.G.S.), Bellinzona, Switzerland; Department of Neurology (T.M.M., T.T.), Helsinki University Central Hospital, Finland; Department of Neurology (S.D.), Bordeaux University Hospital; Inserm U1219 (S.D.), Bordeaux; University of Bordeaux (S.D.), France; Department of Neurology (S.D.), Boston University School of Medicine, MA; Department of Clinical and Experimental Sciences (A.Pezzini.), Neurology Clinic, University of Brescia, Italy; Department of Neurology (J.J.M.), University of Utah, Salt Lake City; Departments of Neurology and Public Health Sciences (A.M.S., B.B.W.), University of Virginia Health System, Charlottesville; Univ-Lille (D.L.), Inserm U1171, CHU Lille, France; Neuro Center (R.B.), Clinic Hirslanden, Zurich, Switzerland; Stroke Unit and Division of Internal and Cardiovascular Medicine (V.C.), University of Perugia, Italy; Centre Hospitalier Universitaire Dijon Bourgogne (Y.B.), EA7460, Pathophysiology and Epidemiology of Cardio-Cerebro-Vascular Diseases, University of Burgundy, Dijon, France; Department of Neurology (H.S.), University Hospital of Zurich, Switzerland; Stroke Theme (V.T.), Florey Institute of Neuroscience and Mental Health, University of Melbourne, Heidelberg; Department of Neurology (V.T.), Austin Health, Heidelberg, Victoria, Australia; Cerebrovascular Unit Fondazione IRCCS Istituto Neurologico Carlo Besta (A.B.), Milan, Italy; Swiss National Accident Insurance Institution (T.B.), Lucerne, Switzerland; Normandie Université (E.T.), Université Caen Normandie, Inserm U1037, Department of Neurology, CHU Caen Normandie; Department of Neurology (E.T.), CH Sainte-Anne, University Paris Descartes, France; Department of Neurology (J.J.M.), Sanatorio Allende, Cordoba, Argentina; Department of Neurology (H.C.), Lariboisière Hospital, Paris, France; Department of Neurology (T.T.), Sahlgrenska University Hospital; and Department of Clinical Neuroscience Institute for Neuroscience and Physiology (T.T.), Sahlgrenska Academy at University of Gothenburg, Sweden.

Objective: To assess the impact of dissected artery occlusion (DAO) on functional outcome and complications in patients with cervical artery dissection (CeAD).

Methods: We analyzed combined individual patient data from 3 multicenter cohorts of consecutive patients with CeAD (the Cervical Artery Dissection and Ischemic Stroke Patients [CADISP]-Plus consortium dataset). Patients with data on DAO and functional outcome were included. We compared patients with DAO to those without DAO. Primary outcome was favorable functional outcome (i.e., modified Rankin Scale [mRS] score 0-1) measured 3-6 months from baseline. Secondary outcomes included delayed cerebral ischemia, major hemorrhage, recurrent CeAD, and death. We performed univariate and multivariable binary logistic regression analyses and calculated odds ratios (OR) with 95% confidence intervals (CI), with adjustment for potential confounders.

Results: Of 2,148 patients (median age 45 years [interquartile range (IQR) 38-52], 43.6% women), 728 (33.9%) had DAO. Patients with DAO more frequently presented with cerebral ischemia (84.6% vs 58.5%, < 0.001). Patients with DAO were less likely to have favorable outcome when compared to patients without DAO (mRS 0-1: 59.6% vs 80.1%, < 0.001). After adjustment for age, sex, and initial stroke severity, DAO was independently associated with less favorable outcome (mRS 0-1: OR 0.65, CI 0.50-0.84, = 0.001). Delayed cerebral ischemia occurred more frequently in patients with DAO than in patients without DAO (4.5% vs 2.9%, = 0.059).

Conclusion: DAO independently predicts less favorable functional outcome in patients with CeAD. Further research on vessel patency, collateral status and effects of revascularization therapies particularly in patients with DAO is warranted.
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http://dx.doi.org/10.1212/WNL.0000000000008654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988986PMC
January 2020

Diagonal earlobe crease (Frank's sign) and increased risk of cerebrovascular diseases: review of the literature and implications for clinical practice.

Neurol Sci 2020 Feb 23;41(2):257-262. Epub 2019 Oct 23.

Division of Neurology, Franz Tappeiner Hospital, Via Rossini, 5, 39012, Merano, BZ, Italy.

Diagonal earlobe crease (DELC) or Frank's sign is a diagonal crease in the earlobe that extends diagonally from the tragus to the edge of the auricle with an angle of approximately 45°. Although its presence increases with advancing age, several studies have shown an independent association between DELC and cardiovascular diseases as well as peripheral vascular diseases. DELC has also been demonstrated to increase the risk of cerebrovascular events (mostly ischaemic stroke), probably through atherosclerotic mechanisms. A systematic literature search was conducted using PubMed and Embase to identify studies investigating the relationship between DELC and the occurrence of cerebrovascular diseases. We identified 5 articles (1469 subjects included). Since the presence of DELC can be easily evaluated, patients with the Frank's sign should undergo a diagnostic workup to detect vascular risk factors and implement preventative therapies.
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http://dx.doi.org/10.1007/s10072-019-04080-2DOI Listing
February 2020

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

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

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

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

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

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

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

Stem cell transplantation for ischemic stroke.

Cochrane Database Syst Rev 2019 05 5;5:CD007231. Epub 2019 May 5.

Department of Neurology, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Via Celoria 11, Milano, Italy, 20133.

Background: Stroke is a leading cause of morbidity and mortality worldwide, with very large healthcare and social costs, and a strong demand for alternative therapeutic approaches. Preclinical studies have shown that stem cells transplanted into the brain can lead to functional improvement. However, to date, evidence for the benefits of stem cell transplantation in people with ischemic stroke is lacking. This is the first update of the Cochrane review published in 2010.

Objectives: To assess the efficacy and safety of stem cell transplantation compared with control in people with ischemic stroke.

Search Methods: We searched the Cochrane Stroke Group Trials Register (last searched August 2018), CENTRAL (last searched August 2018), MEDLINE (1966 to August 2018), Embase (1980 to August 2018), and BIOSIS (1926 to August 2018). We handsearched potentially relevant conference proceedings, screened reference lists, and searched ongoing trials and research registers (last searched August 2018). We also contacted individuals active in the field and stem cell manufacturers (last contacted August 2018).

Selection Criteria: We included randomized controlled trials (RCTs) that recruited people with ischemic stroke, in any phase of the disease (acute, subacute or chronic), and an ischemic lesion confirmed by computerized tomography or magnetic resonance imaging scan. We included all types of stem cell transplantation, regardless of cell source (autograft, allograft, or xenograft; embryonic, fetal, or adult; from brain or other tissues), route of cell administration (systemic or local), and dosage. The primary outcome was efficacy (assessed as neurologic impairment or functional outcome) at longer term follow-up (minimum six months). Secondary outcomes included post-procedure safety outcomes (death, worsening of neurological deficit, infections, and neoplastic transformation).

Data Collection And Analysis: Two review authors independently applied the inclusion criteria, assessed trial quality and risk of bias, and extracted data. If needed, we contacted study authors for additional information. We performed random effects meta-analyses when two or more RCTs were available for any outcome. We assessed the certainty of the evidence by using the GRADE approach.

Main Results: In this updated review, we included seven completed RCTs with 401 participants. All tested adult human non-neural stem cells; cells were transplanted during the acute, subacute, or chronic phase of ischemic stroke; administered intravenously, intra-arterially, intracerebrally, or into the lumbar subarachnoid space. Follow-up ranged from six months to seven years. Efficacy outcomes were measured with the National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), or Barthel Index (BI). Safety outcomes included case fatality, and were measured at the end of the trial.Overall, stem cell transplantation was associated with a better clinical outcome when measured with the NIHSS (mean difference [MD] -1.49, 95% confidence interval [CI] -2.65 to -0.33; five studies, 319 participants; low-certainty evidence), but not with the mRS (MD -0.42, 95% CI -0.86 to 0.02; six studies, 371 participants; very low-certainty evidence), or the BI (MD 14.09, 95% CI -1.94 to 30.13; three studies, 170 participants; very low-certainty evidence). The studies in favor of stem cell transplantation had, on average, a higher risk of bias, and a sample size of 32 or fewer participants.No significant safety concerns associated with stem cell transplantation were raised with respect to death (risk ratio [RR] 0.66, 95% CI 0.39 to 1.14; six studies, participants; low-certainty evidence).We were not able to perform the sensitivity analysis according to the quality of studies, because all of them were at high risk of bias.

Authors' Conclusions: Overall, in participants with ischemic stroke, stem cell transplantation was associated with a reduced neurological impairment, but not with a better functional outcome. No obvious safety concerns were raised. However, these conclusions came mostly from small RCTs with high risk of bias, and the certainty of the evidence ranged from low to very low. More well-designed trials are needed.
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http://dx.doi.org/10.1002/14651858.CD007231.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500737PMC
May 2019

Takotsubo syndrome in Parkinson's disease requires extensive diagnostic workup.

Hellenic J Cardiol 2020 Jan - Feb;61(1):68-69. Epub 2019 Jan 23.

Division Cerebrovascular Disease Unit, IRCCS Foundation "C. Besta", Neurological Institute, Milan, Italy.

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http://dx.doi.org/10.1016/j.hjc.2019.01.007DOI Listing
October 2020

Genetic Imbalance Is Associated With Functional Outcome After Ischemic Stroke.

Stroke 2019 02;50(2):298-304

Center for Genomic Medicine (J.R.), Massachusetts General Hospital, Boston.

Background and Purpose- We sought to explore the effect of genetic imbalance on functional outcome after ischemic stroke (IS). Methods- Copy number variation was identified in high-density single-nucleotide polymorphism microarray data of IS patients from the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) and SiGN (Stroke Genetics Network)/GISCOME (Genetics of Ischaemic Stroke Functional Outcome) networks. Genetic imbalance, defined as total number of protein-coding genes affected by copy number variations in an individual, was compared between patients with favorable (modified Rankin Scale score of 0-2) and unfavorable (modified Rankin Scale score of ≥3) outcome after 3 months. Subgroup analyses were confined to patients with imbalance affecting ohnologs-a class of dose-sensitive genes, or to those with imbalance not affecting ohnologs. The association of imbalance with outcome was analyzed by logistic regression analysis, adjusted for age, sex, stroke subtype, stroke severity, and ancestry. Results- The study sample comprised 816 CADISP patients (age 44.2±10.3 years) and 2498 SiGN/GISCOME patients (age 67.7±14.2 years). Outcome was unfavorable in 122 CADISP and 889 SiGN/GISCOME patients. Multivariate logistic regression analysis revealed that increased genetic imbalance was associated with less favorable outcome in both samples (CADISP: P=0.0007; odds ratio=0.89; 95% CI, 0.82-0.95 and SiGN/GISCOME: P=0.0036; odds ratio=0.94; 95% CI, 0.91-0.98). The association was independent of age, sex, stroke severity on admission, stroke subtype, and ancestry. On subgroup analysis, imbalance affecting ohnologs was associated with outcome (CADISP: odds ratio=0.88; 95% CI, 0.80-0.95 and SiGN/GISCOME: odds ratio=0.93; 95% CI, 0.89-0.98) whereas imbalance without ohnologs lacked such an association. Conclusions- Increased genetic imbalance was associated with poorer functional outcome after IS in both study populations. Subgroup analysis revealed that this association was driven by presence of ohnologs in the respective copy number variations, suggesting a causal role of the deleterious effects of genetic imbalance.
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http://dx.doi.org/10.1161/STROKEAHA.118.021856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441497PMC
February 2019

GEN-O-MA project: an Italian network studying clinical course and pathogenic pathways of moyamoya disease-study protocol and preliminary results.

Neurol Sci 2019 Mar 3;40(3):561-570. Epub 2019 Jan 3.

Stroke Unit, Nuovo Ospedale Civile S Agostino Estense, University Hospital of Modena, Modena, Italy.

Background: GENetics of mOyaMoyA (GEN-O-MA) project is a multicenter observational study implemented in Italy aimed at creating a network of centers involved in moyamoya angiopathy (MA) care and research and at collecting a large series and bio-repository of MA patients, finally aimed at describing the disease phenotype and clinical course as well as at identifying biological or cellular markers for disease progression. The present paper resumes the most important study methodological issues and preliminary results.

Methods: Nineteen centers are participating to the study. Patients with both bilateral and unilateral radiologically defined MA are included in the study. For each patient, detailed demographic and clinical as well as neuroimaging data are being collected. When available, biological samples (blood, DNA, CSF, middle cerebral artery samples) are being also collected for biological and cellular studies.

Results: Ninety-eight patients (age of onset mean ± SD 35.5 ± 19.6 years; 68.4% females) have been collected so far. 65.3% of patients presented ischemic (50%) and haemorrhagic (15.3%) stroke. A higher female predominance concomitantly with a similar age of onset and clinical features to what was reported in previous studies on Western patients has been confirmed.

Conclusion: An accurate and detailed clinical and neuroimaging classification represents the best strategy to provide the characterization of the disease phenotype and clinical course. The collection of a large number of biological samples will permit the identification of biological markers and genetic factors associated with the disease susceptibility in Italy.
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http://dx.doi.org/10.1007/s10072-018-3664-zDOI Listing
March 2019
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