Temporal and spatial patterns in the prescriptions of disease-modifying therapies for multiple sclerosis. Results from the Italian Multiple Sclerosis and Related Disorders Register.

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.

Methodological Quality of Clinical Trials in Amyotrophic Lateral Sclerosis: A systematic Review.

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.

Phase I clinical trial of intracerebroventricular transplantation of allogeneic neural stem cells in people with progressive multiple sclerosis.

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.

Comparative features and outcomes of major neurological complications of COVID-19.

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.

European Academy of Neurology guidance for developing and reporting clinical practice guidelines on rare neurological diseases.

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.

Neutrophils-to-Lymphocyte Ratio Is Associated with Progression and Overall Survival in Amyotrophic Lateral Sclerosis.

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.

Factors Associated with Delirium in COVID-19 Patients and Their Outcome: A Single-Center Cohort Study.

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.

The impact of lifetime coffee and tea loads on Multiple Sclerosis severity.

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.

Immediate antiepileptic drug treatment, versus placebo, deferred, or no treatment for first unprovoked seizure.

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.

The Impact of Lifetime Alcohol and Cigarette Smoking Loads on Amyotrophic Lateral Sclerosis Progression: A Cross-Sectional Study.

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.

Location of first attack predicts the site of subsequent relapses in multiple sclerosis.

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.

Chronic migraine long-term regular treatment with onabotulinumtoxinA: a retrospective real-life observational study up to 4 years of therapy.

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.

The Impact of Lifetime Alcohol and Cigarette Smoking Loads on Multiple Sclerosis Severity.

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.

HLA alleles modulate EBV viral load in multiple sclerosis.

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.

Cerebrospinal fluid analysis and the determination of oligoclonal bands.

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.

Quarterly repeat cycles of onabotulinumtoxinA in chronic migraine patients: the benefits of the prolonged treatment on the continuous responders and quality-of-life conversion rate in a real-life setting.

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.

Transorbital Sonography and Visual Outcome for the Diagnosis and Monitoring of Optic Neuritis.

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.

Multiple sclerosis risk loci and disease severity in 7,125 individuals from 10 studies.

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.