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Background: The management of Multiple Sclerosis (MS) has undergone transformative evolution with the introduction of high-efficacy disease-modifying therapies (DMTs), specifically anti-CD20 monoclonal antibodies, such as ocrelizumab (OCR) and ofatumumab (OFA). Materials and methods: This is an independent retrospective cohort study in Relapsing MS (RMS) patients followed at eight Italian MS centers who initiated treatment with OCR or OFA in the participating centers and with at least 12 months on therapy. A generalized linear regression model inverse probability of treatment weight (IPTW) PS-adjusted was performed to evaluate the relationship between annualized relapse rate (ARR) and treatment groups. No evidence of disease activity-NEDA-3 at 12-month score was also collected. Safety profile of the investigated DMTs was recorded. Results: A total cohort of 396 RMS patients fulfilled the required criteria and were enrolled in the study. Out of them, 216 had a prescription of OCR and 180 of OFA. The mean follow-up was 13.2 ± 1.9 months. The estimated means for ARR did not show differences between the two groups, 0.059 for patients on OCR and 0.038 for patients on OFA (p = 0.185). The generalized regression model IPTW PS-adjusted did not reveal differences between patients on OCR and OFA (ExpBOFA 0.974, 95%CI 934–1.015, p = 0.207). NEDA-3 at 12 months was experienced by 199(92.1%) patients on OCR and 170(94.4%) patients on OFA (p = 0.368). Generally, both therapies exhibit good tolerability. Conclusions: The treatment with OCR and OFA resulted in comparable control of disease activity with good safety profile. Our results need further validation in larger multicentre studies with long-term follow-up. [ABSTRACT FROM AUTHOR]

Introduction: People with multiple sclerosis (PwMS) exhibit a spectrum of needs that extend beyond solely disease-related determinants. Investigating unmet needs from the patient perspective may address daily difficulties and optimize care. Our aim was to identify patterns of unmet needs among PwMS and their determinants. Methods: We conducted a cross-sectional multicentre study. Data were collected through an anonymous, self-administered online form. To cluster PwMS according to their main unmet needs, we performed agglomerative hierarchical clustering algorithm. Principal component analysis (PCA) was applied to visualize cluster distribution. Pairwise comparisons were used to evaluate demographics and clinical distribution among clusters. Results: Out of 1764 mailed questionnaires, we received 690 responses. Access to primary care was the main contributor to the overall unmet need burden. Four patterns were identified: cluster C1, 'information-seekers with few unmet needs'; cluster C2, 'high unmet needs'; cluster C3, 'socially and assistance-dependent'; cluster C4, 'self-sufficient with few unmet needs'. PCA identified two main components in determining the patterns: the 'public sphere' (access to information and care) and the 'private sphere' (need for assistance and social life). Older age, lower education, longer disease duration and higher disability characterized clusters with more unmet needs in the private sphere. However, demographic and clinical factors failed in explaining the four identified patterns. Conclusion: Our study identified four unmet need patterns among PwMS, emphasizing the importance of personalized care. While clinical and demographic factors provide some insight, additional variables warrant further investigation to fully understand unmet needs in PwMS. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) predominantly affects women of fertile age. Various aspects of MS could impact on fertility, such as sexual dysfunction, endocrine alterations, autoimmune imbalances, and disease-modifying therapies (DMTs). The proportion of women with MS (wMS) requesting infertility management and assisted reproductive technology (ART) is increasing over time. In this review, we report on data regarding ART in wMS and address safety issues. We also discuss the clinical aspects to consider when planning a course of treatment for infertility, and provide updated recommendations to guide neurologists in the management of wMS undergoing ART, with the goal of reducing the risk of disease activation after this procedure. According to most studies, there is an increase in relapse rate and magnetic resonance imaging activity after ART. Therefore, to reduce the risk of relapse, ART should be considered in wMS with stable disease. In wMS, especially those with high disease activity, fertility issues should be discussed early as the choice of DMT, and fertility preservation strategies might be proposed in selected cases to ensure both disease control and a safe pregnancy. For patients with stable disease taking DMTs compatible with pregnancy, treatment should not be interrupted before ART. If the ongoing therapy is contraindicated in pregnancy, then it should be switched to a compatible therapy. Prior to beginning fertility treatments in wMS, it would be reasonable to assess vitamin D serum levels, thyroid function and its antibody serum levels; start folic acid supplementation; and ensure smoking and alcohol cessation, adequate sleep, and food hygiene. Cervico-vaginal swabs for Ureaplasma urealyticum, Mycoplasma hominis, and Chlamydia trachomatis, as well as serology for viral hepatitis, HIV, syphilis, and cytomegalovirus, should be performed. Steroids could be administered under specific indications. Although the available data do not clearly show a definite raised relapse risk associated with a specific ART protocol, it seems reasonably safe to prefer the use of gonadotropin-releasing hormone (GnRH) antagonists for ovarian stimulation. Close clinical and radiological monitoring is reasonably recommended, particularly after hormonal stimulation and in case of pregnancy failure. [ABSTRACT FROM AUTHOR]

Background: Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT) is a rare but potentially reversible autoimmune encephalopathy. The most frequent neuroimaging correlates are normal brain MRI or non-specific white matter hyperintensities. Methods: We present the first description of conus medullaris involvement, also providing an extensive review of MRI patterns described so far. Results: Our results show that in less than 30% of cases, it is possible to find focal SREAT neuroanatomical correlates. Among these, T2w/FLAIR temporal hyperintensities are the most frequent, followed by basal ganglia/thalamic and brainstem involvement, respectively. Conclusions: Unfortunately, spinal cord investigation is an uncommon practice in the diagnostic approach of encephalopathies, thus neglecting potential pathological lesions of the medulla spinalis. In our opinion, the extension of the MRI study to the cervical, thoracic, and lumbosacral regions may allow finding new, and hopefully specific, anatomical correlates. [ABSTRACT FROM AUTHOR]

Objective: Multiple sclerosis (MS) is a chronic disease with different clinical courses and a tendency to worsening. The relapsing–remitting MS presents acute onset and relapses of neurological symptoms, followed by their remission. This form can convert to secondary progressive MS (SPMS) with irreversible neurological worsening and disability. The identification of signs, symptoms, markers of progression, and strategies to manage MS patients is mandatory to allow early identification of those at higher risk of conversion to SPMS, for prompt intervention to cope with the progression of the disease. Methods: A panel of Italian experts from Southern Italy have reviewed the current knowledge on MS and its management and identified the crucial tools for SPMS recognition. Results: More effective communication between patients and clinicians should be established, with the support of digital tools. Moreover, the improvement in the clinical use of biomarkers for progression (cellular structures and tissue organization, such as neurofilaments and chitinase 3-like 1, axonal and neurons density) and of instrumental analyses for recognition of whole-brain atrophy, chronic active lesions, spinal cord lesions and atrophy, and the improvement the combination of the Expanded Disability Status Scale and the evaluation of cognitive dysfunction are discussed. Conclusion: Given the availability of a pharmacological option, adequate education both for patients, regarding the evolution of the disease and the specific treatment, and for professionals, to allow more effective and sensitive communication and the best use of diagnostic and management tools, could represent a strategy to improve patient management and their quality of life. [ABSTRACT FROM AUTHOR]

Ocrelizumab is a humanized monoclonal anti-CD20 antibody, approved for the treatment of relapsing and primary-progressive multiple sclerosis. We reported a case of pericarditis in an RRMS patient treated with ocrelizumab, who presented with chest pain, high body temperature and laboratory findings of systemic inflammation, with a favorable clinical outcome. [ABSTRACT FROM AUTHOR]

Patients afflicted by multiple sclerosis experience a relapsing-remitting course in about 85% of the cases. Furthermore, after a 10/15-year period their situation tends to worse, resulting in what is considered the second phase of multiple sclerosis. While treatments are now available to reduce the symptoms and slow down the progression of the disease, the administration of drugs must be adapted to the course of the disease, and predicting relapsing periods and the worsening of the symptoms can greatly improve the outcome of the treatment. For this reason, indicators such as the patient-reported outcome measures (PROMs) have been largely used to support early diagnosis and prediction of future relapsing periods in patients affected by multiple sclerosis. However, such indicators are insufficient, as the prediction they provide is often not accurate enough. In this paper, machine learning techniques have been applied to data obtained from clinical trial, in order to improve the prediction capabilities and provide doctors with an additional instrument to evaluate the clinical situation of patients. After the application of correlation indicators and the use of principal component analysis for the reduction of the dimensionality of the feature space, classification algorithms have been applied and compared, in order to identify the best suiting one for our purposes. After the application of re-balance algorithms, the accuracy of the machine learning-based prediction system reaches 79%, demonstrating the capability of the framework to correctly predict future progression of disability. [ABSTRACT FROM AUTHOR]

Background: Migraine affects more than a billion people all over the world and requires critical employment of healthcare resources. Telemedicine could be a reasonable tool to manage people suffering from headaches, and it received a big push from the COVID-19 pandemic. Objective: This review aims to propose a practical approach for the virtual management of these patients. Methods: To do this, we conducted a literature search, including 32 articles relevant to the topic treated in this review. Results: The most challenging step in telemedicine applied to practical neurology remains the clinical assessment, but through a careful headache history and a recently proposed entirely virtual neurological assessment, this hitch can be easily overcome. Electronic diary compilations and virtual administration of disability-measuring scales, conversely, are the key features of effective long-term follow-up although we do not have apps that met the criteria of scientific reliability. Furthermore, tele-rehabilitation seems to be effective and has demonstrated to be a solution to alternatively treat chronic patients at home, and can be considered part of the remote management of headache patients. Moreover, virtual management of headaches finds an application in specific communities of patients, as pediatric patients and for rural communities of low- and middle-income countries suffer from health disparities, with inadequate resources and knowledge gaps. Conclusion: Telemedicine could be promising for patients with no regular or convenient access to headache specialists and seems to be a priority in managing migraine patients to avoid non-urgent hospitalizations [ABSTRACT FROM AUTHOR]

Background: Stress is a potential trigger for clinical and radiological activity in Multiple Sclerosis (MS). COVID-19 pandemic has been a relevant source of mental distress in people with MS (pwMS) and deeply impacted on disease management. Objective: To investigate the association between stress, anxiety, depression, and risk of relapse during the COVID-19 pandemic. Methods: From an electronic database used for clinical practice, we extracted data of relapsing–remitting (RR) or relapsing-progressive (RP) MS patients and calculated the annualized relapse rate (ARR) during 2019 and 2020. From 01/12/2020 to 30/12/2020, enrolled patients were invited to fill in a Google Forms survey to investigate depression, anxiety, stress, and Post-Traumatic Stress Disorder (PTSD). Results: We selected 216 patients with RR or RP-MS to calculate ARR: compared to 2019, in 2020 there was a significant increase in ARR (p = 0.0142). Over 216 selected pwMS, 154 completed the survey. Matching the survey responses and incidence of relapses in 2020, there was a significant association between relapses and stress (p = 0.030) and relapses and depression (p = 0.011), but not between relapses and anxiety (p = 0.130) or PTSD (p = 0.279). Conclusions: Our results support the hypothesis that pandemic-related stress is associated to clinical exacerbations, both as a possible consequence of the COVID-19 impact on MS care. [ABSTRACT FROM AUTHOR]

Purpose: To investigate in multiple sclerosis (MS) patients, the relationship between pain and religiosity and to determine whether distinct dimensions of religiosity were associated with quality of life. Methods: MS patients during clinical follow-up filled out the visual analogue scale for pain (VAS), the Mc Gill questionnaire (McGQ), the 36-Item Short Form Health Survey (SF-36), and the religious attitude scale (RAS), and expanded disability status scale (EDSS) was assessed. Results: Ninety-two MS patients were enrolled, only two declined. There was a negative correlation between religious practice and faith and some domains of the SF-36 and a positive correlation between sensory, affective, and evaluative aspects of pain (at McGQ) and religious practices, and between evaluative aspects of pain (at McGQ) and faith. EDSS was significantly higher in practitioner believers compared to not practitioners. Conclusions: More disabled MS patients, with worse quality of life, also due to physical pain, find a source of comfort in faith and religious practices. Pain is not relieved by prayer; therefore, we may guess that in MS the poor beneficial effect of religiosity and practice on pain perception may be linked to a structural/functional damage of neural circuits involved in reducing pain during prayer. [ABSTRACT FROM AUTHOR]

Background: Friedreich's ataxia (FRDA) is an untreatable disease that negatively impacts patients' and caregivers' quality of life. Objectives: The aims were to improve the quality of the information for FRDA patients and caregivers and suggest a possible tool to spread this information. Material and methods: Thirty-four FRDA patients and 45 caregivers were interviewed separately using a structured self-administered survey about their information-seeking behavior, their level of expectation and satisfaction for the information received, and the need for further information. Results and conclusion: For patients and caregivers, the main source of information was the FRDA specialist and the media. The most searched items were "general information"; patients and particularly caregivers desired to get more information on existing and experimental therapies. Adequate information supply is part of good medical care; therefore, a deeper insight of clinicians in information-seeking behavior of FRDA patients and caregivers would provide tailored information and improve therapeutic alliance. [ABSTRACT FROM AUTHOR]

Introduction: Blood coagulation constituents might exert immunomodulatory functions in the CNS and may trigger neuroinflammation and demyelination. We evaluated whether particular single-nucleotide polymorphisms (SNPs), thought to be involved in fibrinogen-mediated hemostatic pathways, are overrepresented in patients with MS compared with controls. Methods: The case–control study consisted of 119 MS patients recruited consecutively at our clinic, and 68 healthy controls. Afterwards, we created a cumulative genetic risk score (CGRS) which included the 5 selected hemostatic risk alleles (Beta-Fibrinogen 455G/A, Glycoprotein IIIa P1A2, Factor V Leiden, Factor V H2R, and Prothrombin 20210G/A). Multivariate ordinal logistic regression and multivariate multinomial logistic regression were applied to evaluate the effect of CGRS on MS susceptibility. Results: The FGB 455 G/A and Factor V H1299R variants might be associated with MS status, in the recessive and dominant model, respectively. A cumulative association of the five SNPs investigated with the disease was observed. Discussion: We found that MS patients carried more pro-hemostatic variants than healthy controls. An increasing number of unfavorable alleles might increase the likelihood of being in the MS group, in the cumulative analysis. Our findings encourage to evaluating these variants in a larger population-based cohort. [ABSTRACT FROM AUTHOR]

Background: Natalizumab (NTZ) is an effective treatment for relapsing–remitting multiple sclerosis (RRMS). However, patients and physicians may consider discontinuing NTZ therapy due to safety or efficacy issues. The aim of our study was to evaluate the NTZ discontinuation rate and reasons of discontinuation in a large Italian population of RRMS patients. Materials and methods: The data were extracted from the Italian MS registry in May 2018 and were collected from 51,845 patients in 69 Italian multiple sclerosis centers. MS patients with at least one NTZ infusion in the period between June 1st 2012 to May 15th 2018 were included. Discontinuation rates at each time point were calculated. Reasons for NTZ discontinuation were classified as "lack of efficacy", "progressive multifocal leukoencephalopathy (PML) risk" or "other". Results: Out of 51,845, 5151 patients, 3019 (58.6%) females, with a mean age of 43.6 ± 10.1 years (median 40), were analyzed. Out of 2037 (39.5%) who discontinued NTZ, a significantly higher percentage suspended NTZ because of PML risk compared to lack of efficacy [1682 (32.7% of 5151) vs 221 (4.3%), p < 0.001]; other reasons were identified for 99 (1.9%) patients. Patients discontinuing treatment were older, had longer disease duration and worse EDSS at the time of NTZ initiation and at last follow-up on NTZ treatment. The JCV index and EDSS at baseline were predictors for stopping therapy (HR 2.94, 95% CI 1.22–4.75; p = 0.02; HR 1.36, 95% CI 1.18–5.41; p = 0.04). Conclusions: Roughly 60% of MS patients stayed on NTZ treatment during the observation period. For those patients in whom NTZ discontinuation was required, it was mainly due to PML concerns. [ABSTRACT FROM AUTHOR]

COVID-19 pandemic has induced an urgent reorganization of the healthcare system to ensure continuity of care for patients affected by chronic neurological diseases including myasthenia gravis (MG). Due to the fluctuating nature of the disease, early detection of disease worsening, adverse events, and possibly life-threatening complications is mandatory. This work analyzes the main unresolved issues in the management of the myasthenic patient, the possibilities offered so far by digital technologies, and proposes an online evaluation protocol based on 4 simple tests to improve MG management. Telemedicine and Digital Technology might help neurologists in the clinical decision-making process of MG management, avoiding unnecessary in presence consultations and allowing a rational use of the time and space reduced by the pandemic. [ABSTRACT FROM AUTHOR]

The organization of brain functional connectivity (FC) has been shown to differ between sexes. Amyotrophic lateral sclerosis (ALS) is characterized by sexual dimorphism, showing sex-specific trends in site of onset, phenotypes, and prognosis. Here, we explored resting state (RS) FC differences within major large-scale functional networks between women and men in a sample of ALS patients, in comparison to healthy controls (HCs). A group-level independent component analysis (ICA) was performed on RS-fMRI time-series enabling spatial and spectral analyses of large-scale RS FC networks in 45 patients with ALS (20 F; 25 M) and 31 HCs (15 F; 16 M) with a focus on sex-related differences. A whole-brain voxel-based morphometry (VBM) was also performed to highlight atrophy differences. Between-sex comparisons showed: decreased FC in the right middle frontal gyrus and in the precuneus within the default mode network (DMN), in affected men compared to affected women; decreased FC in the right post-central gyrus (sensorimotor network), in the right inferior parietal gyrus (right fronto-parietal network) and increased FC in the anterior cingulate cortex and right insula (salience network), in both affected and non-affected men compared to women. When comparing affected men to affected women, VBM analysis revealed atrophy in men in the right lateral occipital cortex. Our results suggest that in ALS sex-related trends of brain functional and structural changes are more heavily represented in DMN and in the occipital cortex, suggesting that sex is an additional dimension of functional and structural heterogeneity in ALS. [ABSTRACT FROM AUTHOR]

Introduction: COVID-19 pandemic radically transformed our daily clinical practice, raising the need not to lose close contact with patients without being able to see them face-to-face. These issues are even more felt and evident in fragile patients, as those affected by neuromuscular disease. An important help came from new digital technologies that allow clinicians to remotely monitor health status and any deterioration of chronically ill patients. Methods: In this mini-review, an initiative of the "Digital Technologies, Web and Social Media Study Group" of the Italian Society of Neurology, we propose to analyze the approach to neuromuscular patients by looking over raising evidence on the main cornerstones of Telemedicine (TM): clinician-patient interaction, remote clinical assessment, remote monitoring, and digital therapeutics. In particular, we explored the strategies developed by researchers and their impact on the physical and emotional status of the patients, with particular focusing on their adherence to the program of virtual monitoring. Results: TM plays an important role in each of four stages of approach to neuromuscular disease, having demonstrated validity in keep close clinical patient interaction, clinical assessment, remote monitoring, and telerehabilitation. Nevertheless, there is no remote alternative to electrophysiological testing neither validate tools to assess disability. Conclusion: The role of TM in neuromuscular care is yet underestimated but is crucial, beyond the pandemic era. Further development of TM is advisable, through making specific apps, remotely controlled by clinicians, and making more engaging clinicians-patients interaction. Last, it is necessary to ensure adequate internet access to everyone. [ABSTRACT FROM AUTHOR]

Emerging evidence suggests that memory deficit in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease with varying impairment of motor abilities and cognitive profile, may be independent from executive dysfunction. Our multimodal magnetic resonance imaging (MRI) approach, including resting state functional MRI (RS-fMRI), diffusion tensor imaging (DTI) and voxel-based morphometry (VBM), aimed to investigate structural and functional changes within and beyond the Papez circuit in non-demented ALS patients (n = 32) compared with healthy controls (HCs, n = 21), and whether these changes correlated with neuropsychological measures of verbal and non-verbal memory. We revealed a decreased functional connectivity between bilateral hippocampus, bilateral parahippocampal gyri and cerebellum in ALS patients compared with HCs. Between-group comparisons revealed white matter abnormalities in the genu and body of the corpus callosum and bilateral cortico-spinal tracts, superior longitudinal and uncinate fasciculi in ALS patients (p <.05, family-wise error corrected). Interestingly, changes of Digit Span forward performance were inversely related to RS-fMRI signal fluctuations in the cerebellum, while changes of both episodic and visual memory scores were inversely related to mean and radial diffusivity abnormalities in several WM fiber tracts, including middle cerebellar peduncles. Our findings revealed that ALS patients showed significant functional and structural connectivity changes across the regions comprising the Papez circuit, as well as more extended areas including cerebellum and frontal, temporal and parietal areas, supporting the theory of a multi-system pathology in ALS that spreads from cortical to subcortical structures. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is the most common age-related dementia. Besides its typical presentation with amnestic syndrome at onset, atypical AD cases are being increasingly recognized, often in presenile age.Objectives: To provide an extensive clinical and genetic characterization of six AD patients carrying one or more singular features, including age of onset, atypical phenotype and disease progression rate. By reviewing the pertinent literature and accessing publicly available databases, we aimed to assess the frequency and the significance of the identified genetic variants.Methods: Biomarkers of amyloid-β deposition and neurodegeneration were used to establish the in vivo diagnosis of probable AD, in addition to neurological and neuropsychological evaluation, extensive laboratory assays and neuroradiological data. Considering the presenile onset of the majority of the cases, we hypothesized genetically determined AD and performed extensive genetic analyses by both Sanger sequencing and next generation sequencing (NGS).Results: We disclosed two known missense variants, one in PSEN1 and the other in PSEN2, and a novel silent variant in PSEN2. Most notably, we identified several additional variants in other dementia-related genes by NGS. Some of them have never been reported in any control or disease databases, representing variants unique to our cases.Conclusions: This work underlines the difficulties in reaching a confident in vivo diagnosis in cases of atypical dementia. Moreover, a wider genetic analysis by NGS approach may prove to be useful in specific cases, especially when the study of the so-far known AD causative genes produces negative or conflicting results. [ABSTRACT FROM AUTHOR]

Introduction: The pandemic has implemented the need for new digital technologies as useful tools during the emergency and the long recovery phase that will follow. SARS-CoV-2 has strongly impacted stroke care with significant contraction in a number of patients treated. Methods: This mini-review is an initiative of the "Digital Technologies, Web and Social Media Study Group" of the Italian Society of Neurology and briefly discusses digital tools for managing the acute phase and the rehabilitation after stroke, even considering the new apps that will improve the process of remote monitoring of patients after discharge at home. Results: Telemedicine and digital technologies could play a role in each of the three stroke-belt stages: hyperacute treatment and reperfusion, acute care, etiological classification and secondary prevention and rehabilitation. Conclusion: The global emergency represented by the COVID-19 pandemic can be the stimulus to accelerate the digitalization process in the field of stroke for the use of new methods on a large scale. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) is characterized by a large spectrum of symptoms, involving all functional systems. Psychiatric symptoms are common in people with MS (pwMS) having an important impact on quality of life and on some features of MS (fatigue, sleep, disability, adherence to disease-modifying drugs). The main psychiatric disturbances in MS are depressive, bipolar, anxiety, schizophrenic and obsessive–compulsive syndromes. Methods: Literature search for original articles and review in the databases, including PubMed and Scopus from 1959 to 2019. Results and conclusion: Studies answering the aim of this review were selected and reported. Epidemiological and clinical aspects of psychiatric syndromes (PS) in MS as well as self-report diagnostic scales and radiological correlates of PS in MS are described. Moreover, some radiological studies about primary psychiatric disorders (PD) are reported to underline how gray matter atrophy, white matter abnormalities and corpus callosum involvement in these diseases, as features in common with MS, may explain the more frequent occurrence of PD in MS than in the general population. [ABSTRACT FROM AUTHOR]

Over the last months, due to coronavirus disease (COVID-19) pandemic, containment measures have led to important social restriction. Healthcare systems have faced a complete rearrangement of resources and spaces, with the creation of wards devoted to COVID-19 patients. In this context, patients affected by chronic neurological diseases, such as amyotrophic lateral sclerosis (ALS), are at risk to be lost at follow-up, leading to a higher risk of morbidity and mortality. Telemedicine may allow meet the needs of these patients. In this commentary, we briefly discuss the digital tools to remotely monitor and manage ALS patients. Focusing on detecting disease progression and preventing life-threatening conditions, we propose a toolset able to improve ALS management during this unprecedented situation. [ABSTRACT FROM AUTHOR]

Mild cognitive impairment (MCI) defines an intermediate state between normal ageing and dementia, including Alzheimer's disease (AD). Identification of MCI subjects who will progress to AD (MCI-AD) is today of crucial importance, especially in light of the possible development of new pathogenic therapies. Several evidences suggest that miRNAs could play relevant roles in the biogenesis of AD, and the links between selected miRNAs and specific pathogenic aspects have been partly explored. In this study, we analysed the composition of microRNA transcriptome in blood, serum and cerebrospinal fluid samples from MCI-AD subjects, from an enriched small RNA library. Real-time qPCR from MCI-AD and AD patients and normal controls was performed to profile miRNA expression. In particular, four microRNAs, hsa-mir-5588-5p, hsa-mir-3658, hsa-mir-567 and hsa-mir-3908, among all selected microRNAs, are dysregulated. Hsa-mir-567 was found to be differentially expressed in cerebrospinal fluid samples, blood and serum from MCI-AD patients, showing the highest fold change and statistical significance. Target prediction analysis have been performed to evaluate mRNAs whose expression was controlled by miRNAs found to be dysregulated here, showing that hsa-mir-567 target genes are functionally active in neuronal cells. We propose that miRNA profiles found in samples from MCI-AD patients might be relevant for a better understanding of AD-related cognitive decline and could lead to set up suitable and potential biomarkers for MCI-AD progression to AD. [ABSTRACT FROM AUTHOR]

Background: The introduction of oral disease-modifying therapies (DMTs) for relapsing–remitting multiple sclerosis (RRMS) changed algorithms of RRMS treatment. Objectives: To compare the effectiveness of treatment with dimethyl fumarate (DMF) and teriflunomide (TRF) in a large multicentre Italian cohort of RRMS patients. Materials and Methods: Patients with RRMS who received treatment with DMF and TRF between January 1st, 2012 and December 31st, 2018 from twelve MS centers were identified. The events investigated were "time-to-first-relapse", "time-to-Magnetic-Resonance-Imaging (MRI)-activity" and "time-to-disability-progression". Results: 1445 patients were enrolled (1039 on DMF, 406 on TRF) and followed for a median of 34 months. Patients on TRF were older (43.5 ± 8.6 vs 38.8 ± 9.2 years), with a predominance of men and higher level of disability (p < 0.001 for all). Patients on DMF had a higher number of relapses and radiological activity (p <.05) at baseline. Time-varying Cox-model for the event "time-to-first relapse" revealed that no differences were found between the two groups in the first 38 months of treatment (HRt < 38DMF = 0.73, CI = 0.52 to 1.03, p = 0.079). When the time-on-therapy exceeds 38 months patients on DMF had an approximately 0.3 times lower relapse hazard risk than those who took TRF (HRt>38DMF = 3.83, CI = 1.11 to 13.23, p = 0.033). Both DMTs controlled similarly MRI activity and disability progression. Conclusions: Patients on DMF had higher relapse-free survival time than TRF group after the first 38 months on therapy. [ABSTRACT FROM AUTHOR]

Background: erenumab was safe and effective in clinical trials for the prevention of migraine. However, real-life data are still lacking. Here we report the clinical experience from an Italian real-world setting using erenumab in patients with chronic migraine experiencing previous unsuccessful preventive treatments. Methods: Seventy patients with chronic migraine and failure to ≥4 migraine preventive medication classes initially received monthly erenumab 70 mg s.c. Patients without a clinically meaningful improvement, considered as a > 30% reduction in headache days per month, after ≥3 months of therapy switched to monthly erenumab 140 mg. At the first administration and after 3 and 6 months, patients underwent extensive interviews to assess clinical parameters of disease severity and migraine-related disability and impact, and validated questionnaires to explore depression/anxiety, sleep, and quality of life (QoL). Finally, the Pain Catastrophizing Scale, Allodynia Symptom Checklist-12 and MIGraine attacks-Subjective COGnitive impairments scale (MIG-SCOG) were administered. Results: 70% of patients were "responders" after the third administration of erenumab 70 mg, whereas 30% switched to erenumab 140 mg; 29% (6 pts) responded after the sixth administration. The headache-day frequency was reduced from 21.1 ± 0.7 to 11.4 ± 0.9 days after the third administration (p < 0.001) and to 8.9 ± 0.7 days after the sixth administration (p < 0.001). 53% and 70% of patients, respectively, showed a reduction of ≥50% of headache days/month after the third and the sixth administrations. Also improved were headache pain severity, migraine-related disability, and impact on daily living, QoL, pain catastrophizing and allodynia (all p < 0.001), quality of sleep, symptoms of depression or anxiety (p < 0.05) but not MIG-SCOG. There were no new adverse event signals. Conclusion: These real-world data support monthly erenumab 70 or 140 mg s.c. as a safe and effective preventive treatment to reduce headache frequency and severity in chronic migraine patients experiencing previous unsuccessful preventive treatments. [ABSTRACT FROM AUTHOR]

Background: The increase in disease-modifying drugs (DMDs) allows individualization of treatment in relapsing multiple sclerosis (RMS); however, the long-term impact of different treatment sequences is not well established. This is particularly relevant for MS patients who may need to postpone more aggressive DMD strategies. Objective: To evaluate different therapeutic strategies and their long-term outcomes, measured as relapses and confirmed disability progression (CDP), in MS 'real-world' settings. Methods: Multicentre, observational, retrospectively acquired cohort study evaluating the long-term impact of different treatment strategies on disability outcomes in patients with RMS in the Italian MS Register. Results: We evaluated 1152 RMS-naïve patients after propensity-score adjustment. Patients included were receiving: interferon beta-1a (IFN-β1a) 44 µg switching to fingolimod (FTY; IFN-switchers; n = 97); FTY only (FTY-stayers; n = 157); IFN-β1a only (IFN-stayers; n = 849). CDP and relapses did not differ between FTY-stayers and IFN-switchers [HR (95% CI) 0.99 (0.48–2.04), p = 0.98 and 0.81 (0.42–1.58), p = 0.55, respectively]. However, IFN-stayers showed increased risk of relapses compared with FTY-stayers [HR (95% CI) 1.46 (1.00–2.12), p = 0.05]. Conclusion: The ideal treatment option for MS is becoming increasingly complex, with the need to balance benefit and risks. Our results suggest that starting with FTY affects the long-term disease outcome similarly to escalating from IFN-β1a to FTY. [ABSTRACT FROM AUTHOR]

Background: A high reactivation of multiple sclerosis (MS) was reported in patients treated with alemtuzumab after fingolimod. We aimed to understand whether this shift enhanced the risk for reactivation in a real-life cohort. Methods: Subjects with relapsing MS, shifting from fingolimod to alemtuzumab were enrolled. We collected the following data: age, sex, disease duration, relapses after fingolimod withdrawal, new T2/gadolinium (Gd)-enhancing lesions in the last magnetic resonance imaging (MRI) during fingolimod and in the first, while on alemtuzumab, lymphocyte counts at alemtuzumab start, and Expanded Disability Status Scale (EDSS) before and after alemtuzumab. Results: We enrolled 77 patients (women 61 (79%); mean age 36.2 years (SD 9.6), and disease duration 12.3 years (SD 6.8) at fingolimod discontinuation; median washout 1.8 months). The annualised relapse rate was 0.89 during fingolimod, 1.32 during washout, and 0.15 after alemtuzumab (p = 0.001). The EDSS changed from a median of 3 (IQR 2–4) at the end of fingolimod to 2.5 after alemtuzumab (IQR 1.5–4) (p = 0.013). The washout length and the lymphocyte count before alemtuzumab were not associated with EDSS change after alemtuzumab (p = 0.59 and p = 0.33, respectively). MRI activity decreased after alemtuzumab compared to that during fingolimod (p = 0.001). At alemtuzumab start, lymphocyte counts were < 0.8 × 103/mL in 21 patients. Conclusions: In our cohort, alemtuzumab reduced relapse, new T2/Gd-enhancing lesions, and EDSS score, as compared to the previous periods (fingolimod/washout). These results were not related to washout length or lymphocyte counts. Therefore, a rapid initiation of alemtuzumab after fingolimod does not seem to be a risk factor for MS reactivation. [ABSTRACT FROM AUTHOR]

Due to the COVID-19 pandemic, most memory clinics have had to suspend their activities. On the other hand, international dementia experts have recommended to provide urgently worldwide support for people living with dementia. This situation urges to play out new strategies to guarantee adequate care. Telemedicine and digital technology (DT) devices, such as smartphones, can be very helpful in remote monitoring and care. Technological devices such as videoconference or smartphone apps might be used for follow-up visits and support to patients and caregivers and to acquire digital markers of clinical progression. Hopefully, this dramatic situation would facilitate the process of progressive familiarization of neurologists with telemedicine and DT approach. [ABSTRACT FROM AUTHOR]

Background: As a consequence of the coronavirus disease 2019 (COVID-19) pandemic, a large amount of consultations will be delivered through tele-medicine, especially for diseases causing chronic disability and requiring immunomodulatory treatments, such as multiple sclerosis (MS).Methods: We have hereby reviewed available tools for tele-neurology examination in MS, including components of neurological examination that can be assessed through video, patient-reported outcome measures (PROMs), and digital technology.Results: Overall, we have suggested a battery for assessing MS disability and relapses on tele-medicine, which brings together conventional examination, PROMs (e.g., Patient Determined Disease Steps, MS Impact Scale), and cognitive tests (Symbol Digit Modalities Test) that can be delivered remotely and in multiple languages.Discussion: The use of common tools for neurological examination could improve tele-neurology practice for both general neurologists and MS specialists, and quality of care for people with MS. [ABSTRACT FROM AUTHOR]

We propose a possible approach for the remote monitoring of infection risk in people with multiple sclerosis, especially those on immunosuppressant drugs, during COVID-19 pandemic. We developed a digital triage tool to be sent to patients to quickly identify people with high risk of COVID-19 infection. This tool will also limit unnecessary accesses to the MS centers reducing the risk of spreading the infection. [ABSTRACT FROM AUTHOR]

Cognitive reserve (CR) is a construct that originates from the observation of poor correspondence between brain damage and clinical symptoms. The aim of the study was to investigate the association between cognitive reserve (CR), brain reserve (BR) and cognitive functions and to evaluate whether CR might attenuate/moderate the negative impact of brain atrophy and lesion load on cognitive functions in multiple sclerosis (MS). To achieve these aims, ninety-eight relapsing-remitting MS patients underwent the brief repeatable battery of neuropsychological tests and Stroop test (ST). CR was assessed by vocabulary-based estimate of lifetime intellectual enrichment. All patients underwent a 3T MRI to assess T2-lesion load and atrophy measures, including normalized gray matter and white matter (nWMV) volumes. The BR was evaluated by maximal lifetime brain volume expressed by intracranial volume (ICV). Hierarchical regressions were used to investigate whether higher BR and/or CR is related to better cognitive performances after controlling for potentially confounding factors. The ICV was not associated with any cognitive tests. Intellectual enrichment was positively associated with performance on tests assessing memory, attention and information processing speed, verbal fluency and inhibitory control. Significant relationship between nWMV and ST was moderated by intellectual enrichment. In conclusion, the findings suggested that CR seems to mitigate cognitive dysfunction in MS patients and can reduce the negative impact of brain atrophy on inhibitory control, relevant for integrity of instrumental activities of daily living. [ABSTRACT FROM AUTHOR]

Cognitive reserve (CR) contributes to preserve cognition despite brain damage. This theory has been applied to multiple sclerosis (MS) to explain the partial relationship between cognition and MRI markers of brain pathology. Our aim was to determine the relationship between two measures of CR and cognition in MS. One hundred and forty-seven MS patients were enrolled. Cognition was assessed using the Rao's Brief Repeatable Battery and the Stroop Test. CR was measured as the vocabulary subtest of the WAIS-R score (VOC) and the number of years of formal education (EDU). Regression analysis included raw score data on each neuropsychological (NP) test as dependent variables and demographic/clinical parameters, VOC, and EDU as independent predictors. A binary logistic regression analysis including clinical/CR parameters as covariates and absence/presence of cognitive deficits as dependent variables was performed too. VOC, but not EDU, was strongly correlated with performances at all ten NP tests. EDU was correlated with executive performances. The binary logistic regression showed that only the Expanded Disability Status Scale (EDSS) and VOC were independently correlated with the presence/absence of CD. The lower the VOC and/or the higher the EDSS, the higher the frequency of CD. In conclusion, our study supports the relevance of CR in subtending cognitive performances and the presence of CD in MS patients. [ABSTRACT FROM AUTHOR]

Nowadays, the Internet is the major source to obtain information about diseases and their treatments. The Internet is gaining relevance in the neurological setting, considering the possibility of timely social interaction, contributing to general public awareness on otherwise less-well-known neurological conditions, promoting health equity and improving the health-related coping. Neurological patients can easily find several online opportunities for peer interactions and learning. On the other hand, neurologist can analyze user-generated data to better understand patient needs and to run epidemiological studies. Indeed, analyses of queries from Internet search engines on certain neurological diseases have shown a strict temporal and spatial correlation with the "real world." In this narrative review, we will discuss how the Internet is radically affecting the healthcare of people with neurological disorders and, most importantly, is shifting the paradigm of care from the hands of those who deliver care, into the hands of those who receive it. Besides, we will review possible limitations, such as safety concerns, financial issues, and the need for easy-to-access platforms. [ABSTRACT FROM AUTHOR]

Cognitive impairment (CI), mainly involving attention and processing speed (A-PS), is a common and disabling symptom in multiple sclerosis (MS). Symbol Digit Modalities Test (SDMT) is one of the more sensitive and reliable tests to assess A-PS deficits in MS. Structural MRI correlates of A-PS in MS still need to be clarified. This study aimed to investigate, in a large group of MS patients, the relationship between regional gray matter (GM) atrophy and SDMT performance. 125 relapsing remitting MS patients and 52 healthy controls (HC) underwent a 3 T-MRI protocol including high-resolution 3D-T1 imaging. All subjects underwent a neurological evaluation and SDMT. A Voxel Based Morphometry analysis was performed to assess: 1) correlations between regional GM volume and SDMT performance in MS patients; 2) regional differences in GM volume between MS patients and HC. Thalamic, putamen and cerebellar volumes were also calculated using FIRST tool from the FMRIB Software Library. A linear regression analysis was performed to assess the contribution of each one of these structures to A-PS performance. A significant negative correlation was found between regional GM volume and SDMT score at the level of the thalamus, cerebellum, putamen, and occipital cortex in MS patients. Thalamus, cerebellum and putamen also showed significant GM atrophy in MS patients compared to HC. Thalamic atrophy is also an independent and additional contributor to A-PS deficits in MS patients. These findings support the role of thalamus as the most relevant GM structure subtending A-PS performance in MS, as measured by SDMT. [ABSTRACT FROM AUTHOR]

The original article can be found online at https://doi.org/10.1007/s10072-021-05759-1 B Correction to: Neurological Sciences (2021) b https://doi.org/10.1007/s10072-021-05759-1 Originally, the article was published online with inverted author names. Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. [Extracted from the article]

Objective: The discrimination between recurrent glioma and radiation injury is often a challenge on conventional magnetic resonance imaging (MRI). We verified whether adding and combining proton MR spectroscopic imaging (H-MRSI), diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) information at 3 Tesla facilitate such discrimination. Materials and methods: Twenty-nine patients with histologically verified high-grade gliomas, who had undergone surgical resection and radiotherapy, and had developed new contrast-enhancing lesions close to the treated tumour, underwent MRI, H-MRSI, DWI and PWI at regular time intervals. The metabolite ratios choline (Cho)/normal()Cho, N-acetylaspartate (NAA)/NAA, creatine (Cr)/Cr, lactate/lipids (LL)/LL, Cho/Cr, NAA/Cr, Cho/NAA, NAA/Cr and Cho/Cr were derived from H-MRSI; the apparent diffusion coefficient (ADC) from DWI; and the relative cerebral blood volume (rCBV) from PWI. Results: In serial MRI, recurrent gliomas showed a progressive enlargement, and radiation injuries showed regression or no modification. Discriminant analysis showed that discrimination accuracy was 79.3 % when considering only the metabolite ratios (predictor, Cho/Cr), 86.2 % when considering ratios and ADC (predictors, Cho/Cr and ADC), 89.7 % when considering ratios and rCBV (predictors, Cho/Cr, Cho/Cr and rCBV), and 96.6 % when considering ratios, ADC and rCBV (predictors, Cho/Cho, ADC and rCBV). Conclusions: The multiparametric 3-T MR assessment based on H-MRSI, DWI and PWI in addition to MRI is a useful tool to discriminate tumour recurrence/progression from radiation effects. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to assess differences in the presence, size, number and site of dilated cerebral Virchow-Robin spaces (VRSd) between patients with multiple sclerosis (MS) in the inactive phase and healthy controls, and between MS patients with disabling (MSd) or nondisabling (MSnd) disease. Materials and methods: The study was performed by retrospectively analysing the 3 T magnetic resonance studies of 40 MS patients and 30 healthy subjects (matched for age, education and gender). The data were analysed with MIPAV (Medical Image Processing, Analysis and Visualisation) software to assess for VRSd and with FSL SIENA-X to measure global cerebral atrophy (GCA) expressed as brain parenchyma fraction. Results: The MS patients had significantly higher VRSd number ( p < 0.011), area ( p < 0.0073) and volume ( p < 0.0071) than controls, with a marked increase for atypical sites ( p < 0.0069) without significant intragroup differences between the disease forms (MSd vs MSnd). The number and size of VRSd did not correlate with GCA. Conclusions: Our results confirm previous reports regarding the increase in VRSd in nonactive phases of MS and support the immunological role of the VRS within the central nervous system. The lack of correlation between VRSd and the degree of GCA and their prevailing localisation in atypical sites in MS patients make VRSd a potential marker of inflammatory-demyelinating disease. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the usefulness of proton MR spectroscopic imaging ((1)H-MRSI) at 3 T in differentiating high- from low-grade gliomas, and tumour from necrosis, oedema or normal tissue. Forty-four patients with brain gliomas and four with meningiomas were retrospectively reviewed. The normalised metabolites choline (nCho), N-acetylaspartate (nNAA), creatine (nCr) and lactate/lipids (nLL), and the metabolite ratios Cho/NAA, NAA/Cr and Cho/Cr were calculated. Necrotic-appearing areas showed two spectroscopic patterns: "necrosis" with variable nCho and high nLL, and "cystic necrosis" with variable nLL or nonevident peaks. Peri-enhancing oedematous-appearing areas showed three spectroscopic patterns ("tumour" with abnormal Cho/NAA, "oedema" with normal Cho/NAA and "tumour/oedema" with normal nCho and abnormal Cho/NAA) in gliomas, and one ("oedema") in meningiomas. Peri-enhancing or peri-tumour normal-appearing areas showed two patterns ("infiltrated" with abnormal nCho and/or Cho/NAA and "normal" with normal spectra) in gliomas and one ("normal") in meningiomas. Discriminant analysis showed that classification accuracy between high- and low-grade glioma masses was better with normalised metabolites or all parameters together than metabolite ratios and that among peri-enhancing areas was much better with normalised metabolites. The analysis of spatial distribution of normalised metabolites by 3-T (1)H-MRSI helps to discriminate among different tissues, offering information not available with conventional MRI. [ABSTRACT FROM AUTHOR]

Contrast-enhanced MR imaging is the method of choice for routine assessment of brain tumors, but it has limited sensitivity and specificity. We verified if the addition of metabolic, diffusion and hemodynamic information improved the definition of glioma extent and grade. Thirty-one patients with cerebral gliomas (21 high- and 10 low-grade) underwent conventional MR imaging, proton MR spectroscopic imaging (1H-MRSI), diffusion weighted imaging (DWI) and perfusion weighted imaging (PWI) at 3 Tesla, before undergoing surgery and histological confirmation. Normalized metabolite signals, including choline (Cho), N-acetylaspartate (NAA), creatine and lactate/lipids, were obtained by 1H-MRSI; apparent diffusion coefficient (ADC) by DWI; and relative cerebral blood volume (rCBV) by PWI. Perienhancing areas with abnormal MR signal showed 3 multiparametric patterns: “tumor”, with abnormal Cho/NAA ratio, lower ADC and higher rCBV; “edema”, with normal Cho/NAA ratio, higher ADC and lower rCBV; and “tumor/edema”, with abnormal Cho/NAA ratio and intermediate ADC and rCBV. Perienhancing areas with normal MR signal showed 2 multiparametric patterns: “infiltrated”, with high Cho and/or abnormal Cho/NAA ratio; and “normal”, with normal spectra. Stepwise discriminant analysis showed that the better classification accuracy of perienhancing areas was achieved when regarding all MR variables, while 1H-MRSI variables and rCBV better differentiated high- from low-grade gliomas. Multiparametric MR assessment of gliomas, based on 1H-MRSI, PWI and DWI, discriminates infiltrating tumor from surrounding vasogenic edema or normal tissues, and high- from low-grade gliomas. This approach may provide useful information for guiding stereotactic biopsies, surgical resection and radiation treatment. [ABSTRACT FROM AUTHOR]

Background Cognitive impairment may occur at any time during the course of multiple sclerosis (MS), and it is often a major cause of disability in patients with the disease. The APOE-e4 allele is the major known genetic risk factor for late onset familial and sporadic Alzheimer's Disease (AD), and it seems to be implicated in cognitive decline in normal elderly persons. Objective To investigate the clinical and genetic variables that can be associated with the cognitive decline in patients with MS. Methods Five-hundred and three patients with clinically definite MS underwent a battery of neuropsychological tests and, according to the number of failed tests, were divided into cognitively normal and impaired. All patients were genotyped for APOE gene polymorphisms. Results Fifty-six percent of MS patients showed, to different extents, cognitive impairment. Cognitive decline was predominant in men and was associated with disease duration, Kurtzke Expanded Disability Status Scale (EDSS) score, a low level of education, and, interestingly, the ε4 allele of the APOE gene. By contrast, cognitive impairment in women was independent of any investigated variable. Conclusion The findings demonstrate that clinical and genetic factors play a role in men affected by MS developing cognitive impairment. [ABSTRACT FROM AUTHOR]

Objective:. To investigate the association between apolipoprotein E (APOE) polymorphisms and the progression of MS. Methods:. We investigated 428 subjects affected by clinically defined MS, with a disease duration of at least three years. We collected data concerning the age at onset of MS, clinical type, disease duration and disability according to the expanded disability status scale (EDSS). We also calculated the progression index (PI) to evaluate disease progression. APOE genotyping and the –491 A/T polymorphism of the APOE promoter were determined. Results:. No association was observed between the APOE ε4 allele and clinical characteristics of our study population. We also investigated the –491 A/T APOE promoter polymorphism in 236 MS subjects and did not find any association between the –491 A/T polymorphism and the selected clinical variables. Conclusions:. In our population the APOE ε4 allele and the –491 A/T APOE promoter polymorphism are not associated with a more rapid course of MS. [ABSTRACT FROM AUTHOR]

An assessment of the detectability of white matter lesions and of concordance between observers with different levels of MRI reading experience was performed with comparative evaluation of spin-echo MRI images and of corresponding “multispectral”maps in 16 patients with definite multiple sclerosis (MS). Multispectral maps were obtained by means of a recently described post-processing technique based on the simultaneous display of MRI parameters and a standardized colour scale with red, green and blue coding for relaxation rates R1 and R2 and proton density, respectively. Spin-echo images on films and multispectral maps displayed on a personal computer were randomly rated at 2-month intervals. Interobserver concordance (k-test) was assessed among three readers with different levels of MRI experience (an experienced neuroradiologist, a radiology resident and a neurologist). For multispectral maps we found increased interobserver concordance with the experienced neuroradiologist (multispectral vs conventional images: k = 0.77 vs 0.66 for the radiology resident and 0.66 vs 0.56 for the neurologist), an increased number of detected lesions and decreased reading time. Multispectral maps permit easy detection of MS lesions and may improve interobserver concordance compared with conventional spin-echo studies. [ABSTRACT FROM AUTHOR]