Search

PRINCIPLES: The risk of seizures increases in patients with brain tumours (BT) and brain vascular malformations (BVM), but not all risk factors are known. We aimed to identify factors that increase the risk of a first seizure in patients with BT or BVM. METHODS: Multicentre case-control study; 102 cases with a first seizure as a presenting symptom of BT or BVM; 121 hospital controls with BT or BVM, but without seizures, matched by centre, gender and age. RESULTS: In the univariate analysis, the risk of first seizure (Odds Ratio, 95% Confidence Limits) was 6.4 (2.3–17.6) for supratentorial lesions, 4.7 (2.4–9.3) for cortical involvement, 2.5 (1.0–7.7) for family history of seizures, and 2.1 (1.2–4.1) for frontal location. The types of lesion with higher risk were low grade glioma (4.7; 1.7–13.9) and cavernous malformations (13.2; 2.1–58.0). After multivariate analysis, including all the imaging characteristics and family history, the strongest independent predictors of first seizure were cortical involvement (OR 4.0; 2.0–8.1) and type of lesion (low grade glioma: 4.0; 1.3–12.8; cavernous malformations: 12.6 (1.5–103.5). CONCLUSIONS: Cortical involvement and type of lesion are the independent risk factors for a first-ever seizure as a presenting symptom of BT or BVM.

Excessive daytime sleepiness (EDS) and insomnia (IN) complaints represent the most common sleep/wake disorders. Currently, the specific needs of these patients and their relatives, as well as the overall socio-economic burden of IN and EDS remains widely unexplored. This pilot study to be carried out in Switzerland is a retro- and prospective, national, one-center cohort observational study for the systematic evaluation of the burden of EDS and IN and its evolution 12 months after the first assessment. Patient recruitment will be organized through 7-8 primary care providers (primary/general care practitioners and pharmacies). Primary outcomes are the prevalence of EDS/IN in the primary care setting and the association between EDS/IN with health-related quality of life (QOL) as assessed with the established instruments. Secondary outcomes are the association between EDS/IN with the presence of comorbidities, number of injuries/accidents, and number of sick/leave days for the subgroup of working subjects. Calculation of direct per-patient costs will be undertaken to analyze the economic implications of sleep/wake disorders, providing valuable insights into the financial burden experienced by affected individuals within the healthcare system. This research will provide information on the feasibility of such a study and inform on aspects of the QOL most associated with EDS/IN. Based on this pilot project, a European multicenter study on the burden of sleep/wake disorders will be conducted by the European Academy of Neurology.

Background: The therapeutic scenario in multiple sclerosis (MS) has evolved over recent years with the progressive introduction of new drugs focused to better balance efficacy, safety and management requirements. The objective of this study was to examine the prescribing patterns of disease-modifying therapies (DMT) over time and across different geographic areas, and the latency between disease onset, first Register center visit, disease diagnosis, and the start of treatment in a large cohort of persons with MS from the Italian Multiple Sclerosis and Related Disorders Register., Methods: Up to 2022, the Register collected data from 124 centers on more than 78,000 persons, of whom 56,872 received at least one DMT prescription. Beside baseline demographic and clinical characteristics, we focused on DMT according to their efficacy distinguishing between moderate-efficacy (ME), or high-efficacy (HE)., Results: There was a higher probability of prescribing HE-DMT for increasing calendar years (multivariable odds ratio, OR=11.51 in 2021 or thereafter vs before 2000), in males (OR=1.08 vs females), patients with primary progressive with or without relapse (OR=3.00 vs clinically isolated syndrome), those with a higher Expanded Disability Status Scale score (OR=3.85 for >4 versus 0-1), and those from larger referral centers (OR=1.89 vs smaller ones). Conversely, higher age at onset was associated to a lower probability of prescribing HE-DMT (OR=0.74 at 40 or more vs <20 years). A trend to shorter times was observed in subsequent calendar years for disease onset, first center visit, diagnosis and first DMT prescription. No trend was detected based on the location of the geographic referral centers. The times between disease onset, first center visit, and diagnosis and the first DMT prescription showed significant decreases according to the year, while differences were less evident for the geographic areas., Conclusion: This study highlights some factors influencing the choice of HE-DMT, including aspects of both healthcare and clinical phenotype. The absence of a geographic pattern may indicate some homogeneity in DMT prescriptions across different Italian MS centers., Competing Interests: Declaration of competing interest VL, PP, CB, CS, MP, EP, and PM declare no conflict of interest. MAL received a grant from FISM. RB received compensation for travel, grants, participation in advisory board/data safety monitoring board and/or speaking activities from Biogen, Merck Serono, Roche, Novartis, Celgene, Janssen, Sanofi Genzyme., (Copyright © 2024. Published by Elsevier B.V.)

Several neurological manifestations are part of the post-COVID condition. We aimed to: (1) evaluate the 6-month outcome in the cohort of patients with neurological manifestations during the COVID-19 acute phase and surviving the infection, and find outcome predictors; (2) define the prevalence and type of neurological symptoms persistent at six months after the infection. Data source was an international registry of patients with COVID-19 infection and neurological symptoms, signs or diagnoses established by the European Academy of Neurology. Functional status at six-month follow-up was measured with the modified Rankin scale (mRS), and defined as: "stable/improved" if the mRS at six months was equal as or lower than the baseline score; "worse" if it was higher than the baseline score. By October 30, 2022, 1,003 lab-confirmed COVID-19 patients were followed up for a median of 6.5 months. Compared to their pre-morbid status, 522 patients (52%) were stable/improved, whereas 465 (46%) were worse (functional status missing for 16). Age, hospitalization, several pre-COVID-19 comorbidities, and COVID-19 general complications were predictors of a worse status. Amongst neurological manifestations, stroke carried the highest risk for worse outcome (OR 5.96), followed by hyperactive delirium (2.8), and peripheral neuropathies (2.37). On the other hand, hyposmia/hypogeusia (0.38), headache (0.40), myalgia (0.45), and COVID-19 vaccination (0.52) were predictors of a favourable prognosis. Persisting neurological symptoms or signs were reported by 316/1003 patients (31.5%), the commonest being fatigue (n = 133), and impaired memory or concentration (n = 103). Our study identified significant long-term prognostic predictors in patients with COVID-19 and neurological manifestations., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: More than 200 clinical trials have been performed worldwide in ALS so far, but no agents with substantial efficacy on disease progression have been found., Objective: To describe the methodological quality of all clinical trials performed in ALS and published before December 31, 2022., Methods: We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta Analyses., Results: 213 trials were included. 47.4% manuscripts described preclinical study evaluation, with a positive effect in all. 67.6% of trials were conducted with a parallel-arm design, while 12.7% were cross-over studies; 77% were randomized, while in 5.6% historical-controls were used for comparison. 70% of trials were double blind. Participant inclusion allowed forced vital capacity (or corresponding slow vital capacity)<50% in 15% cases, between 55-65% in 21.6%, between 70-80% in 14.1% reports, and 49.3% of the evaluated manuscripts did not provide a minimum value for respiratory capacity at inclusion. Disease duration was < 6-months in 6 studies, 7-36 months in 68, 37-60 months in 24, 8 trials requested more than 1-month of disease duration, while in 107 reports a disease duration was not described. Dropout rate was ≥20% in 30.5% trials, while it was not reported for 8.5%., Conclusion: The methodological quality of the included studies was highly variable. Major issues to be addressed in future ALS clinical trials include: the requirement for standard animal toxicology and phase I studies, the resource-intensive nature of phase II-III studies, adequate study methodology and design, a good results reporting.

We report the analysis of 1 year of data from the first cohort of 15 patients enrolled in an open-label, first-in-human, dose-escalation phase I study (ClinicalTrials.gov: NCT03282760, EudraCT2015-004855-37) to determine the feasibility, safety, and tolerability of the transplantation of allogeneic human neural stem/progenitor cells (hNSCs) for the treatment of secondary progressive multiple sclerosis. Participants were treated with hNSCs delivered via intracerebroventricular injection in combination with an immunosuppressive regimen. No treatment-related deaths nor serious adverse events (AEs) were observed. All participants displayed stability of clinical and laboratory outcomes, as well as lesion load and brain activity (MRI), compared with the study entry. Longitudinal metabolomics and lipidomics of biological fluids identified time- and dose-dependent responses with increased levels of acyl-carnitines and fatty acids in the cerebrospinal fluid (CSF). The absence of AEs and the stability of functional and structural outcomes are reassuring and represent a milestone for the safe translation of stem cells into regenerative medicines., Competing Interests: Declaration of interests S.P. is founder, CSO, and shareholder (>5%) of CITC Ltd. and Chair of the Scientific Advisory Board at ReNeuron plc., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Purpose: The aim of this study was to assess the neurological complications of SARS-CoV-2 infection and compare phenotypes and outcomes in infected patients with and without selected neurological manifestations., Methods: The data source was a registry established by the European Academy of Neurology during the first wave of the COVID-19 pandemic. Neurologists collected data on patients with COVID-19 seen as in- and outpatients and in emergency rooms in 23 European and seven non-European countries. Prospective and retrospective data included patient demographics, lifestyle habits, comorbidities, main COVID-19 complications, hospital and intensive care unit admissions, diagnostic tests, and outcome. Acute/subacute selected neurological manifestations in patients with COVID-19 were analysed, comparing individuals with and without each condition for several risk factors., Results: By July 31, 2021, 1523 patients (758 men, 756 women, and nine intersex/unknown, aged 16-101 years) were registered. Neurological manifestations were diagnosed in 1213 infected patients (79.6%). At study entry, 978 patients (64.2%) had one or more chronic general or neurological comorbidities. Predominant acute/subacute neurological manifestations were cognitive dysfunction (N = 449, 29.5%), stroke (N = 392, 25.7%), sleep-wake disturbances (N = 250, 16.4%), dysautonomia (N = 224, 14.7%), peripheral neuropathy (N = 145, 9.5%), movement disorders (N = 142, 9.3%), ataxia (N = 134, 8.8%), and seizures (N = 126, 8.3%). These manifestations tended to differ with regard to age, general and neurological comorbidities, infection severity and non-neurological manifestations, extent of association with other acute/subacute neurological manifestations, and outcome., Conclusions: Patients with COVID-19 and neurological manifestations present with distinct phenotypes. Differences in age, general and neurological comorbidities, and infection severity characterize the various neurological manifestations of COVID-19., (© 2022 European Academy of Neurology.)

Background and Purpose: Rare diseases affect up to 29 million people in the European Union, and almost 50% of them affect the nervous system or muscles. Delays in diagnosis and treatment onset and insufficient treatment choices are common. Clinical practice guidelines (CPGs) may improve the diagnosis and treatment of patients and optimize care pathways, delivering the best scientific evidence to all clinicians treating these patients. Recommendations are set for developing and reporting high-quality CPGs on rare neurological diseases (RNDs) within the European Academy of Neurology (EAN), through a consensus procedure., Methods: A group of 27 experts generated an initial list of items that were evaluated through a two-step Delphi consensus procedure and a face-to-face meeting. The final list of items was reviewed by an external review group of 58 members., Results: The consensus procedure yielded 63 final items. Items are listed according to the domains of the AGREE instruments and concern scope and purpose, stakeholder involvement, rigour of development, and applicability. Additional items consider reporting and ethical issues. Recommendations are supported by practical examples derived from published guidelines and are presented in two tables: (1) items specific to RND CPGs, and general guideline items of special importance for RNDs, or often neglected; (2) items for guideline development within the EAN., Conclusions: This guidance aims to provide solutions to the issues specific to RNDs. This consensus document, produced by many experts in various fields, is considered to serve as a starting point for further harmonization and for increasing the quality of CPGs in the field of RNDs., (© 2022 European Academy of Neurology.)

Background: A significant proportion of patients with coronavirus disease 2019 (COVID-19) suffer from delirium during hospitalization. This single-center observational study investigates the occurrence of delirium, the associated risk factors and its impact on in-hospital mortality in an Italian cohort of COVID 19 inpatients., Methods: Data were collected in the COVID units of a general medical hospital in the South of Italy. Socio-demographic, clinical and pharmacological features were collected. Diagnosis of delirium was based on a two-step approach according to 4AT criteria and DSM5 criteria. Outcomes were: dates of hospital discharge, Intensive Care Unit (ICU) admission, or death, whichever came first. Univariable and multivariable proportional hazards Cox regression models were estimated, and risks were reported as hazard ratios (HR) along with their 95% confidence intervals (95% CI)., Results: A total of 47/214 patients (22%) were diagnosed with delirium (21 hypoactive, 15 hyperactive, and 11 mixed). In the multivariable model, four independent variables were independently associated with the presence of delirium: dementia, followed by age at admission, C-reactive protein (CRP), and Glasgow Coma Scale. In turn, delirium was the strongest independent predictor of death/admission to ICU (composite outcome), followed by Charlson Index (not including dementia), CRP, and neutrophil-to-lymphocyte ratio. The probability of reaching the composite outcome was higher for patients with the hypoactive subtype than for those with the hyperactive subtype., Conclusions: Delirium was the strongest predictor of poor outcome in COVID-19 patients, especially in the hypoactive subtype. Several clinical features and inflammatory markers were associated with the increased risk of its occurrence. The early recognition of these factors may help clinicians to select patients who would benefit from both non-pharmacological and pharmacological interventions in order to prevent delirium, and in turn, reduce the risk of admission to ICU or death.

Background and Aims: The association between lifestyle factors and Multiple Sclerosis (MS) disease severity and progression has been investigated to a lesser extent compared with susceptibility to the disease. We aimed to assess the impact of lifetime coffee and tea consumption on MS severity., Methods: Design: cross-sectional study. Two hundred and eight patients (139 females and 69 males) consecutively recruited at the Department of Neurology in Novara, Italy were asked about their lifetime consumption of coffee and tea. The lifetime intensity of consumption (cups/day) was estimated as the weighted sum of the mean number of standard cups drunk per day at different ages. A measure of cumulative lifetime load of the exposure was expressed in terms of cup-years. Disease severity was estimated by the Multiple Sclerosis Severity Score (MSSS). HLA-DRB1∗15 and HLA-A∗02 genotyping was performed in 167 patients., Results: The MSSS was not associated with the status of coffee or tea consumer, or the amount of cups/day or cup-years. The Odds Ratios (OR) for falling in the upper tertile of the MSSS distribution was 1.30 (95% Confidence Interval (CI): 0.47-3.58) for coffee consumers of 1-3 cups/day and 1.14 (95%CI: 0.33-3.95) for 4-8 cups/day vs. non-consumers. The OR was 0.69 (95%CI: 0.35-1.34) for tea consumers vs. non-consumers. However, heavy consumers of coffee (4-8 cups/day) more frequently had a progressive form than small consumers (1-3 cups/day) and non-consumers (19% vs. 14% vs. 0%), and had a significantly higher age at MS onset (36.6 ± 10.3; 31.5 ± 9.5; 28.6 ± 8.1 years, p = 0.001). Although not reaching statistical significance, coffee consumers positive for HLA-A∗02 had a six-fold risk of being in the worst tertile compared to never consumers, whereas the risk was only 1.3 for coffee consumers negative for the same allele., Conclusions: Coffee or tea intake is not associated with different severity of MS. However, we cannot exclude a possible effect of higher doses of coffee for the subgroup of progressive patients., Competing Interests: Declaration of competing interest All the Authors report no conflict of interest related to this study., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Amyotrophic lateral sclerosis (ALS) is a devastating and untreatable motor neuron disease, with a 3-5-year survival from diagnosis. Possible prognostic serum biomarkers include albumin, C-reactive protein, ferritin, creatinine, uric acid, hemoglobin, potassium, sodium, calcium, glucose, and the neutrophil-to-lymphocyte ratio (NLR), a marker of subclinical inflammation., Objective: To ascertain the influence of NLR on ALS progression rate and survival., Methods: Cross-sectional multicenter study including 146 consecutive incident and prevalent patients (88 males), aged >18 years, diagnosed according to the El Escorial criteria. The exclusion criteria were: (1) patients with tracheostomy or receiving mechanical ventilation; (2) patients with percutaneous endoscopic gastrostomy; and (3) patients who did not sign the informed consent. The rate of disease progression (ΔFS score) represents the monthly decline of the ALSFRS-R score, and was computed as (48 - total ALSFRS-R at recruitment)/symptom duration in months. Patients were followed up to tracheotomy, death, or the end of the follow-up, whichever occurred first. To validate our findings, we used data retrieved from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) Database., Results: The median disease duration was 15 (range = 2-30) months. The mean ALSFRS-R score at recruitment was 35.8 ± 8.0 (range: 10-48), and the median ΔFS was 0.66 (range: 0-5.33). Age at onset, at diagnosis, and at recruitment were significantly lower in the lowest NLR tertile. NLR values positively correlated with ΔFS values (r = 0.28): the regression slope of NLR (log-values) was 0.60 ( p < 0.001) before and 0.49 ( p = 0.006) after adjustment for age at recruitment. The ΔFS score progressively increased from the lowest to the highest NLR tertile: 0.35 (IQR: 0.18-0.93), 0.62 (IQR: 0.25-1.09), and 0.86 (IQR: 0.53-1.92). Patients were followed for a median of 2 years. The mortality rate passed from 15.9 events per 100 person-years in patients belonging to the lowest NLR tertile to 52.8 in those in the highest tertile. The optimal cut-off value which best classified patients with the lowest and the highest mortality rate was set at the NLR value of 2.315. Indeed, the mortality rate of patients with an NLR value above such cut-off was twice the mortality rate of patients with a value below the cut-off (age adjusted hazard ratio (HR): 2.16, 95% confidence interval (CI): 1.32-3.53). In the PRO-ACT validation sample, patients with an NLR value above the cut-off consistently had a higher mortality rate than those with a value below the cut-off (age adjusted HR: 1.17, 95%CI: 1.01-1.35)., Conclusions: NLR could be a candidate easy, fast, and low-cost marker of disease progression and survival in ALS. It may be associated with low-grade inflammation either as a direct mirror of the pathological process of disease progression, or as a consequence of neuronal death (reverse causation). However, prospective studies are needed to understand whether NLR changes during the course of the disease, before using it to monitor disease progression in ALS.

Background: The clinical course of COVID-19 is more severe in elderly patients with cardio-metabolic co-morbidities. Chronic kidney disease is considered an independent cardiovascular risk factor. We aimed to evaluate the impact of reduced eGFR on the composite outcome of admission to ICU and death in a sample of consecutive COVID-19 hospitalized patients., Methods: We retrospectively evaluated clinical records of a consecutive sample of hospitalized COVID-19 patients. A total of 231 patients were considered for statistical analysis. The whole sample was divided in two groups on the basis of eGFR value, e.g., ≥ or <60 mL/min/1.73 m 2 . Patients with low eGFR were further divided among those with a history of chronic kidney disease (CKD) and those without (AKI, acute kidney injury). The primary outcome was a composite of admission to ICU or death, whichever occurred first. The single components were secondary outcomes., Results: Seventy-nine (34.2%) patients reached the composite outcome. A total of 64 patients (27.7%) died during hospitalization, and 41 (17.7%) were admitted to the ICU. A significantly higher number of events was present among patients with low eGFR ( p < 0.0001). Age ( p < 0.001), SpO2 ( p < 0.001), previous anti-platelet treatment ( p = 0.006), Charlson's Comorbidities Index ( p < 0.001), serum creatinine ( p < 0.001), eGFR ( p = 0.003), low eGFR ( p < 0.001), blood glucose levels ( p < 0.001), and LDH ( p = 0.003) were significantly associated with the main outcome in univariate analysis. Low eGFR (HR 1.64, 95% CI 1.02-2.63, p = 0.040) and age (HR per 5 years 1.22, 95% CI 1.10-1.36, p < 0.001) were significantly and independently associated with the main outcome in the multivariate model. Patients with AKI showed an increased hazard ratio to reach the combined outcome ( p = 0.059), while those patients with both CKD had a significantly higher probability of developing the combined outcome ( p < 0.001)., Conclusions: Patients with reduced eGFR at admission should be considered at high risk for clinical deterioration and death, requiring the best supportive treatment in order to prevent the worst outcome.

Background/objectives: Amyotrophic lateral sclerosis (ALS) is a devastating and still untreatable motor neuron disease. The causes of ALS are unknown, but nutritional factors may impact the rate of disease progression. We aimed to ascertain the influence of coffee and tea consumption on ALS progression rate. Subjects/methods: In this multicenter cross-sectional study, we recruited 241 patients, 96 females, and 145 males; the mean age at onset was 59.9 ± 11.8 years. According to El Escorial criteria, 74 were definite ALS, 77 probable, 55 possible, and 35 suspected; 187 patients had spinal onset and 54 bulbar. Patients were categorized into three groups, according to their ΔFS (derived from ALS Functional Rating Scale-Revised score and disease duration from onset): slow (81), intermediate (80), and fast progressors (80). Results: Current coffee consumers were 179 (74.3%), 34 (14.1%) were non-consumers, and 22 (9.1%) were former consumers, whereas six (2.5%) consumed decaffeinated coffee only. The log-ΔFS was weakly correlated with the duration of coffee consumption ( p = 0.034), but not with the number of cup-years, or the intensity of coffee consumption (cups/day). Current tea consumers were 101 (41.9%), 6 (2.5%) were former consumers, and 134 (55.6%) were non-consumers. Among current and former consumers, 27 (25.2%) consumed only green tea, 51 (47.7%) only black tea, and 29 (27.1%) both. The log-ΔFS was weakly correlated only with the consumption duration of black tea ( p = 0.028) but not with the number of cup-years. Conclusions: Our study does not support the hypothesis that coffee or tea consumption is associated with the ALS progression rate., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cucovici, Ivashynka, Fontana, Russo, Mazzini, Mandrioli, Lisnic, Muresanu and Leone.)

Background: This is an updated version of the Cochrane review previously published in 2016. There is considerable disagreement about the risk of recurrence following a first unprovoked epileptic seizure. A decision about whether to start antiepileptic drug treatment following a first seizure should be informed by information on the size of any reduction in risk of future seizures, the impact on long-term seizure remission, and the risk of adverse effects., Objectives: To review the probability of seizure recurrence, seizure remission, mortality, and adverse effects of antiepileptic drug (AED) treatment given immediately after the first seizure compared to controls (placebo, deferred treatment, or no treatment) in children and adults., Search Methods: For the latest update, we searched the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid, 1946 to May 24, 2019) on 28 May 2019. There were no language restrictions. The Cochrane Register of Studies includes the Cochrane Epilepsy Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), and randomised or quasi-randomised, controlled trials from Embase, ClinicalTrials.gov and the World Health Organisation International Clinical Trials Registry Platform (ICTRP)., Selection Criteria: Randomised controlled trials (RCTs) and quasi-RCTs that could be blinded or unblinded. People of any age with a first unprovoked seizure of any type. Included studies compared participants receiving immediate antiepileptic treatment versus those receiving deferred treatment, those assigned to placebo, and those untreated., Data Collection and Analysis: Two review authors independently assessed the studies identified by the search strategy for inclusion in the review and extracted data. The certainty of the evidence for the outcomes was classified in four categories according to the GRADE approach. Dichotomous outcomes were expressed as Risk Ratios (RR) with 95% confidence intervals (CI). Time-to-event outcomes were expressed as Hazard Ratios (HR) with 95% CI. Only one trial used a double-blind design, and the two largest studies were unblinded. Most of the recurrences were generalised tonic-clonic seizures, a major type of seizures that is easily recognised, which should reduce the risk of outcome reporting bias., Main Results: After exclusion of irrelevant papers, six studies (eleven reports) were selected for inclusion. Individual participant data were available from the two largest studies for meta-analysis. Selection bias and attrition bias could not be excluded within the four smaller studies, but the two largest studies reported attrition rates and adequate methods of randomisation and allocation concealment. Only one small trial used a double-blind design and the other trials were unblinded; however, most of the recurrences were generalised tonic-clonic seizures, a type of seizure that is easily recognisable. Compared to controls, participants randomised to immediate treatment had a lower probability of relapse at one year (RR 0.49, 95% CI 0.42 to 0.58; 6 studies, 1634 participants; high-certainty evidence), at five years (RR 0.78; 95% CI 0.68 to 0.89; 2 studies, 1212 participants; high-certainty evidence) and a higher probability of an immediate five-year remission (RR 1.25; 95% CI 1.02 to 1.54; 2 studies, 1212 participants; high-certainty evidence). However, there was no difference between immediate treatment and control in terms of five-year remission at any time (RR 1.02, 95% CI 0.87 to 1.21; 2 studies, 1212 participants; high-certainty evidence). Antiepileptic drugs did not affect overall mortality after a first seizure (RR 1.16; 95% CI 0.69 to 1.95; 2 studies, 1212 participants; high-certainty evidence). Compared to deferred treatment, treatment of the first seizure was associated with a significantly higher risk of adverse events (RR 1.49, 95% CI 1.23 to 1.79; 2 studies, 1212 participants; moderate-certainty evidence). We assessed the certainty of the evidence as moderate to low for the association of higher risk of adverse events when treatment of the first seizure was compared to no treatment or placebo, (RR 14.50, 95% CI 1.93 to 108.76; 1 study; 118 participants) and (RR 4.91, 95% CI 1.10 to 21.93; 1 study, 228 participants) respectively., Authors' Conclusions: Treatment of the first unprovoked seizure reduces the risk of a subsequent seizure but does not affect the proportion of patients in remission in the long term. Antiepileptic drugs are associated with adverse events, and there is no evidence that they reduce mortality. In light of this review, the decision to start antiepileptic drug treatment following a first unprovoked seizure should be individualised and based on patient preference, clinical, legal, and sociocultural factors., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background-Amyotrophic lateral sclerosis (ALS) is a devastating and untreatable motor neuron disease; smoking and alcohol drinking may impact its progression rate. Objective-To ascertain the influence of smoking and alcohol consumption on ALS progression rates. Methods-Cross-sectional multicenter study, including 241 consecutive patients (145 males); mean age at onset was 59.9 ± 11.8 years. Cigarette smoking and alcohol consumption data were collected at recruitment through a validated questionnaire. Patients were categorized into three groups according to ΔFS (derived from the ALS Functional Rating Scale-Revised and disease duration from onset): slow ( n = 81), intermediate (80), and fast progressors (80). Results-Current smokers accounted for 44 (18.3%) of the participants, former smokers accounted for 10 (4.1%), and non-smokers accounted for 187 (77.6%). The age of ALS onset was lower in current smokers than non-smokers, and the ΔFS was slightly, although not significantly, higher for smokers of >14 cigarettes/day. Current alcohol drinkers accounted for 147 (61.0%) of the participants, former drinkers accounted for 5 (2.1%), and non-drinkers accounted for 89 (36.9%). The log(ΔFS) was weakly correlated only with the duration of alcohol consumption ( p = 0.028), but not with the mean number of drinks/day or the drink-years. Conclusions: This cross-sectional multicenter study suggested a possible minor role for smoking in worsening disease progression. A possible interaction with alcohol drinking was suggested.

Background: The diagnosis of Coronavirus disease 2019 (COVID-19) relies on the positivity of nasopharyngeal swab. However, a significant percentage of symptomatic patients may test negative. We evaluated the reliability of COVID-19 diagnosis made by radiologists and clinicians and its accuracy versus serology in a sample of patients hospitalized for suspected COVID-19 with multiple negative swabs., Methods: Admission chest CT-scans and clinical records of swab-negative patients, treated according to the COVID-19 protocol or deceased during hospitalization, were retrospectively evaluated by two radiologists and two clinicians, respectively., Results: Of 254 patients, 169 swab-confirmed cases and one patient without chest CT-scan were excluded. A total of 84 patients were eligible for the reliability study. Of these, 21 patients died during hospitalization; the remaining 63 underwent serological testing and were eligible for the accuracy evaluation. Of the 63, 26 patients showed anti-Sars-Cov-2 antibodies, while 37 did not. The inter-rater agreement was "substantial" (kappa 0.683) between radiologists, "moderate" (kappa 0.454) between clinicians, and only "fair" (kappa 0.341) between radiologists and clinicians. Both radiologic and clinical evaluations showed good accuracy compared to serology., Conclusions: The radiologic and clinical diagnosis of COVID-19 for swab-negative patients proved to be sufficiently reliable and accurate to allow a diagnosis of COVID-19, which needs to be confirmed by serology and follow-up.

Introduction: Italy is considered a high-risk country for multiple sclerosis (MS). Exploiting electronic health archives (EHAs) is highly useful to continuously monitoring the prevalence of the disease, as well as the care delivered to patients and its outcomes. The aim of this study was to validate an EHA-based algorithm to identify MS patients, suitable for epidemiological purposes, and to estimate MS prevalence in Piedmont (North Italy)., Methods: MS cases were identified, in the period between January 1, 2012 and December 31, 2017, linking data from 4 different sources: hospital discharges, drug prescriptions, exemptions from co-payment to health care, and long-term care facilities. Sensitivity of the algorithm was tested through record linkage with a cohort of 656 neurologist-confirmed MS cases; specificity was tested with a cohort of 2,966,293 residents presumably not affected by MS. Undercount was estimated by a capture-recapture method. We calculated crude, and age- and gender-specific prevalence. We also calculated age-adjusted prevalence by level of urbanization of the municipality of residence., Results: On December 31, 2017, the algorithm identified 8,850 MS cases. Sensitivity was 95.9%, specificity was 99.97%, and the estimated completeness of ascertainment was 91.9%. The overall prevalence, adjusted for undercount, was 152 per 100,000 among men and 286 among women; it increased with increasing age and reached its peak value in the 45- to 54-year class, followed by a progressive reduction. The age-adjusted prevalence of residents in cities was 15% higher than in those living in the countryside., Discussion/conclusion: We validated an algorithm based on EHAs to identify cases of MS for epidemiological use. The prevalence of MS, adjusted for undercount, was among the highest in Italy. We also found that the prevalence was higher in highly urbanized areas., (© 2021 S. Karger AG, Basel.)

Neuromuscular junction (NMJ) disorders include several dysfunctions that ultimately lead to muscle weakness. Myasthenia gravis (MG) is the most prevalent NMJ disorder with a highly polymorphic clinical presentation and many different faces. Being an autoimmune disease, MG correlates with the presence of detectable antibodies directed against the acetylcholine receptor, muscle-specific kinase, lipoprotein-related protein 4, agrin, titin, and ryanodine in the postsynaptic membrane at the NMJ. MG has become a prototype serving to understand both autoimmunity and the function of the NMJ better. The aim of this review is to synthesize some of the epidemiological data available. Epidemiological data regarding MG are important for postulating hypotheses regarding its etiology and facilitating the description of MG subtypes. Thus, adequate documentation through broad databases is essential. The incidence and prevalence of MG reported around the globe have been rising steadily and consistently over the past decades. Ethnic aspects, gender-related differences, and environmental risk factors have been described, implying that these might contribute to a specific phenotype, further suggesting that MG may be considered an umbrella term that covers several clinical entities., (©2020 JOURNAL of MEDICINE and LIFE.)

Background and Purpose: The recent SARS-CoV-2 pandemic has posed multiple challenges to the practice of clinical neurology including recognition of emerging neurological complications and management of coexistent neurological diseases. In a fast-evolving pandemic, evidence-based studies are lacking in many areas. This paper presents European Academy of Neurology (EAN) expert consensus statements to guide neurologists caring for patients with COVID-19., Methods: A refined Delphi methodology was applied. In round 1, statements were provided by EAN scientific panels (SPs). In round 2, these statements were circulated to SP members not involved in writing them, asking for agreement/disagreement. Items with agreement >70% were retained for round 3, in which SP co-chairs rated importance on a five-point Likert scale. Results were graded by importance and reported as consensus statements., Results: In round one, 70 statements were provided by 23 SPs. In round two, 259/1061 SP member responses were received. Fifty-nine statements obtained >70% agreement and were retained. In round three, responses were received from 55 co-chairs of 29 SPs. Whilst general recommendations related to prevention of COVID-19 transmission had high levels of agreement and importance, opinion was more varied concerning statements related to therapy., Conclusion: This is the first structured consensus statement on good clinical practice in patients with neurological disease during the COVID-19 pandemic that provides immediate guidance for neurologists. In this fast-evolving pandemic, a rapid response using refined Delphi methodology is possible, but guidance may be subject to change as further evidence emerges., (© 2020 The Authors. European Academy of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Introduction: OnabotulinumtoxinA (BoNT-A) was proved effective and safe in chronic migraine (CM) prevention by the Phase III Research Evaluating Migraine Prophylaxis (PREEMPT) and Phase IV Chronic migraine OnabotulinuMtoxinA Prolonged Efficacy open-Label (COMPEL) trials over 1 and 2 years of treatment, respectively. Real-life studies highlighted BoNT-A sustained benefits up to 3 years of administration. Aim of this retrospective real-life study was observing within a 4-year timeframe the progress of a consecutive series of CM patients treated with BoNT-A and evaluating whether long-term quarterly treatment (up to 16 cycles) confirms the outcomes of previous studies over shorter periods of therapy., Methods: One hundred nine chronic migraineurs were quarterly treated with BoNT-A according to the PREEMPT paradigm. Headache days and hours, analgesics intake and latency time together with disability were analysed at baseline, thereafter bi-annually up to 48 months. Patient responsiveness (improvement in monthly headache days and hours versus baseline) was computed at each study timepoint., Results: A significant overall decrease from baseline to the 48-month assessment (p < 0.001) was evidenced for the mean number of monthly headache days and hours, analgesics intake and latency time. Severe disability cases significantly decreased at 6 months (p < 0.001), and a progressive shift towards lower degrees of disability was observed at each subsequent timepoint. A gradual percentage increase of responsive cases was observed as treatment was repeated over time. Transitory neck pain was reported in 6 cases., Conclusions: This study appears to reconfirm the benefits of long-lasting CM prevention with BoNT-A, thus supporting quarterly treatment with BoNT-A over several year.

Predictors of attack location in relapsing-remitting multiple sclerosis (RRMS) are poorly known. It has been suggested that the site of the first relapse may influence the location of the subsequents. We aimed to ascertain this hypothesis in a sample of patients consecutively recruited in two Italian MS Centres, with at least two MS attacks. The following data were collected from medical records: demographic data, locations involved in the first two (or three) MS attacks (optic nerve, spinal cord, brain stem/cerebellum, cerebral hemispheres, according to symptoms presented), time elapsed between relapses and onset of disease-modifying treatment (DMT). We enrolled 199 patients (67% females; MS onset age 30.0 ± 8.69 years), in 148 of whom we could define the precise attack location. In 70/148 patients (47%) the second attack involved exactly the same location as the first. There was an increased risk of relapsing in the same location of the first attack when this involved the optic nerve (OR 4.5, 95% CI 2.2-9.2, p < 0.0001), the brainstem/cerebellum (OR 3.5, 95% CI 1.7-6.9, p < 0.0001), or the spinal cord (OR 3.0, 95% CI 1.5-5.9, p = 0.001). The location of third relapse (N = 90) was equally influenced by the site of first attack. In 24 patients with optic neuritis in both the two first attacks, the side coincided in 50% of cases. The location of first attack has a major role in influencing the site of subsequent ones in RRMS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The association between lifestyle factors and Multiple Sclerosis (MS) disease severity and progression has been investigated to a lesser extent compared with susceptibility to the disease. Objective: We aimed to assess the impact of lifetime alcohol and cigarette smoking load on MS severity. Methods: Design: a cross-sectional study. Three hundred fifty-one patients consecutively admitted to the Department of Neurology were asked to complete the "Questionnaire of Lifestyle" (part of the European Prospective Investigation into Cancer and Nutrition project). An estimation of the cumulative lifetime cigarette smoking and alcohol load was calculated as the weighted sum of the mean number of cigarettes smoked and standard alcoholic drinks consumed per day at different ages. The measure of exposure was expressed in terms of pack-year and drink-year. Disease severity was estimated by the Multiple Sclerosis Severity Score (MSSS). Logistic regression analyses were performed using MSSS (first tertile vs. third tertile) as the outcome. Results: The median MSSS was higher (3.2 vs. 2.3, p = 0.002) in ever- vs. never-smokers, but we did not find a difference between ever- and never-drinkers (2.7 vs. 2.8, p = ns). Ever-smokers were almost twice as likely to fall in the upper MSSS tertile than never-smokers. Ever-drinkers did not show a statistically significant association between alcohol intake and MS severity. The risk of falling in the worst MSSS tertile for smokers was 10.81 (2.0-58.48; p < 0.01) if they were never-drinkers, whereas it was only 1.65 (0.89-3.03, p = 0.11) if they were also drinkers. On the other side, the risk of falling in the worst MSSS tertile for drinkers did not change as much, whether they also were smokers (0.46; 0.13-1.65; p = 0.23) or not (1.49; 0.55-4.04, p = 0.43). Conclusions: Cigarette smoking, unlike alcohol consumption, is associated with MS severity. Alcohol consumption may attenuate the effect of smoking on disease severity, acting as an effect modifier. The biological background of this effect is unknown. The limitations of our study are mostly due to its cross-sectional design.

Background: Lumbar puncture (LP) is a safe procedure commonly performed in the diagnostic work-up of multiple sclerosis (MS), and its main adverse event is post-LP headache (PLPH). Predictors for PLPH in MS are not established., Aims: To describe the occurrence of, and, factors related to PLPH in patients with suspected MS, studied on a daily-basis admission., Patients and Methods: One hundred patients (70 females) were admitted for a diagnostic LP (standardized with a traumatic 19-G needle), observed for 6 h, and evaluated for adverse events 2 and 7 days later. Descriptive statistics and a multivariate analysis (for PLPH) were performed., Results: Fifty-seven (57%) patients had PLPH at 48 h, which persisted 1 week in 31, and only two presented beyond the first 2 days. Other adverse events were tinnitus and neck stiffness. None required investigations or was hospitalized. Age was the only predictor for PLPH at day 2, whereas the onset of headache within 48 h and female gender were predictors for PLPH at day 7., Conclusion: PLPH is a frequent complication of LP performed on daily-basis admission in MS work-up. The maximum onset is within the first 48 h. Age and gender seem the only predictors for the appearance and persistence of PLPH.

Background: The etiopathology of multiple sclerosis (MS) is believed to include genetic and environmental factors. Human leukocyte antigen (HLA) alleles, in particular,  are associated with disease susceptibility, whereas Epstein Barr Virus (EBV) infection has long been suspected to play a role in disease pathogenesis. The aim of the present study is to evaluate correlations between HLA alleles and EBV infection in MS., Methods: HLA alleles, EBV viral load (VL) and serum anti-EBV antibody titers were evaluated in EBV-seropositive MS patients (N = 117) and age- and sex-matched healthy controls (HC; N = 89)., Results: Significantly higher DNA viral loads (p = 0.048) and EBNA-1 antibody titer (p = 0.0004) were seen in MS compared to HC. EBV VL was higher in HLA-B*07+ (p = 0.02) and HLA-DRB1*15+ (p = 0.02) MS patients, whereas it was lower in HLA-A*02+ (p = 0.04) subjects. EBV VL was highest in HLA-A*02-/B*07+/DRB1*15+ patients and lowest in HLA-A*A02+/B*07-/DRB1*15- individuals (p < 0.0001). HLA-B*07 resulted the most associated allele to EBV VL after multiple regression analysis considering altogether the three alleles, (p = 0.0001). No differences were observed in anti-EBV antibody titers in relationship with HLA distribution., Conclusions: Host HLA-B*07 allele influence EBV VL in MS. As HLA-class I molecules present antigens to T lymphocytes and initiate immune response against viruses, these results could support a role for EBV in MS.

This document presents the guidelines for the cerebrospinal fluid (CSF) analysis and the determination of oligoclonal bands (OCBs) as pivotal tests in neuroinflammatory pathologies of the central nervous system. The guidelines have been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of the sponsoring Italian Association of Neuroimmunology (AINI) congresses. Essential clinical information on the pathologies in which the CSF analysis is indicated, and, particularly, on those characterized by the presence of OCBs in the intrathecal compartment, indications and limits of CSF analysis and OCB determination, instructions for result interpretation, and agreed laboratory protocols (Appendix) are reported for the communicative community of neurologists and clinical pathologists.

OnabotulinumtoxinA was approved for treatment of chronic migraine (CM) after publication of Phase 3 Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) trials. However, the PREEMPT trials lasted only up to 1 year. The main aim of our retrospective study was to evaluate whether a prolonged treatment of onabotulinumtoxinA (18 months, six quarterly cycles) will sustain or further improve the efficacy results and the quality of life achieved at 6 and 12 months. Patients were adults with CM with or without overuse of drugs, with at least six regularly repeat onabotulinumtoxinA treatments, administered according to the PREEMPT protocol. The outcomes were investigated after 6, 12, and 18 months of treatment with respect to baseline and with respect to each previous study time point. Headache days and hours, and dosage of headache medication taken with latency period, were collected from the patients daily. Quality of life was evaluated by means of the Migraine Disability Assessment (MIDAS) questionnaire. At each study time point, the proportion of responder patients with respect to baseline was evaluated. For all measures, the baseline data were referred to the previous month before starting. Forty-seven patients were evaluated. Our data show a decrease in the monthly headache days and hours, at each study evaluation, with respect to the previous one. They showed that beyond the first year, a statistically significant difference in the monthly days of headache compared at 18 vs. 12 months is observed. A significantly higher proportion of patients (with a response greater than 75% decrease from baseline in the frequency of headache days and hours) was observed at month 18 compared to month 12. The proportion of patients in MIDAS grade I increased over time, and a statistically significant improvement in MIDAS I score was obtained from month 12 to month 18. A positive modification in the consumption of analgesics over time was observed (p for trend <0.001). The mean acute drug latency strongly decreased over time. Our study confirmed that onabotulinumtoxinA is an effective treatment to reduce headache-related disability and improve patients' quality of life, highlighting that upon repeated administration, the therapy efficacy increases significantly and a progressive trend of "first-time response" is observed for the entire period under consideration.

The alcohol withdrawal syndrome is a well-known condition occurring after intentional or unintentional abrupt cessation of heavy/constant drinking in patients suffering from alcohol use disorders (AUDs). AUDs are common in neurological departments with patients admitted for coma, epileptic seizures, dementia, polyneuropathy, and gait disturbances. Nonetheless, diagnosis and treatment are often delayed until dramatic symptoms occur. The purpose of this review is to increase the awareness of the early clinical manifestations of AWS and the appropriate identification and management of this important condition in a neurological setting., (© 2016 The Authors. Acta Neurologica Scandinavica Published by John Wiley & Sons Ltd.)

Background and Purpose: Transorbital sonography (TOS) is a promising tool to support the clinical diagnosis of optic neuritis (ON) by showing thickening of optic nerve. In this study, we aimed to define its specific role in follow-up of ON patients., Methods: We measured ultrasonography parameters and visual acuity (VA) at presentation and after 1 year in 45 patients with newly diagnosed ON. Two vascular sonographers used B-mode TOS to evaluate mean optic nerve diameter (OND) and optic nerve sheath diameter (ONSD)., Results: Median ONSD values were significantly thicker in patients with ON in the affected eye (6.4 mm, interquartile range [IQR]: 6.0-6.9) at presentation compared with the nonaffected side (5.7 mm; IQR: 5.2-6.1) (P < .001). The median OND was not significantly thicker at presentation in the affected eye (3.0 mm; IQR: 2.9-3.4) compared with the fellow eye (2.9 mm; IQR: 2.8-3.2) (P = .09). Logarithmic VA was significantly compromised at presentation in the affected eye (.16; IQR: .00-.55) compared with fellow eye (.00; IQR: .00-.00) (P < .001). After 1 year, no significant difference (P ≥ .05) was found between ONSD or OND of the affected side compared with the nonaffected side. VA improved in most of the patients but remained significantly impaired in affected eye after 1 year., Conclusions: TOS is a useful tool to support diagnosis of ON. This technique seems to have less value to evaluate atrophy of the optic nerve after 12 months., (Copyright © 2016 by the American Society of Neuroimaging.)

Background: Posterior Reversible Encephalopathy Syndrome (PRES) is a clinical-radiological syndrome, usually reversible and with a favorable prognosis, which recognizes a variety of etiologies and clinical patterns and is likely due to an impairment in cerebral blood flow autoregulation. It is typically characterized by subcortical, predominantly parieto-occipital, vasogenic brain oedema in patients with acute-subacute neurological symptoms. Infratentorial oedema on neuroimaging has been mostly described in association with the typical supratentorial pattern and seldom as isolated., Case Report: We report a case of PRES with isolated pons involvement on MRI. A woman affected by Turner syndrome, epilepsy, slight mental deficiency, obesity and hypothyroidism, experienced a progressive gait and standing impairment, worsening in the last 2 weeks. At admission blood pressure was 220/110 mmHg. Brain MRI showed a wide FLAIR signal hyperintensity on T2-weighted sequences affecting the entire pons, without contrast enhancement. Clonidine, doxazosine, furosemide and telmisartan were effective in restoring normal blood pressure. Pons hyperintensity completely resolved on MRI 3 weeks later, together with return to normal neurological examination., Conclusions: Though isolated infratentorial involvement in PRES recognizes several causes, hypertension, which is a common feature in Turner syndrome, would have played a key role in our case with solely pons MRI T2-hyperintensity.

Objective: We investigated the association between 52 risk variants identified through genome-wide association studies and disease severity in multiple sclerosis (MS)., Methods: Ten unique MS case data sets were analyzed. The Multiple Sclerosis Severity Score (MSSS) was calculated using the Expanded Disability Status Scale at study entry and disease duration. MSSS was considered as a continuous variable and as 2 dichotomous variables (median and extreme ends; MSSS of ≤5 vs >5 and MSSS of <2.5 vs ≥7.5, respectively). Single nucleotide polymorphisms (SNPs) were examined individually and as both combined weighted genetic risk score (wGRS) and unweighted genetic risk score (GRS) for association with disease severity. Random-effects meta-analyses were conducted and adjusted for cohort, sex, age at onset, and HLA-DRB1*15:01., Results: A total of 7,125 MS cases were analyzed. The wGRS and GRS were not strongly associated with disease severity after accounting for cohort, sex, age at onset, and HLA-DRB1*15:01. After restricting analyses to cases with disease duration ≥10 years, associations were null (p value ≥0.05). No SNP was associated with disease severity after adjusting for multiple testing., Conclusions: The largest meta-analysis of established MS genetic risk variants and disease severity, to date, was performed. Results suggest that the investigated MS genetic risk variants are not associated with MSSS, even after controlling for potential confounders. Further research in large cohorts is needed to identify genetic determinants of disease severity using sensitive clinical and MRI measures, which are critical to understanding disease mechanisms and guiding development of effective treatments.

Background: There is considerable disagreement about the risk of recurrence following a first unprovoked epileptic seizure. A decision about whether to start antiepileptic drug treatment following a first seizure should be informed by information on the size of any reduction in risk of future seizures, the impact on long-term seizure remission, and the risk of adverse effects., Objectives: To review the probability of seizure recurrence, seizure remission, mortality, and adverse effects of antiepileptic drug (AED) treatment given immediately after the first seizure compared to controls, in children and adults., Search Methods: We searched the following databases: Cochrane Epilepsy Group Specialized Register (accessed 13 October 2015), Cochrane Central Register of Controlled Trials (The Cochrane Library September 2015, issue 9, accessed 13 October 2015), PUBMED (accessed 22 April 2015), MEDLINE (Ovid, 1946 to 13 October 2015), EMBASE (accessed 22 April 2015), ClinicalTrials.gov (accessed 15 October 2015), and the WHO International Clinical Trials Registry Platform (ICTRP, accessed 13 October 2015). There were no language restrictions., Selection Criteria: Randomised controlled trials (RCTs) and quasi-RCTs that could be blinded or unblinded. People of any age with a first unprovoked seizure of any type. Included studies compared participants receiving immediate antiepileptic treatment versus those receiving deferred treatment, those assigned to placebo, and those untreated., Data Collection and Analysis: Two review authors independently assessed the studies identified by the search strategy for inclusion in the review and extracted data. The quality of the evidence was classified in four categories according to the GRADE approach. Dichotomous outcomes were expressed as Risk Ratios (RR) with 95% confidence intervals (CI). Time-to-event outcomes were expressed as Hazard Ratios (HR) with 95% CI. Only one trial used a double-blind design, and the two largest studies were unblinded. Most of the recurrences were generalized tonic-clonic seizures, a major type of seizures that is easily recognised, which should reduce the risk of outcome reporting bias., Main Results: After exclusion of uninformative papers, only six studies (nine reports) were selected for inclusion. For the two largest studies data were available for individual participant meta-analysis. Compared to controls, participants randomised to immediate treatment had a lower probability of relapse at one year (RR 0.49, 95% CI 0.42 to 0.58, high quality evidence), at five years (RR 0.78; 95% CI 0.68 to 0.89; high quality evidence) and a higher probability of an immediate five-year remission (RR 1.25; 95% CI 1.02 to 1.54, high quality evidence). However there was no difference between immediate treatment and control in terms of five year remission at any time (RR 1.02, 95% CI 0.87 to 1.21, high quality evidence). Antiepileptic drugs did not affect overall mortality after a first seizure (RR 1.16; 95% CI 0.69 to 1.95, high quality evidence). Compared to deferred treatment (RR 1.49, 95% CI 1.23 to 1.79, moderate quality evidence), treatment of the first seizure was associated with a significantly higher risk of adverse events. Moderate to low quality imprecise evidence was available for the association of treatment of the first seizure compared to no treatment or placebo (RR 14.50, 95% CI 1.93 to 108.76) and(RR 4.91, 95% CI 1.10 to 21.93) respectively), Authors' Conclusions: Treatment of the first unprovoked seizure reduces the risk of a subsequent seizure but does not affect the proportion of patients in remission in the long-term. Antiepileptic drugs are associated with adverse events, and there is no evidence that they reduce mortality. In light of this review, the decision to start antiepileptic drug treatment following a first unprovoked seizure should be individualized and based on patient preference, clinical, legal, and socio-cultural factors.

Background: The occurrence of multiple sclerosis (MS) increases in populations featuring both high and low disease burden, and variations across regions at the same latitude are reported. MS epidemiological data in Eastern Europe are scarce and out of date. We report on sex- and age-specific prevalence of MS in the Republic of Moldova., Methods: Benefitting from a nationwide survey aimed to quantify the MS burden in Moldovans (3,559,541 population in 2012), multiple epidemiological sources were scrutinized., Results: On prevalence day, December 31, 2012, 747 MS patients (McDonald criteria) resided in the study area, yielding a crude prevalence of 20.9 per 100,000 (95% CI 14.7-27.1), 25.7 (95% CI 20.5-30.5) in women and 15.8 (95% CI 12.2-19.3) in men (F:M ratio of 1.63), and standardized estimates of 20.2, 24.3 and 15.5 per 100,000, respectively. Prevalence was highest in the age group 40-49 years (43.9 per 100,000) and higher in rural (72.6%) than in urban (27.4%) areas., Conclusions: This is the first report on sex- and age-specific prevalence of MS in the Republic of Moldova, which was lower than in Europe on average, but consistent with that of neighboring countries, Romania and Ukraine. Moldovans represent a population wherein MS natural history is not yet influenced by use of disease-modifying drugs., (© 2016 S. Karger AG, Basel.)

Objective: In patients with acute optic neuritis (AON) transorbital sonography may reveal a thickening of the retrobulbar portion of the optic nerve. Our aim was to systematically review the diagnostic accuracy of ultrasonography of optic nerve diameter (OND) for assessment of AON., Methods: MEDLINE, EMBASE (1966-October 2014) was searched to identify studies reporting data on patients with AON (with/without multiple sclerosis) assessed by B-mode transorbital ultrasonography. Thereafter, the studies retrieved were screened based on predefined inclusion and exclusion criteria. Data were extracted and the quality of the included studies was evaluated., Results: Seven studies (162 patients) were included. The OND was significantly thicker in the affected eye compared with its unaffected fellow or controls. An increased OND was found in 78-100% of patients. Four studies determined papilledema in 6-43% of patients., Conclusions: Transorbital sonography is a sensitive, highly accessible and user-friendly technique for the detection of significant optic nerve thickening on the side affected by AON and represents an adjunctive tool for the diagnosis of AON. Compared to visual evoked potentials, TOS may provide different, though complementary, information on the pathophysiology of AON., Significance: B-mode transorbital ultrasonography provides promising support for the clinical diagnosis of AON., (Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

The European Academy of Neurology (EAN), founded in 2014 after the merging of the two previously active European Neurological Societies, considers the production of neurological guidelines a major obligation, as this is a major tool to improve clinical practice in neurology. This paper updates practical suggestions to develop guidelines about the treatment and diagnosis of neurological diseases within the framework of the EAN. Its aim is to make uniform, traceable and explicit the path from the decision to write an EAN guideline to its publication. We explain the protocol structure, handling of conflicts of interest, format, timeline and process of revision and acceptance. It provides the view of the Scientific Committee and the Board of the EAN. We hope to make easier a larger involvement of the EAN scientific community in producing guidelines., (© 2015 EAN.)

Objectives: To evaluate the relationship between chronic cerebrospinal venous insufficiency (CCSVI) and the presence of a Chronic Venous Disorder (CVD)., Method: We included 55 subjects with CCSVI aged >18 years, and 186 controls without CCSVI. Each subject was evaluated with color Doppler sonography in accordance with Zamboni's five criteria, examined by two neurologists and interviewed with an ad-hoc designed form. The neurologists and the sonographers were mutually blinded. CVD were classified according to CEAP., Results: Mean age was 42 years (SD = 9) in cases and 43 years (10) in controls (p = ns). The odds ratios in subjects CCSVI were 0.6 (0.2-2.2) for CEAP 1, 0.9 (0.2-4.5) for CEAP 2, and 1.0 (0.6-1.9) for family history of varicose veins. The prevalence of CVD and, family history of varicose veins, was similar between cases and controls for each Zamboni criterion., Conclusions: We found no association of CCSVI with the presence of CVD or family history of varicose veins., (© The Author(s) 2014.)

Immunological hallmarks of multiple sclerosis include the production of antibodies in the central nervous system, expressed as presence of oligoclonal bands and/or an increased immunoglobulin G index-the level of immunoglobulin G in the cerebrospinal fluid compared to serum. However, the underlying differences between oligoclonal band-positive and -negative patients with multiple sclerosis and reasons for variability in immunoglobulin G index are not known. To identify genetic factors influencing the variation in the antibody levels in the cerebrospinal fluid in multiple sclerosis, we have performed a genome-wide association screen in patients collected from nine countries for two traits, presence or absence of oligoclonal bands (n = 3026) and immunoglobulin G index levels (n = 938), followed by a replication in 3891 additional patients. We replicate previously suggested association signals for oligoclonal band status in the major histocompatibility complex region for the rs9271640*A-rs6457617*G haplotype, correlated with HLA-DRB1*1501, and rs34083746*G, correlated with HLA-DQA1*0301 (P comparing two haplotypes = 8.88 × 10(-16)). Furthermore, we identify a novel association signal of rs9807334, near the ELAC1/SMAD4 genes, for oligoclonal band status (P = 8.45 × 10(-7)). The previously reported association of the immunoglobulin heavy chain locus with immunoglobulin G index reaches strong evidence for association in this data set (P = 3.79 × 10(-37)). We identify two novel associations in the major histocompatibility complex region with immunoglobulin G index: the rs9271640*A-rs6457617*G haplotype (P = 1.59 × 10(-22)), shared with oligoclonal band status, and an additional independent effect of rs6457617*G (P = 3.68 × 10(-6)). Variants identified in this study account for up to 2-fold differences in the odds of being oligoclonal band positive and 7.75% of the variation in immunoglobulin G index. Both traits are associated with clinical features of disease such as female gender, age at onset and severity. This is the largest study population so far investigated for the genetic influence on antibody levels in the cerebrospinal fluid in multiple sclerosis, including 6950 patients. We confirm that genetic factors underlie these antibody levels and identify both the major histocompatibility complex and immunoglobulin heavy chain region as major determinants., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background and Purpose: Acute unilateral optic neuritis is associated with a thickening of the retrobulbar portion of the optic nerve as revealed by transorbital sonography, but no comparison has been made between nerve sheath diameter and optic nerve diameter in patients with acute optic neuritis versus healthy controls. We evaluated optic nerve sheath diameter and optic nerve diameter in patients with acute optic neuritis and healthy controls and compared optic nerve sheath diameter and optic nerve diameter with visual-evoked potentials in patients., Materials and Methods: A case-control study was performed in 2 centers. Twenty-one consecutive patients with onset of visual loss during the prior 10 days and established acute noncompressive unilateral optic neuritis were compared with 21 healthy controls, matched for sex and age (±5 years). Two experienced vascular sonographers performed the study by using B-mode transorbital sonography. Visual-evoked potentials were performed on the same day as the transorbital sonography and were evaluated by an expert neurophysiologist. Sonographers and the neurophysiologist were blinded to the status of the patient or control and to clinical information, including the side of the affected eye., Results: The median optic nerve sheath diameter was thicker on the affected side (6.3 mm; interquartile range, 5.9-7.2 mm) compared with the nonaffected side (5.5 mm; interquartile range, 5.1-6.2 mm; P < .0001) and controls (5.2 mm; interquartile range, 4.8-5.5 mm; P < .0001). The median optic nerve diameter was 3.0 mm (range, 2.8-3.1 mm) on the affected side and 2.9 mm (range, 2.8-3.1 mm) on the nonaffected side (P = not significant.). Both sides were thicker than those in controls (2.7 mm; interquartile range, 2.5-2.8 mm; P = .001 and .009). No correlation was found between optic nerve sheath diameter and optic nerve diameter and amplitude and latency of visual-evoked potentials in patients with optic neuritis., Conclusions: Transorbital sonography is a promising tool to support the clinical diagnosis of acute optic neuritis. Further studies are needed to define its specific role in the diagnosis and follow-up of optic neuritis., (© 2014 by American Journal of Neuroradiology.)

Purpose: Transorbital optic nerve sonography (TOS) can measure the optic nerve inclusive the sheath diameter (ONSD) and the optic nerve diameter (OND), which are useful parameters in the diagnosis of several neurological disorders. Data on the reproducibility of TOS are, however, required to use B-mode sonography for clinical purposes. The aim of this study was to assess intra- and interobserver reliability of ultrasound-based evaluations of both OND and ONSD in healthy subjects., Methods: Using a 4-11-MHz linear array transducer, the OND and ONSD of 20 healthy subjects were independently measured by two expert investigators., Results: Depicting the optic nerve and its sheath was possible in all subjects. The intra- and interobserver reliability was high for both ONSD and OND measurements. Intraobserver agreement, analyzed with Cronbach´s Alpha, was higher for ONSD (range: 0.69-0.72) than for OND measurements (range: 0.55-0.65). No differences in interobserver reliability between ONSD and OND measurements were found (p = 0.83 for right and 0.47 for left eye)., Conclusions: Transorbital B-mode sonography is a feasible method to assess both ONSD and OND with a high intra- and interobserver reliability. Technical difficulties in differentiating the optic nerve from its sheaths may explain the lower intraobserver agreement for OND than that for ONSD measurements.

Background: Month of birth has been associated in some studies with the susceptibility to develop Multiple Sclerosis (MS). However, only few studies have evaluated whether birth timing also affects disease progression., Objectives: To assess whether season and month of birth are associated with disease progression in a large cohort of Italian patients., Methods: Quantile regression was used to analyze the impact of each month and season of birth with all the others combined on the median Multiple Sclerosis Severity Score of 1866 MS patients., Results: No significant temporal trend was found after adjustment for multiple comparisons., Conclusions: Birth timing showed no association with MS progression in Italian patients., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objective: Marchiafava-Bignami disease (MBD) is a rare condition mainly associated with alcoholism, although it may be mimicked by several other disorders that cause corpus callosum lesions. Our objective was to identify helpful features for differential diagnosis and assess whether any treatment can be recommended., Methods: We reviewed 122 reports containing data on 153 subjects with confirmed MBD that was associated with either alcoholism or malnutrition, and 20 reports with data on 53 subjects with conditions mimicking MBD. All the cases had been verified antemortem by brain imaging. Unconditional logistic regression was used to demonstrate factors that were associated with the outcome of MBD., Results: The mimicking conditions were differentiated from MBD by the occurrence of solitary and rapidly disappearing splenial lesions; fewer signs and symptoms with exception of seizures, hemiparesis and tetraparesis; nystagmus; and rapid and complete recovery. MBD occurred most frequently among alcoholics, but it was also reported in 11 non-alcoholics (7.2% of all the MBD cases). A better outcome was observed among those who were treated within 2 weeks after onset of symptoms with parenteral thiamine (p=0.033)., Conclusions: As thiamine deficiency is frequently associated with alcoholism, malnutrition and prolonged vomiting; we recommend prompt treatment of MBD with parenteral thiamine in such subjects. Recovery should be followed by repeated neuropsychological and MRI examinations, preferably using diffusion tensor imaging.

Objective: Chronic cerebrospinal venous insufficiency (CCSVI) has been extremely variable, associated with multiple sclerosis in colour-Doppler sonographic studies. We aimed to evaluate inter-rater agreement in a colour-Doppler sonography venous examination., Design: Inter-rater agreement study., Setting: First-referral multiple sclerosis centre., Participants: 38 patients with multiple sclerosis and 55 age-matched (±5 years) controls., Intervention: Sonography was carried out in accordance with Zamboni's five criteria by eight sonographers with different expertise, blinded to the status of cases and controls. Each participant was evaluated by two operators., Primary and Secondary Outcome Measures: Inter-rater agreement was measured through the κ statistics and the intraclass correlation coefficient., Results: The agreement was no higher than chance for criterion 2-reflux in the deep cerebral veins (κ=-0.02) and criterion 4-flow not Doppler detectable in one or both the internal jugular veins (IJVs) or vertebral veins (VVs; -0.09). It was substantially low for criterion 1-reflux in the IJVs and/or VVs (0.29), criterion 3-IJV stenosis or malformations (0.23) and criterion 5-absence of IJV diameter increase when passing from the sitting to the supine position (0.22). The κ value for CCSVI as a whole was 0.20 (95% confidence limit -0.01 to 0.42). Intraclass correlation coefficients for the measure of cross-sectional area ranged from 0.05 to 0.25. Inter-rater agreement was low for CCSVI experts (κ=0.24; -0.11 to 0.59) and non-experts (0.20; -0.33 to 0.73); neurologists (0.21; -0.06 to 0.47) and non-neurologists (0.18; -0.20 to 0.56); cases (0.19; -0.14 to 0.52) and controls (0.21; -0.08 to 0.49). Zamboni-trained neurosonographers ascertained CCSVI more frequently than the non-trained neurosonographers., Conclusions: Agreement was unsatisfactory for the diagnosis of CCSVI as a whole, for each of its five criteria and according to the different subgroups. Standardisation of the method is urgently needed prior to its further application in studies of patients with multiple sclerosis or other neurological diseases.

Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.

Objective: to explore the association between genetic markers and Oligoclonal Bands (OCB) in the Cerebro Spinal Fluid (CSF) of Italian Multiple Sclerosis patients., Methods: We genotyped 1115 Italian patients for HLA-DRB1*15 and HLA-A*02. In a subset of 925 patients we tested association with 52 non-HLA SNPs associated with MS susceptibility and we calculated a weighted Genetic Risk Score. Finally, we performed a Genome Wide Association Study (GWAS) with OCB status on a subset of 562 patients. The best associated SNPs of the Italian GWAS were replicated in silico in Scandinavian and Belgian populations, and meta-analyzed., Results: HLA-DRB1*15 is associated with OCB+: p = 0.03, Odds Ratio (OR) = 1.6, 95% Confidence Limits (CL) = 1.1-2.4. None of the 52 non-HLA MS susceptibility loci was associated with OCB, except one SNP (rs2546890) near IL12B gene (OR: 1.45; 1.09-1.92). The weighted Genetic Risk Score mean was significantly (p = 0.0008) higher in OCB+ (7.668) than in OCB- (7.412) patients. After meta-analysis on the three datasets (Italian, Scandinavian and Belgian) for the best associated signals resulted from the Italian GWAS, the strongest signal was a SNP (rs9320598) on chromosome 6q (p = 9.4×10(-7)) outside the HLA region (65 Mb)., Discussion: genetic factors predispose to the development of OCB.

This paper is meant to provide guidance to anyone wishing to write a neurological guideline for diagnosis or treatment, and is directed at the Scientist Panels and task forces of the European Federation of Neurological Societies (EFNS). It substitutes the previous guidance paper from 2004. It contains several new aspects: the guidance is now based on a change of the grading system for evidence and for the resulting recommendations, and has adopted The Grading of Recommendations, Assessment, Development and Evaluation system (GRADE). The process of grading the quality of evidence and strength of recommendations can now be improved and made more transparent. The task forces embarking on the development of a guideline must now make clearer and more transparent choices about outcomes considered most relevant when searching the literature and evaluating their findings. Thus, the outcomes chosen will be more critical, more patient-oriented and easier to translate into simple recommendations. This paper also provides updated practical recommendations for planning a guideline task force within the framework of the EFNS. Finally, this paper hopes to find the approval also by the relevant bodies of our future organization, the European Academy of Neurology., (© 2013 The Author(s) European Journal of Neurology © 2013 EFNS.)

We aimed to evaluate the reliability of the modified Rankin Scale applied telephonically compared with face-to-face assessment in clinically stable hospitalized patients with acute stroke. One hundred and thirty-one patients were interviewed twice by 2 certified nurses (unstructured interview). Half of the patients were randomized to be interviewed by telephone followed by the face-to-face assessment, and half in the reverse order. The median value of the modified Rankin Scale score was 4 (first to third interquartile range 3-5) by telephone as well as by face-to-face assessment (P=0.8). The weighted kappa between the two methods was 0.82 (95% confidence interval: 0.77-0.88). Sensitivity of the telephone assessment was lower for scores 2 and 3 (17% and 46%, respectively) than for the other scores (range 67-90%). Telephone assessment of stroke disability with the modified Rankin Scale is reliable in comparison to direct face-to-face assessment.

Background: Chronic Cerebrospinal Venous Insufficiency (CCSVI) has been associated with multiple sclerosis (MS) with a risk ranging from as high as two-hundred-fold to a protective effect. However, not all studies were blinded, and the efficacy of blinding was never assessed., Objective: To evaluate the association of CCSVI with MS in a cross-sectional blinded study and look for any association of CCSVI with the severity of MS., Methodology/principal Findings: The Echo-color Doppler examination was carried out in accordance with Zamboni's five criteria in 68 consecutive MS patients and 68 healthy controls, matched by gender and age (±5 years). Four experienced neurosonologists, blinded to the status of cases and controls, performed the study and were then asked to guess the status (case or control) of each participant. The number of positive CCSVI criteria was similar in the two groups. CCSVI, defined as the presence of two or more criteria, was detected in 21 cases (30.9%) and 23 controls (33.8%), with an OR of 0.9 (95%CL = 0.4-1.8, p = 0.71). The prevalence of CCSVI was related to age in cases (OR increasing from 0.2 to 1.4), but not in controls. CCSVI positive (N = 21) and negative (N = 47) MS patients were similar in clinical type, age at disease onset, disability, and fatigue. Disease duration was longer (16.5±9.8 years) in CCSVI positive than negative patients (11.5±7.4; p = 0.04). The operators correctly guessed 34/68 cases (50%) and 45/68 controls (66%) (p = 0.06), indicating a different success of blinding., Conclusions/significance: CCSVI was not associated with MS itself, nor its severity. We cannot rule out the possibility that CCSVI is a consequence of MS or of aging. Blinding of sonographers is a key point in studying CCSVI and its verification should be a requisite of future studies.