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Five-year glioblastoma (GBM) survivors (LTS) are the minority of the isocitrate dehydrogenase (IDH)-wild-type GBM patients, and their molecular fingerprint is still largely unexplored. This multicenter retrospective study analyzed a large LTS-GBM cohort from nine Italian institutions and molecularly characterized a subgroup of patients by mutation, DNA methylation (DNAm) and copy number variation (CNV) profiling, comparing it to standard survival GBM. Mutation scan allowed the identification of pathogenic variants in most cases, showing a similar mutational spectrum in both groups, and highlighted TP53 as the most commonly mutated gene in the LTS group. We confirmed DNAm as a valuable tool for GBM classification with a diagnostic refinement by using brain tumor classifier v12.5. LTS were more heterogeneous with more cases classified as diffuse pediatric high-grade glioma subtypes and having peculiar CNVs. We observed a global higher methylation in CpG islands and in gene promoters of LTS with methylation levels of distinct gene promoters correlating with prognosis., Competing Interests: Declaration of competing interest The authors declared that have no competing interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: The transmission of amyloid β (Aβ) in humans leading to iatrogenic cerebral amyloid angiopathy (iCAA) is a novel concept with analogies to prion diseases. However, the number of published cases is low, and larger international studies are missing., Aims: We aimed to build a large multinational collaboration on iCAA to better understand the clinical spectrum of affected patients., Methods: We collected clinical data on patients with iCAA from Austria, Croatia, Italy, Slovenia, and Spain. Patients were included if they met the proposed Queen Square diagnostic criteria (QSC) for iCAA. In addition, we pooled data on disease onset, latency, and cerebrospinal fluid (CSF) biomarkers from previously published iCAA cases based on a systematic literature review., Results: Twenty-seven patients (22% women) were included in this study. Of these, 19 (70%) met the criteria for probable and 8 (30%) for possible iCAA. Prior neurosurgical procedures were performed in all patients (93% brain surgery, 7% spinal surgery) at median age of 8 (interquartile range (IQR) = 4-18, range = 0-26 years) years. The median symptom latency was 39 years (IQR = 34-41, range = 28-49). The median age at symptom onset was 49 years (IQR = 43-55, range = 32-70). Twenty-one patients (78%) presented with intracranial hemorrhage and 3 (11%) with seizures., Conclusions: Our large international case series of patients with iCAA confirms a wide age boundary for the diagnosis of iCAA. Dissemination of awareness of this rare condition will help to identify more affected patients., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: COVID-19 pandemic had a great impact on outcome in SARS-CoV-2 positive patients with ischemic stroke during the first wave in Italy. Few data are available on outcome stratified by sex., Methods: The Italian Society of Hospital Neuroscience conducted a multi-center, retrospective, observational study on neurological complications in COVID-19 patients with ischemic stroke. All the patients admitted from March 1st to April 30th, 2020 in 20 Neurology Units in Northern Italy were recruited. Demographical and clinical features, treatment and outcome data were compared focusing on sex differences., Results: 812 patients with ischemic stroke were enrolled, of whom 129 with COVID-19; males were 53.8%. In-hospital mortality in COVID-19 patients was 35.3% in males and 27.9% in females while 8.5% in male and 5.8% in female patients without COVID-19. SARS-CoV-2 positive patients had a higher frequency of stroke of undetermined etiology, than negative ones (32.8% vs 22.5%; p = 0.02), especially in females compared to males (36.1% vs 27.9%), albeit without statistical significance. Male patients with SARS-CoV-2 were more likely to require cPAP (30.9% vs 14.8%; p = 0.03), endotracheal tube (14.9% vs 3.3%; p = 0.02) and reperfusion strategies (29.4% vs 11.5%; p = 0.01) than females, as well as to have a higher CRP and D-dimer. These elements together with older age, a total anterior circulation stroke and lymphopenia were predictors of a worse outcome., Discussion: Our study detected some differences due to sex in ischemic stroke with and without COVID-19, supporting the possibility to perform sex analyses for SARS-CoV-2 positive patients for a better clinical management., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Heart failure (HF) is the second most important cardiac risk factor for stroke after atrial fibrillation (AF). Few data are available on mechanical thrombectomy (MT) in acute ischemic stroke (AIS) patients with HF., Methods: The source of data is the multicentre Italian Registry of Endovascular Treatment in Acute Stroke (IRETAS). All AIS patients ≥ 18 years receiving MT were categorised in two groups: HF and no-HF. Baseline clinical and neuroradiological findings on admission were analysed., Results: Of 8924 patients, 642 (7.2%) had HF. Compared to the no-HF group, HF patients had higher prevalence of cardiovascular risk factors. Rate of complete recanalisation (TICI 2b-3) was 76.9% in HF vs 78.1% in no-HF group (p = 0.481). Rate of symptomatic intracerebral haemorrhage at 24-h non-contrast computed tomography (NCCT) was 7.6% in HF vs 8.3% in no-HF patients (p = 0.520). At 3 months, 36.4% of HF patients and 48.2% of no-HF patients (p < 0.001) had mRS 0-2, and mortality was, respectively, 30.7% and 18.5% (p < 0.001). In multivariate logistic regression, HF was independently associated with mortality at 3 months (OR 1.53, 1.24-1.88 95% CI, p < 0.001). In multivariate ordinal regression, HF patients had a probability of transitioning to a higher mRS level of 1.23 (1.05-1.44 95% CI, p = 0.012). The propensity score analysis of two groups matched for age, sex, and NIHSS at admission yielded the same results., Conclusion: MT is safe and effective in HF patients with AIS. Patients with HF and AIS suffered from higher 3-month mortality and unfavourable outcome regardless of acute treatments., (© 2023. Fondazione Società Italiana di Neurologia.)

Introduction: Allgrove syndrome is a genetic disorder characterized by a multisystem involvement manifesting mainly in childhood with esophageal achalasia, adrenal insufficiency, and alacrima. Associated neurological manifestations are frequent in patients with late-onset forms and include peripheral, central, and autonomic dysfunction. The definitive diagnosis remains genetic, but neurological symptoms/signs could be a relevant clue for the diagnosis., Discussion: This syndrome is rare, but it is not impossible for it to occur in adults, so all neurologists must be alert. Moreover, in this regard, neurological symptoms can sometimes be very similar to those of motor neuron disease patients, so that, although rare, Allgrove syndrome may also enter into the differential diagnosis with the bulbar variant of amyotrophic lateral sclerosis. Nevertheless, attention to extra-neurological symptoms must remain high as these play an equally important role in reaching the diagnosis., Case Report: Here we present the case of a patient with some peculiarities that are onset at an advanced age, genetic confirmation of the diagnosis, and prominent neurological involvement, which also opens the differential diagnosis to amyotrophic lateral sclerosis., (© 2023. Fondazione Società Italiana di Neurologia.)

Background and Purpose: Aim of this study was to evaluated anxiety, depression, and possible negative implications on work activities during the Sars-CoV-2 pandemic, in a group of Multiple Sclerosis (MS) patients at risk of flu-like syndrome (FLS) compared with FLS- free treatments., Methods: The present study included patients treated with interferon-ß (IFNß), glatiramer, and natalizumab for at least one year. Collected data included the diagnosis of COVID-19 infection, Beck Depression Inventory-II (BDI-II), Beck Anxiety Inventory (BAI), together with questions about FLS, change in work habits, use of antipyretics, anxiety, and depression., Results: 100 patients were included in the study. Six patients in IFNß and 5 in the natalizumab group had a confirmed COVID-19 infection. 68% in the IFNß patients reported FLS and only one reported an increase in flu-like frequency during the pandemic; 14% reported lower compliance with treatment, and 40% reported uptake of antipyretics several times. Only one IFNß patient reported having lost more working days than the previous year. The average BAI (p = 0.039) was higher in natalizumab group. Correcting these data by age, sex and EDSS to a multivariate analysis we did not find any statistically significant difference in terms of BAI and BDI-II between the three treatment groups., Conclusions: FLS were not perceived as COVID19-like symptoms but as expected by traditional pharmacological treatments indeed. These data suggest that IFNß can be used safely., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

I n the context of an adequate health care organization, the figure of the neurologist as an emergency operator (in the emergency room-ER-and/or in a dedicated outpatient clinic) is crucial for an effective functional connection with the territory (and therefore with general practitioners), a reduction in inappropriate ER accesses, specific diagnostic and therapeutic approaches to neurological emergencies in the ER and a reduction in nonspecific or even unnecessary instrumental investigations. In this position paper of the Italian Association of Emergency Neurology (ANEU: Associazione Neurologia dell'Emergenza Urgenza), these issues are addressed, and two important organizational solutions are proposed: 1) The Neuro Fast Track, as an outpatient organization approach strongly linked to general practitioners and non-neurological specialists and dedicated to cases with deferrable urgency (to be assessed within 72 h) 2) The identification of an emergency neurologist, who is engaged in ER assessments as a consultant and involved in the management of the semi-intensive care unit of the emergency neurology and the stroke unit according to an appropriate rotation, as well as in consultations for patients with neurological emergencies in inpatient wards The possibility of computerizing the screening of patients with deferrable urgency in the Neuro Fast Track is described. A dedicated app represents an important tool that can facilitate the identification of patients for whom deferred assessment is appropriate, the scheduling of neurological examinations and reductions in the booking time through a more rapid approach to specialist assessment and subsequent investigations., (© 2023. Fondazione Società Italiana di Neurologia.)

Background: In 2017, the European Association for Neuro-Oncology (EANO) published the guideline for palliative care (PC) in adults with glioma. The Italian Society of Neurology (SIN), the Italian Association for Neuro-Oncology (AINO), and the Italian Society for Palliative Care (SICP) joined forces to update and adapt this guideline to the Italian context and aimed to involve patients and carers in the formulation of the clinical questions., Methods: During semi-structured interviews with glioma patients and focus group meetings (FGMs) with family carers of deceased patients, participants rated the importance of a set of pre-specified intervention topics, shared their experience, and suggested additional topics. Interviews and FGMs were audio-recorded, transcribed, coded, and analyzed (framework and content analysis)., Results: We held 20 interviews and five FGMs (28 carers). Both parties considered the pre-specified topics as important, chiefly information/communication, psychological support, symptoms management, and rehabilitation. Patients aired the impact of focal neurological and cognitive deficits. Carers reported difficulties in dealing with patient's behavior and personality changes and appreciated the preservation of patient's functioning via rehabilitation. Both affirmed the importance of a dedicated healthcare path and patient's involvement in the decision-making process. Carers expressed the need to be educated and supported in their caregiving role., Conclusions: Interviews and FGMs were well informative and emotionally challenging. Both parties confirmed the importance of the pre-specified topics, and carers suggested one additional topic: education/support to caregivers. Our findings strengthen the importance of a comprehensive care approach and of addressing the needs of both patients and their family carers., (© 2023. Fondazione Società Italiana di Neurologia.)

Metastatic brain disease (MBD) has seen major advances in clinical management, focal radiation therapy approaches and knowledge of biological factors leading to improved prognosis. Extracellular vesicles (EVs) have been found to play a role in tumor cross-talk with the target organ, contributing to the formation of a premetastatic niche. Human lung and breast cancer cell lines were characterized for adhesion molecule expression and used to evaluate their migration ability in an in vitro model. Conditioned culture media and isolated EVs, characterized by super resolution and electron microscopy, were tested to evaluate their pro-apoptotic properties on human umbilical vein endothelial cells (HUVECs) and human cerebral microvascular endothelial cells (HCMEC/D3) by annexin V binding assay. Our data showed a direct correlation between expression of ICAM1, ICAM2, β3-integrin and α2-integrin and the ability to firmly adhere to the blood-brain barrier (BBB) model, whereas the same molecules were down-regulated at a later step. Extracellular vesicles released by tumor cell lines were shown to be able to induce apoptosis in HUVEC while brain endothelial cells showed to be more resistant.

Background: In 2017, the European Association of Neuro-Oncology (EANO) published the guideline for palliative care in adults with glioma. The Italian Society of Neurology (SIN), the Italian Society for Palliative Care (SICP), and the Italian Association for Neuro-Oncology (AINO) joined forces to update the guideline, and adapt it to the Italian context., Aim: We involved patients, caregivers, and (herein presented) healthcare professionals (HPs) in the formulation of the guideline clinical questions., Design and Participants: Online survey of Italian HPs experienced in the care of patients with glioma. Participants rated the importance of 14 pre-specified intervention topics on a 0/10 scale and gave their free comments., Results: Of 244 participants, 149 (61%) were palliative medicine (PM) HPs and 95 Neuro HPs. Their mean age was 48.9 years, 63% were women, and 48% had over 12 years of experience in the care of glioma patients. Physicians were 68%, followed by nurses (28%), psychologists (7%), therapists (3%), and social workers (2%). Most HPs rated the pre-specified topics as important (score ≥ 7) or critical (score ≥ 9), with some differences between PM and Neuro HP groups. There were 58 free comments: 46 (78%) on nine pre-specified topics, and 13 on four new topics, three of which were guideline-pertinent ("caregiver's support and education"; "family physician's training in neuro-oncology"; and "PM HPs' training in neuro-oncology")., Conclusions: Participation in the survey was high and information-rich, between-group rating differences reflecting HP background. Participants endorsed the 14 intervention topics devised by the guideline panel and identified three additional topics., (© 2023. Fondazione Società Italiana di Neurologia.)

Epilepsy is the most common symptom in patients with brain tumors. The shared genetic, molecular, and cellular mechanisms between tumorigenesis and epileptogenesis represent 'two sides of the same coin'. These include augmented neuronal excitatory transmission, impaired inhibitory transmission, genetic mutations in the BRAF, IDH, and PIK3CA genes, inflammation, hemodynamic impairments, and astrocyte dysfunction, which are still largely unknown. Low-grade developmental brain tumors are those most commonly associated with epilepsy. Given this strict relationship, drugs able to target both seizures and tumors would be of extreme clinical usefulness. In this regard, anti-seizure medications (ASMs) are optimal candidates as they have well-characterized effects and safety profiles, do not increase the risk of developing cancer, and already offer well-defined seizure control. The most important ASMs showing preclinical and clinical efficacy are brivaracetam, lacosamide, perampanel, and especially valproic acid and levetiracetam. However, the data quality is low or limited to preclinical studies, and results are sometimes conflicting. Future trials with a prospective, randomized, and controlled design accounting for different prognostic factors will help clarify the role of these ASMs and the clinical setting in which they might be used. In conclusion, brain tumor-related epilepsies are clear examples of how close, multidisciplinary collaborations among investigators with different expertise are warranted for pursuing scientific knowledge and, more importantly, for the well-being of patients needing targeted and effective therapies., Competing Interests: Declaration of Competing Interest EA has received honoraria for lectures or advisory boards from UCB and Novartis.AC received support by EISAI pharmaceutical Company for the PERADET STUDY (Investigator Initiated Study 2015). She also received speakers' honoraria from EISAI and Jazz pharmaceuticals, advisory board honoraria from BIAL, and consultant honoraria from EISAI, JAZZ, and UCB. CC has received research support, speaker honoraria, and travel expenses from Bial, Eisai Europe Limited, GW Pharma, Lusopharma, PIAM Pharma, and UCB Pharma. ER has received speaker fees or funding and has participated in advisory boards for Arvelle Therapeutics, Angelini, Eisai, Kolfarma, JAZZ pharmaceuticals, Pfizer, GW Pharmaceuticals, UCB, and Lundbeck. FP is a strict collaborator of Polistudium Srl. AS declares no conflict of interest. MM and EC declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Cerebral amyloid angiopathy (CAA) is a small vessel disease, causing spontaneous intracerebral hemorrhage (ICH) in the elderly. It is strongly associated with Alzheimer disease (AD), as most CAA patients show deposition of Aβ-i.e. the basic component of parenchymal Alzheimer amyloid deposits-in the cerebral vessels. Iatrogenic early-onset CAA has been recently identified in patients with a history of traumatic brain injury or other cerebral as well as extra-cerebral lesions that led to neurosurgery or other medical procedures as intravascular embolization by cadaveric dura mater extracts many years before the first ICH event. In those patients, a transmission of Aβ seeds from neurosurgical instruments or from cadaveric dura mater exposure was suggested. We report a 51-year-old woman with unremarkable family history who presented abruptly with aphasia and right hemiparesis. A cerebral left lobar haemorrhagic stroke was documented by neuroimaging. Accurate anamnesis revealed a neurosurgical procedure with cadaveric dura mater graft at the age of 2 years for an arachnoid cyst. The neuropathological examination of the cerebral parietal biopsy showed severe amyloid angiopathy in many leptomeningeal and cortical vessels, as well as abundant parenchymal Aβ deposits, neurofibrillary tangles and neuropil threads. The mechanism involved in the human-to-human transmission of the Aβ proteinopathy remains to be clarified. In our patient the cadaver derived dura used for grafting is a very strong candidate as the source of the transmission. A systematic monitoring of individuals who have had neurosurgical procedures in early life, especially those involving cadaveric dural grafts, is required to determine the ratio of those affected by CAA many years later and unaffected. Moreover, our report confirms that in addition to vascular and parenchymal Aβ pathology, neurofibrillary changes indistinguishable from AD may develop in specific conditions with long latency period from the neurosurgical or embolization procedure., (© 2023. The Author(s).)

Objective: To estimate the incidence and describe clinical characteristics and outcome of GBS in COVID-19 patients (COVID19-GBS) in one of the most hit regions during the first pandemic wave, Lombardia., Methods: Adult patients admitted to 20 Neurological Units between 1/3-30/4/2020 with COVID19-GBS were included as part of a multi-center study organized by the Italian society of Hospital Neuroscience (SNO)., Results: Thirty-eight COVID19-GBS patients had a mean age of 60.7 years and male frequency of 86.8%. CSF albuminocytological dissociation was detected in 71.4%, and PCR for SARS-CoV-2 was negative in 19 tested patients. Based on neurophysiology, 81.8% of patients had a diagnosis of AIDP, 12.1% of AMSAN, and 6.1% of AMAN. The course was favorable in 76.3% of patients, stable in 10.5%, while 13.2% worsened, of which 3 died. The estimated occurrence rate in Lombardia ranges from 0.5 to 0.05 GBS cases per 1000 COVID-19 infections depending on whether you consider positive cases or estimated seropositive cases. When we compared GBS cases with the pre-pandemic period, we found a reduction of cases from 165 to 135 cases in the 2-month study period in Lombardia., Conclusions: We detected an increased incidence of GBS in COVID-19 patients which can reflect a higher risk of GBS in COVID-19 patients and a reduction of GBS events during the pandemic period possibly due to a lower spread of more common respiratory infectious diseases determined by an increased use of preventive measures., (© 2022. The Author(s).)

Background: Since the outbreak, in 2019, of COVID-19, the world has experienced marked changes in daily habits, partly reflecting the exceptional social restrictions and health measures adopted to contain the disease. All these measures significantly affected not only peoples's daily lives and psychological well-being but also the possibility for the healthcare system to function properly. In this setting, brain tumour patients were at risk due to their higher physical and mental fragility and their need for regular care. The aim of the present study was to assess, using a self-reported online questionnaire, the patients's perceptions regarding their disease experience., Materials and Methods: We developed an online anonymous self-report survey to assess patients's disease experience during the pandemic. We investigated the impact of the COVID-19 pandemic on patients's cancer care schedules, their psychological distress and emotions felt during the pandemic, their levels of worry about COVID-19, and their oncological conditions., Results: 107 patients answered our survey, most of them suffering from a glioma. Less than one-third of the sample had their appointments cancelled, delayed or converted into online visits due to the pandemic. Of the patients who answered the survey, 95% declared they were satisfied with their Institute's oncological management. The feelings reported most often were peacefulness or anxiety/worry; the majority of the sample reported high levels of loneliness, which tended to increase with age, whilst the psychological distress was correlated with age and with having a recurrence of the disease. Half of the sample declared severe worry about their oncological condition, in particular subjects with a recurrence or who were receiving adjuvant therapies. Patients with recurrence tended to worry more about the possibility of contracting COVID-19, and its effects., Conclusion: Our findings illustrate how fragile and in need of care patients with a brain tumour may be, especially those with more severe clinical conditions. These data may help boost healthcare professionals's knowledge about brain tumour patients's needs and fears, so as to be able to offer them a better hospital experience and improve their clinical management, while possibly also reducing the psychological burden on patients and their families., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflict of interest., (Copyright © 2023 Giorgia, Francesca, Fabiana, Jennifer, Adriana, Antonella, Marco, Andrea, Andrea, Ilaria and Manuela.)

Background: SARS-COV-2 infection has been associated to long-lasting neuropsychiatric sequelae, including cognitive deficits, that persist after one year. However, longitudinal monitoring has been scarcely performed. Here, in a sample of COVID-19 patients, we monitor cognitive, psychological and quality of life-related profiles up to 22 months from resolution of respiratory disease., Methods: Out of 657 COVID-19 patients screened at Manzoni Hospital (Lecco, Italy), 22 underwent neuropsychological testing because of subjective cognitive disturbances at 6 months, 16 months, and 22 months. Tests of memory, attention, and executive functions were administered, along with questionnaires for depressive and Post-traumatic stress disorder (PTSD) symptoms, psychological well-being and quality of life. Cross-sectional descriptives, correlational, as well as longitudinal analyses considering COVID19-severity were carried out. A preliminary comparison with a sample of obstructive sleep apneas patients was also performed., Results: Around 50% of COVID-19 patients presented with cognitive deficits at t0. The most affected domain was verbal memory. Pathological scores diminished over time, but a high rate of borderline scores was still observable. Longitudinal analyses highlighted improvements in verbal and non-verbal long term memory, as well as attention, and executive functioning. Depression and PTSD-related symptoms were present in 30% of patients. The latter decreased over time and were associated to attentional-executive performance., Conclusions: Cognitive dysfunctions in COVID-19 patients may extend over 1 year, yet showing a significant recovery in several cases. Cognitive alterations are accompanied by a significant psychological distress. Many patients displaying borderline scores, especially those at higher risk of dementia, deserve clinical monitoring., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: The assessment of human and diagnostic resources is a prerequisite to improving the management of emergency neurology., Objective: To provide a landscape on the organization of the Lombardy Region hospitals for emergency neurological care management., Methods: We designed an anonymized questionnaire including 6 sections with 21 questions on facilities, human and diagnostic resources, and intra- and between-hospital connections. The time needed to fill the questionnaire was estimated not to exceed 6 min., Results: The questionnaire was returned by 33/41 (80.5%) hospitals, 22 classified as level 1 (spoke), and 11 as level 2 (hub). Five of 33 (15%) did not have a neurology unit. The mean annual rate of neurological consultations accounted for 5-6% of all admissions (range 2-8%) and did not differ between levels 1 and 2 hospitals. Neurologists were 24-h available in 21/33 (64%) hospitals, 12-h and on call at night in 6 (18%), less than 12 h without nocturnal availability in 5 (15%), and neither present nor available in 1 (3%). Brain CT and CSF examinations were 24-h universally available, whereas EEG and neurosonology were not in most hospitals. Despite angio-CT was 24-h available in more than 75% of the hospitals, only 45% of them had 24-h availability of diffusion/perfusion imaging, and 43% were not available at any time. Only 12% of the hospitals had 24-h availability of neuroradiologists and 6% of interventional neuroradiologists., Conclusion: Our data, while emphasizing current critical issues, offer clues for identifying priorities and improving the management of emergency and time-dependent neurological diseases., (© 2022. Fondazione Società Italiana di Neurologia.)

Background and Purpose: Recent studies suggested an increased incidence of cerebral venous thrombosis (CVT) during the coronavirus disease 2019 (COVID-19) pandemic. We evaluated the volume of CVT hospitalization and in-hospital mortality during the 1st year of the COVID-19 pandemic compared to the preceding year., Methods: We conducted a cross-sectional retrospective study of 171 stroke centers from 49 countries. We recorded COVID-19 admission volumes, CVT hospitalization, and CVT in-hospital mortality from January 1, 2019, to May 31, 2021. CVT diagnoses were identified by International Classification of Disease-10 (ICD-10) codes or stroke databases. We additionally sought to compare the same metrics in the first 5 months of 2021 compared to the corresponding months in 2019 and 2020 (ClinicalTrials.gov Identifier: NCT04934020)., Results: There were 2,313 CVT admissions across the 1-year pre-pandemic (2019) and pandemic year (2020); no differences in CVT volume or CVT mortality were observed. During the first 5 months of 2021, there was an increase in CVT volumes compared to 2019 (27.5%; 95% confidence interval [CI], 24.2 to 32.0; P<0.0001) and 2020 (41.4%; 95% CI, 37.0 to 46.0; P<0.0001). A COVID-19 diagnosis was present in 7.6% (132/1,738) of CVT hospitalizations. CVT was present in 0.04% (103/292,080) of COVID-19 hospitalizations. During the first pandemic year, CVT mortality was higher in patients who were COVID positive compared to COVID negative patients (8/53 [15.0%] vs. 41/910 [4.5%], P=0.004). There was an increase in CVT mortality during the first 5 months of pandemic years 2020 and 2021 compared to the first 5 months of the pre-pandemic year 2019 (2019 vs. 2020: 2.26% vs. 4.74%, P=0.05; 2019 vs. 2021: 2.26% vs. 4.99%, P=0.03). In the first 5 months of 2021, there were 26 cases of vaccine-induced immune thrombotic thrombocytopenia (VITT), resulting in six deaths., Conclusions: During the 1st year of the COVID-19 pandemic, CVT hospitalization volume and CVT in-hospital mortality did not change compared to the prior year. COVID-19 diagnosis was associated with higher CVT in-hospital mortality. During the first 5 months of 2021, there was an increase in CVT hospitalization volume and increase in CVT-related mortality, partially attributable to VITT.

Objective: To characterize patients with acute ischemic stroke related to SARS-CoV-2 infection and assess the classification performance of clinical and laboratory parameters in predicting in-hospital outcome of these patients., Methods: In the setting of the STROKOVID study including patients with acute ischemic stroke consecutively admitted to the ten hub hospitals in Lombardy, Italy, between March 8 and April 30, 2020, we compared clinical features of patients with confirmed infection and non-infected patients by logistic regression models and survival analysis. Then, we trained and tested a random forest (RF) binary classifier for the prediction of in-hospital death among patients with COVID-19., Results: Among 1013 patients, 160 (15.8%) had SARS-CoV-2 infection. Male sex (OR 1.53; 95% CI 1.06-2.27) and atrial fibrillation (OR 1.60; 95% CI 1.05-2.43) were independently associated with COVID-19 status. Patients with COVID-19 had increased stroke severity at admission [median NIHSS score, 9 (25th to75th percentile, 13) vs 6 (25th to75th percentile, 9)] and increased risk of in-hospital death (38.1% deaths vs 7.2%; HR 3.30; 95% CI 2.17-5.02). The RF model based on six clinical and laboratory parameters exhibited high cross-validated classification accuracy (0.86) and precision (0.87), good recall (0.72) and F1-score (0.79) in predicting in-hospital death., Conclusions: Ischemic strokes in COVID-19 patients have distinctive risk factor profile and etiology, increased clinical severity and higher in-hospital mortality rate compared to non-COVID-19 patients. A simple model based on clinical and routine laboratory parameters may be useful in identifying ischemic stroke patients with SARS-CoV-2 infection who are unlikely to survive the acute phase., (© 2021. The Author(s).)

Introduction: Mutations of the skeletal muscle sodium channel gene SCN4A are associated with several neuromuscular disorders including hyper/hypokaliemic periodic paralysis, paramyotonia congenita and sodium channel myotonia. These disorders are distinguished from dystrophic myotonias by the absence of progressive weakness and extramuscular systemic involvement., Methods: We present an Italian family with 2 subjects carrying a p.Asn1180Ile mutation in SCN4A gene showing a peculiar clinical picture characterized by the association of myopathic features and myotonia., Results: The clinical, electromyographic and histological findings of these patients are reported. The possible pathogenicity of the mutation was tested by three different software, all giving positive results., Discussion: This is the first report of a dominant, heterozygous mutation in SCN4A causing a complex phenotype of non-congenital myopathy and myotonic syndrome. We suggest that, in patients with myotonia and myopathy not related to dystrophic myotonias, the sequence analysis of SCN4A gene should be performed., (© 2021. Fondazione Società Italiana di Neurologia.)

Introduction: The simultaneous presence of multiple foci of high-grade glioma is a rare condition with a poor prognosis. By definition, if an anatomical connection through white matter bundles cannot be hypothesized, multiple lesions are defined as multicentric glioma (MC); on the other hand, when this connection exists, it is better defined as multifocal glioma (MF). Whether surgery can be advantageous for these patients has not been established yet. The aim of our study was to critically review our experience and to compare it to the existing literature., Materials and Methods: Retrospective analysis of patients operated on for MC HGG in two Italian institutions was performed. Distinction between MC and MF was achieved through revision of MR FLAIR images. Clinical and radiological preoperative and postoperative data were analyzed through chart revision and phone interviews. The same data were extracted from literature review. Univariate and multivariate analyses were conducted for the literature review only, and the null hypothesis was rejected for a p -value ≥ 0.05., Results: Sixteen patients met the inclusion criteria; male predominance and an average age of 66.5 years were detected. Sensory/motor deficit was the main onset symptom both in clinical study and literature review. A tendency to operate on the largest symptomatic lesion was reported and GTR was reached in the majority of cases. GBM was the histological diagnosis in most part of the patients. OS was 8.7 months in our series compared to 7.5 months from the literature review. Age ≤ 70 years, a postoperative KPS ≥ 70, a GTR/STR, a second surgery and adjuvant treatment were shown to be significantly associated with a better prognosis. Pathological examination revealed that MC HGG did not originate by LGG., Conclusions: MC gliomas are rare conditions with high malignancy and a poor prognosis. A maximal safe resection should be attempted whenever possible, especially in younger patients with life-threatening large mass.

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

Introduction: Growing evidence has been published as to the impact of SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) on cerebrovascular events over the last few months, with considerable attention paid to ischemic strokes. Conversely, little is known about the clinical course of intracerebral haemorrhage (ICH) and simultaneous SARS-CoV-2 infection., Method: The Italian Society of Hospital Neurosciences (SNO) promoted a multicentre, retrospective, observational study (SNO-COVID-19), involving 20 Neurological Departments in Northern Italy. Clinical data on patients with acute cerebrovascular diseases, admitted from March 1st to April 30th, 2020, were collected. A comparison was made of the demographical and clinical features of both SARS-CoV-2 positive and negative patients with ICH., Results: 949 patients were enrolled (average age 73.4 years; 52.7% males); 135 patients had haemorrhagic stroke and 127 (13.4%) had a primary ICH. Only 16 patients with ICH (12.6%) had laboratory confirmed SARS-CoV-2 infection, both symptomatic and asymptomatic. SARS-CoV-2 related pneumonia or respiratory distress (OR 5.4), lobar location (OR 5.0) and previous antiplatelet or anticoagulant treatment (OR 2.9) were the only factors significantly associated with increased mortality in ICH. SARS-CoV-2 infection, regardless of respiratory involvement, led to a non-significantly increased risk of in-hospital death (37.5% vs 23.4%, p = 0.2)., Discussion: ICH patients with COVID-19 did not experience an increase in mortality as striking as ischemic stroke. The inflammatory response and respiratory complications could justify the slight increase of death in ICH. Bleeding sites and previous antiplatelet or anticoagulant treatment were the only other predictors of a worse outcome., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Glioblastoma is characterized by a high proliferative rate and drug resistance. The standard of care includes maximal safe surgery, followed by radiotherapy and temozolomide chemotherapy. The expression of glutamate receptors has been previously reported in human glioma cell lines. The aim of this study was to examine the cellular effects of perampanel, a broad-spectrum antiepileptic drug acting as an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) glutamate receptor antagonist, alone or in combination with temozolomide. Four human glioma cell lines were exposed to different concentrations of perampanel and temozolomide, alone or in combination. The type of drug interaction was assessed using the Chou-Talalay method. Apoptosis, cell cycle perturbation, and glutamate receptors (GluRs) subunit expression were assessed by flow cytometry. Perampanel significantly inhibited the growth, inducing high levels of apoptosis. A strong synergistic effect of the combination of perampanel with temozolomide was detected in U87 and A172, but not in U138. Treatment with perampanel resulted in an increased GluR2/3 subunit expression in U87 and U138. Perampanel displays a pro-apoptotic effect on human glioblastoma cell lines when used alone, possibly due to increased GluR2/3 expression. The observed synergistic effect of the combination of temozolomide with perampanel suggests further investigation on the impact of this combination on oncologic outcomes in glioblastoma.

Background and Purpose: Adult brainstem gliomas are rare primary brain tumours with heterogeneous clinical course. The low frequency of these tumours makes it difficult to achieve high-quality evidence regarding prognostic factors, adequate therapeutic approach and outcome in such patients., Methods: In this retrospective study, we analysed clinical, radiological, molecular, prognostic and therapeutic factors in a series of 47 histologically proven adult brainstem gliomas recruited over a 20-year period (1998-2018)., Results: Twenty-two patients were male, 25 female with median age of 39 years. The tumour involved one brainstem segment in 20 cases and 2 or more segments in 27. Contrast enhancement was reported in 28 cases. Surgical procedures included biopsy in 26 cases and partial/total resection in the remaining 21. Histological diagnosis was of low-grade glioma in 23 patients, high-grade glioma in 22 and non-diagnostic in 2 cases. Data regarding molecular biology were available for 22 patients. Median overall survival was 35 months, in particular 16 months in high-grade glioma and 84 months in low-grade glioma. At univariate analysis, tumour grade was the only factor with a statistically significant impact on survival time (p = 0,003), whereas younger age, better performance status and total/subtotal resection showed a trend to more prolonged survival. This study also confirms safety of biopsy/surgery in adult brainstem glioma patients and shows a clear trend to a more frequent assessment of molecular biology data., Conclusions: Further prospective multicentre efforts, and hopefully clinical trials, are necessary to improve outcome in this neglected glioma patient population.

Introduction: Nowadays, reports of beriberi are rare in developed countries. Wernicke encephalopathy may be present in about 25% of patients with beriberi., Case Report: We report the case of a woman with history of depression and chronic eating disorder, who complained Wernicke encephalopathy and beriberi. Sural nerve and muscular biopsy were performed, showing severe axonal neuropathy. Thiamine supplementation was started with rapid improvement of the pulmonary and cardiac affections; improvement of peripheral neuropathy was incomplete., Conclusions: Thiamine deficiency can be misdiagnosed. Beriberi is an important cause of acute flaccid paralysis; hence, clinicians should consider this diagnosis and prompt start thiamine treatment to avoid permanent neurological sequelae.

Introduction: Contrast-induced encephalopathy is a rare and usually reversible entity due to the administration of iodinated contrast. Clinical manifestations include cortical blindness, encephalopathy, seizures and focal neurological deficits., Methods: We report the case of a 56-year-old woman who developed global aphasia and right hemiplegia after a cerebral angiography performed for a subarachnoid haemorrhage. A prompt brain MRI resulted negative, while CT scan revealed left cerebral oedema with the cerebral sulci effacement. Complete recovery was observed in 10 days., Discussion: Diagnosis of contrast-induced encephalopathy requires a temporal correlation between neurological dysfunction and administration of iodinated contrast. Usually, the symptomatology is transient with a full recovery within 48-72 h. The most common symptom is cortical blindness, while other symptoms have been rarely reported. Only 20 cases previously reported global aphasia and/or hemiplegia or mimed anterior circulation strokes. Prompt brain neuroimaging is essential in order to exclude an alternative diagnosis that requires a distinct therapeutic approach.

Introduction: Medulloblastoma (MB) is the most common primary malignant intracranial tumor in childhood, but it is very rare in adults, and for this reason, the optimal treatment has not yet been defined. We designed a multicentric study in order to define relevant outcome measures for future prospective studies., Materials and Methods: The project involved 10 Italian centers. The database shared among the centers contains epidemiological, diagnostic (radiological and histological/molecular), therapeutic, recurrence information, and survival data., Results: A total of 152 patients (102 males and 50 females, median age 32) were included in the study. Twenty-three of 152 patients had a diagnosis of classic medulloblastoma, 52/152 had desmoplastic/extensive nodularity, 2/152 had large-cell anaplastic medulloblastoma, and the remaining had diagnoses not otherwise specified. Almost all patients underwent craniospinal irradiation after surgery; in 85.5% of patients, adjuvant chemotherapy, mainly platinum- and etoposide-based chemotherapy, was performed immediately after RT. Upon recurrence, most patients were retreated with various chemotherapy regimens, including intrathecal chemotherapy in patients with leptomeningeal dissemination. The overall survival (OS) rate at 5 years was 73.3% (95% CI, 65.0-80.0%). The median OS for the whole group of patients was 112 months., Conclusions: The data collected were mainly consistent with the literature. A limitation of this study was the large number of patients lost to follow-up and the lack of molecular data for most patients diagnosed until 2010. An important challenge for the future will be MB biologic characterization in adults, with the identification of specific genetic patterns. It will be important to have more national and international collaborations to provide evidence-based management strategies that attempt to obtain a standard of care.

Glioblastoma multiforme (GBM) is considered the most malignant form of primary brain tumor. Despite multimodal treatment, prognosis remains poor. Ketogenic diet (KD) has been suggested for the treatment of GBM. In this study, the syngenic, orthotopic GL261 mouse glioma model was used to evaluate the effects of KD on the metabolic responses of the tumor using 7T magnetic resonance imaging/spectroscopy. GL261 cells were injected into the caudate nucleus of mice. Following implantation, animals were fed with standard chow or underwent a KD. 18 days after initiating the diet, mice fed with KD displayed significantly higher plasmatic levels of ketone bodies and survived longer than those fed with the standard diet. Decreased concentrations of gamma-aminobutyric acid, N-Acetyl-Aspartate and N-acetylaspartylglutamate were found in tumor tissue after 9 days into the KD, while a huge increase in beta-hydroxybutyrate (bHB) was detected in tumor tissue as compared to normal brain. The accumulation of bHB in the tumor tissue in mice undergoing the KD, may suggest either elevated uptake/release of bHB by tumor cells, or the inability of tumor cells in this context to use it for mitochondrial metabolism.

Posterior reversible encephalopathy cases are increasingly being reported in patients affected by COVID-19, but the largest series so far only includes 4 patients. We present a series of 6 patients diagnosed with PRES during COVID-19 hospitalized in 5 Centers in Lombardia, Italy. 5 out of the 6 patients required intensive care assistence and seizures developed at weaning from assisted ventilation. 3 out of 6 patients underwent cerebrospinal fluid analysis which was normal in all cases, with negative PCR for Sars-CoV-2 genome search. PRES occurrence may be less rare than supposed in COVID-19 patients and a high suspicion index is warranted for prompt diagnosis and treatment., (© 2020 Published by Elsevier B.V.)

Background and Purpose: Neuromodulation is a promising approach to increasing motor recovery in stroke; however, to date, there is a scarcity of evidence documenting the clinical potential of transcranial direct current stimulation (tDCS) administered in the acute phase of stroke. The present study aims to examine the clinical effects of a treatment involving the application of tDCS in the acute stage post-stroke., Methods: This was a randomized, double-blind, sham-controlled trial. A cohort of 32 stroke patients with severe motor impairment underwent 5 days of treatment with real or sham bi-hemispheric tDCS over the motor cortex. During the treatment, tDCS was applied twice per day (two daily applications each of 15 min), starting 48 to 72 h after stroke onset., Results: We found statistically significant improvements after both real and sham tDCS treatments in primary (hand grip strength, Motricity Index) and secondary (National Institutes of Health Stroke Scale score, Barthel Index) outcomes. Patients receiving real tDCS showed a larger improvement of upper-limb muscle strength at the end of treatment phase; this advantage was no longer present after 6 months., Conclusions: Transcranial direct current stimulation may be used to accelerate the rate of upper-limb motor recovery during the spontaneous recovery period., (© 2020 European Academy of Neurology.)

Multifocal motor neuropathy is a purely motor neuropathy with a probably dysimmune pathogenesis, supported by the presence of anti-GM1 IgM antibodies in about half of the cases. Single nerve involvement allows for diagnosis of possible multifocal motor neuropathy. We present the case of a middle age man presenting with progressive weakness and hypotrophy in the left leg and difficulty in walking, in which we have diagnosed a dysimmune mononeuropathy. Treatment with IVIg was performed with substantial improvement. Although only one nerve is involved, early diagnosis of dysimmune mononeuropathy is important to start IVIg treatment that is often decisive., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Headache has been consistently reported as the most common symptom of cerebral venous thrombosis and as the most frequent presenting feature. It is often the heralding symptom, preceding other manifestations of the disease by days or even weeks. This aspect highlights the importance of recognizing headache due to cerebral venous thrombosis, as early recognition of the disease can lead to a rapid diagnosis with appropriate imaging techniques and as early treatment with heparin can dramatically change the course of the disease and alter the prognosis. Unfortunately, although common, the headache has no specific features, and the clinical presentation of CVT is highly variable, making the correct diagnosis in the emergency setting a challenging task for clinicians, even in the case of highly specialized ones such as neurologists. In this review, we will briefly summarize the epidemiology and physiopathology of CVT, and then we will discuss in more details the causes, features, and course of headache, focusing on its relevance for differential diagnosis and on red flags that should suggest the possibility of CVT as the cause of the headache.

Introduction: Italy has been the first European country severely affected by the COVID-19 pandemic., Objective: To analyze the incidence of the clinical presentations suggestive for COVID-19 infection among patients with Multiple Sclerosis in the province of Lecco, in the North Italy, the closest province capital to Bergamo. To describe the association of demographics, clinical characteristics, and use of DMTs categories with the risk of contracting the disease., Methods: We telephonically interviewed all the 275 MS patients followed in the MS center. The collected data included recent contact with a patient with COVID-19 diagnosis or a subject with respiratory symptoms and the developing of COVID-19 symptoms or a confirmed diagnosis., Results: 15 out of 275 patients reported symptoms suggestive for COVID-19 infection, only one of them with PCR-confirmed diagnosis. No one of them presented severe symptoms or needed hospitalization. Using a multivariable logistic regression model, the only factor associated with being in the COVID-suspect group was the report of a recent contact with a patient with a COVID-19 diagnosis., Conclusions: The prevalence of COVID-19 within MS patients seems to resemble the prevalence in general population. The lack of associations with other factors assessed, including DMTs, may reflect a lack of statistical power. Larger population studies are needed to explore the correlation between different disease-modifying therapies and COVID-19 course., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Competing Interests: The authors have no potential conflicts of interest to disclose.

The sudden worldwide outbreak of Coronavirus Disease 2019 (COVID-19) has certainly provided new challenges in the management of acute ischaemic stroke, and the risk-benefit ratio of intravenous thrombolysis in COVID-19 positive patients is not well known. We describe four COVID-19 patients treated with intravenous thrombolysis for acute ischaemic stroke. Although rt-PA administration is the main therapeutic strategy, our patients experienced unpredictable complications and showed atypical features: the overall mortality was very high. In conclusion, in this article, we provide information about these cases and discuss the possible explanation behind this trend.

In 2018, the SINch (Italian Society of Neurosurgery) Neuro-Oncology Section, AINO (Italian Association of Neuro-Oncology) and SIN (Italian Association of Neurology) Neuro-Oncology Section formed a collaborative Task Force to look at the diagnosis and treatment of low-grade gliomas (LGGs). The Task Force included neurologists, neurosurgeons, neuro-oncologists, pathologists, radiologists, radiation oncologists, medical oncologists, a neuropsychologist and a methodologist. For operational purposes, the Task Force was divided into five Working Groups: diagnosis, surgical treatment, adjuvant treatments, supportive therapies, and follow-up. The resulting guidance document is based on the available evidence and provides recommendations on diagnosis and treatment of LGG patients, considering all aspects of patient care along their disease trajectory.

Competing Interests: The authors have no potential conflicts of interest to disclose.