Publications by authors named "Maurizio A Leone"

40 Publications

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

Cochrane Database Syst Rev 2021 05 4;5:CD007144. Epub 2021 May 4.

Laboratorio di Malattie Neurologiche, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.

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.
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http://dx.doi.org/10.1002/14651858.CD007144.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094016PMC
May 2021

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

Life (Basel) 2021 Apr 17;11(4). Epub 2021 Apr 17.

Neurology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy.

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 ( = 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 ( = 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.
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http://dx.doi.org/10.3390/life11040352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072690PMC
April 2021

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

J Clin Neurosci 2020 Apr 24;74:175-179. Epub 2020 Feb 24.

Neurosciences Unit, Department of Medicine and Surgery, University of Parma, Parma, Italy.

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.
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http://dx.doi.org/10.1016/j.jocn.2020.02.017DOI Listing
April 2020

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

Neurol Sci 2020 Jul 12;41(7):1809-1820. Epub 2020 Feb 12.

Unit of Neurology, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy.

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.
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http://dx.doi.org/10.1007/s10072-020-04283-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359167PMC
July 2020

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

Front Neurol 2019 13;10:866. Epub 2019 Aug 13.

Neurology Unit, Department of Medical Sciences, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.

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 alcohol and cigarette smoking load on MS severity. 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. The median MSSS was higher (3.2 vs. 2.3, = 0.002) in ever- vs. never-smokers, but we did not find a difference between ever- and never-drinkers (2.7 vs. 2.8, = 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; < 0.01) if they were never-drinkers, whereas it was only 1.65 (0.89-3.03, = 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; = 0.23) or not (1.49; 0.55-4.04, = 0.43). 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.
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http://dx.doi.org/10.3389/fneur.2019.00866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700269PMC
August 2019

HLA alleles modulate EBV viral load in multiple sclerosis.

J Transl Med 2018 03 27;16(1):80. Epub 2018 Mar 27.

Don C. Gnocchi Foundation IRCCS - ONLUS, Piazzale Morandi 3, 20121, Milan, Italy.

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.
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http://dx.doi.org/10.1186/s12967-018-1450-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870171PMC
March 2018

Cerebrospinal fluid analysis and the determination of oligoclonal bands.

Neurol Sci 2017 Oct;38(Suppl 2):217-224

IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy.

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.
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http://dx.doi.org/10.1007/s10072-017-3034-2DOI Listing
October 2017

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.

Neurol Sci 2017 Oct 19;38(10):1779-1789. Epub 2017 Jul 19.

Unit of Neurology, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy.

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.
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http://dx.doi.org/10.1007/s10072-017-3054-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605581PMC
October 2017

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

J Neuroimaging 2017 01 13;27(1):92-96. Epub 2016 Nov 13.

Department of Neuroscience, Biomedicine and Movement. Section of Clinical Neurology, University of Verona, Verona, Italy.

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.
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http://dx.doi.org/10.1111/jon.12405DOI Listing
January 2017

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

Neurol Genet 2016 Aug 4;2(4):e87. Epub 2016 Aug 4.

Author affiliations are listed at the end of the article.

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.
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http://dx.doi.org/10.1212/NXG.0000000000000087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4974846PMC
August 2016

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

Cochrane Database Syst Rev 2016 May 6(5):CD007144. Epub 2016 May 6.

SC Neurologia, IRCCS "Casa Sollievo della Sofferenza", V.le Cappuccini 1, San Giovanni Rotondo, Italy, 71013.

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.
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http://dx.doi.org/10.1002/14651858.CD007144.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478062PMC
May 2016

Intra- and interobserver reliability of transorbital sonographic assessment of the optic nerve sheath diameter and optic nerve diameter in healthy adults.

J Ultrasound 2016 Mar 20;19(1):41-5. Epub 2014 Nov 20.

Section of Clinical Neurology, Department of Neurological and Movement Sciences, University of Verona, Piazzale L.A. Scuro, 10-37134 Verona, Italy.

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.
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http://dx.doi.org/10.1007/s40477-014-0144-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4762843PMC
March 2016

B-mode transorbital ultrasononography for the diagnosis of acute optic neuritis. A systematic review.

Clin Neurophysiol 2016 Jan 11;127(1):803-809. Epub 2015 May 11.

Department of Neurology, University A. Avogadro, Novara, Italy; Department of Neurological, Neuropsychological, Morphological and Movement Sciences, Section of Clinical Neurology, University of Verona, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.clinph.2015.05.005DOI Listing
January 2016

Genetic variants are major determinants of CSF antibody levels in multiple sclerosis.

Brain 2015 Mar 22;138(Pt 3):632-43. Epub 2015 Jan 22.

18 Danish Multiple Sclerosis Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

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.
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http://dx.doi.org/10.1093/brain/awu405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408440PMC
March 2015

Multiple sclerosis progression is not associated with birth timing in Italy.

J Neurol Sci 2014 Nov 23;346(1-2):194-6. Epub 2014 Aug 23.

MS Centre, SCDU Neurology, Head and Neck Department, AOU "Maggiore della Carità", Corso Mazzini 18, 28100 Novara, Italy; Interdisciplinary Research Center of Autoimmune Diseases IRCAD, University of Eastern Piedmont, Via Solaroli 17, 28100 Novara, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jns.2014.08.021DOI Listing
November 2014

Chronic cerebrospinal venous insufficiency is not associated with chronic venous disorders: A case-control study.

Phlebology 2015 Dec 31;30(10):736-8. Epub 2014 Jul 31.

SC Neurologia, Maria Vittoria Hospital, Torino, Italy.

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.
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http://dx.doi.org/10.1177/0268355514544782DOI Listing
December 2015

A reliability study of colour-Doppler sonography for the diagnosis of chronic cerebrospinal venous insufficiency shows low inter-rater agreement.

BMJ Open 2013 Nov 15;3(11):e003508. Epub 2013 Nov 15.

MS Centre, SCDU Neurology, Head and Neck Department, AOU 'Maggiore della Carità', Novara, Italy.

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.
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http://dx.doi.org/10.1136/bmjopen-2013-003508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3831103PMC
November 2013

Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.

Nat Genet 2013 Nov 29;45(11):1353-60. Epub 2013 Sep 29.

1] John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA. [2].

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.
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http://dx.doi.org/10.1038/ng.2770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3832895PMC
November 2013

Diagnosis and management of Marchiafava-Bignami disease: a review of CT/MRI confirmed cases.

J Neurol Neurosurg Psychiatry 2014 Feb 26;85(2):168-73. Epub 2013 Aug 26.

Department of Neurology, Oulu University Hospital, , Oulu, Finland.

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.
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http://dx.doi.org/10.1136/jnnp-2013-305979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4160728PMC
February 2014

Association of genetic markers with CSF oligoclonal bands in multiple sclerosis patients.

PLoS One 2013 13;8(6):e64408. Epub 2013 Jun 13.

MS Centre, SCDU Neurology, AOU Maggiore della Carità, Novara, Italy.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0064408PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3681825PMC
January 2014

Reliability of the modified Rankin Scale applied by telephone.

Neurol Int 2013 Feb 19;5(1):e2. Epub 2013 Feb 19.

SCDU Neurologia, AOU Maggiore della Carità and Università del Piemonte Orientale A. Avogadro, Novara, Italy.

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.
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http://dx.doi.org/10.4081/ni.2013.e2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3661983PMC
February 2013

Chronic cerebrospinal venous insufficiency is not associated with multiple sclerosis and its severity: a blind-verified study.

PLoS One 2013 13;8(2):e56031. Epub 2013 Feb 13.

MS Centre, Head and Neck Department, AOU Maggiore della Carità, Novara, Italy.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0056031PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572163PMC
August 2013

Basic and advanced imaging of a case of Balò's concentric sclerosis.

BMJ Case Rep 2013 Jan 25;2013. Epub 2013 Jan 25.

Department of Neurology, University of Turin, Torino, Italy.

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http://dx.doi.org/10.1136/bcr-2012-008413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3604547PMC
January 2013

Polymorphisms in the genes coding for iron binding and transporting proteins are associated with disability, severity, and early progression in multiple sclerosis.

BMC Med Genet 2012 Aug 10;13:70. Epub 2012 Aug 10.

Department of Biomedical Sciences & Advanced Therapies, Hematology Unit-Center Hemostasis & Thrombosis, University of Ferrara, Ferrara, Italy.

Background: Iron involvement/imbalance is strongly suspected in multiple sclerosis (MS) etiopathogenesis, but its role is quite debated. Iron deposits encircle the veins in brain MS lesions, increasing local metal concentrations in brain parenchyma as documented by magnetic resonance imaging and histochemical studies. Conversely, systemic iron overload is not always observed. We explored the role of common single nucleotide polymorphisms (SNPs) in the main iron homeostasis genes in MS patients.

Methods: By the pyrosequencing technique, we investigated 414 MS cases [Relapsing-remitting (RR), n=273; Progressive, n=141, of which: Secondary (SP), n=103 and Primary (PP), n=38], and 414 matched healthy controls. Five SNPs in 4 genes were assessed: hemochromatosis (HFE: C282Y, H63D), ferroportin (FPN1: -8CG), hepcidin (HEPC: -582AG), and transferrin (TF: P570S).

Results: The FPN1-8GG genotype was overrepresented in the whole MS population (OR=4.38; 95%CI, 1.89-10.1; P<0.0001) and a similar risk was found among patients with progressive forms. Conversely, the HEPC -582GG genotype was overrepresented only in progressive forms (OR=2.53; 95%CI, 1.34-4.78; P=0.006) so that SP and PP versus RR yielded significant outputs (P=0.009). For almost all SNPs, MS disability score (EDSS), severity score (MSSS), as well as progression index (PI) showed a significant increase when comparing homozygotes versus individuals carrying other genotypes: HEPC -582GG (EDSS, 4.24±2.87 vs 2.78±2.1; P=0.003; MSSS, 5.6±3.06 vs 3.79±2.6; P=0.001); FPN1-8GG (PI, 1.11±2.01 vs 0.6±1.31; P=0.01; MSSS, 5.08±2.98 vs 3.85±2.8; P=0.01); HFE 63DD (PI, 1.63±2.6 vs 0.6±0.86; P=0.009). Finally, HEPC -582G-carriers had a significantly higher chance to switch into the progressive form (HR=3.55; 1.83-6.84; log-rank P=0.00006).

Conclusions: Polymorphisms in the genes coding for iron binding and transporting proteins, in the presence of local iron overload, might be responsible for suboptimal iron handling. This might account for the significant variability peculiar to MS phenotypes, particularly affecting MS risk and progression paving the way for personalized pharmacogenetic applications in the clinical practice.
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http://dx.doi.org/10.1186/1471-2350-13-70DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3490944PMC
August 2012

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Nature 2011 Aug 10;476(7359):214-9. Epub 2011 Aug 10.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
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http://dx.doi.org/10.1038/nature10251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3182531PMC
August 2011

Vitamin D receptor (VDR) gene SNPs influence VDR expression and modulate protection from multiple sclerosis in HLA-DRB1*15-positive individuals.

Brain Behav Immun 2011 Oct 12;25(7):1460-7. Epub 2011 Jun 12.

Don C. Gnocchi Foundation ONLUS, P.le Morandi 6, 20121 Milan, Italy.

Multiple sclerosis (MS) is an autoimmune disease with a multifactorial etiology. The HLA-DRB1*15 allele, is the main genetic risk factor for MS in Caucasians; recent findings showed that the transcription of this molecule is regulated by the vitamin D/vitamin D receptor (VDR) complex. We analyzed SNPs within the VDR gene in association with the HLA-DRB1 locus in 641 MS patients diagnosed according to McDonald criteria and 558 age- and sex-matched healthy controls, to verify possible correlations between the vitamin D/VDR complex, HLA-DRB1, and susceptibility to MS. Results confirmed that HLA-DRB1*15 is a strong predisposing allele (p<1×10(-7); OR: 3.04; 95% CI: 2.02-4.60) for MS. Cosegregation analyses of VDR SNPs with HLA-DRB1*15 indicated a reduction of risk for MS given by the presence of the -DRB1*15-rs731236 T VDR haplotype (p=9.5×10(-5); OR: 2.52; 95% CI: 1.56-4.06) and, conversely, an augmented risk for disease associated with the -DRB1*15-rs731236 C VDR haplotype. Analyses performed on HLA-DRB1*15-positive MS patients and HC alone confirmed the protective role of rs731236 TT VDR genotype (p(y)=0.004; OR: 0.53; 95% CI: 0.33-0.83); notably, FACS, PCR, and confocal microscopy analyses showed that rs731236 TT genotype is associated with an augmented VDR expression in MBP-stimulated PBMC from patients. In conclusion, rs731236 TT VDR genotype modulates VDR expression and confers protection against MS in HLA-DRB1*15-positive individuals. Results herein offer a model justifying the interaction between the major genetic (HLA-DRB*15) and environmental (vitamin D) factors associated with MS onset.
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http://dx.doi.org/10.1016/j.bbi.2011.05.015DOI Listing
October 2011

Treatment of first tonic-clonic seizure does not affect mortality: long-term follow-up of a randomised clinical trial.

J Neurol Neurosurg Psychiatry 2011 Aug 28;82(8):924-7. Epub 2011 Apr 28.

SCDU Neurologia, AOU Maggiore della Carità, C.so Mazzini 18, 28100 Novara, Italy.

Background: Information on the effects of early treatment of seizures on mortality is scarce. The authors assessed the survival of patients with a first generalised tonic-clonic seizure, randomised to immediate treatment (treated) versus treatment only in the event of seizure recurrence (untreated), over a 20-year period.

Methods: The authors followed 419 patients. The median follow-up was 19.7 years (range 0.2-21.5) for a total of 7867 person-years.

Results: 40 persons (9.6%) died during follow-up, 19 (8.9%) treated and 21 (10.3.%) untreated. The probability of surviving was 100% at 1 year, 97% (95% CI 95% to 99%) at 5 years, 94% (91-97) at 10 years and 91% (87-95) at 20 years in treated patients and 100%, 98% (95-100), 97% (94-99) and 89% (85-94), respectively, in untreated patients (p=0.7). After adjustment for treatment of first seizure and putative risk factors (gender, age, seizure type, previous uncertain seizures, family history of seizures, pre-, peri- and postnatal risk factors, remote aetiological factors for epilepsy, abnormal neurological examination, CT or MRI abnormalities, EEG abnormalities and acute treatment), only the presence of aetiological factors for epilepsy predicted a higher mortality (HR 3.4, 95% CI 2.5 to 4.3%; p<0.01). Patients with remote aetiological factors and who did not achieve 5-year remission had the poorest survival.

Conclusion: Starting antiepileptic treatment immediately after the first generalised tonic-clonic seizure or only after seizure recurrence did not affect survival over the following 20 years.
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http://dx.doi.org/10.1136/jnnp.2010.240069DOI Listing
August 2011

Validity and reliability of the Barthel index administered by telephone.

Stroke 2011 Jul 28;42(7):2077-9. Epub 2011 Apr 28.

SCDU Neurologia, Ospedale Maggiore della Carità, C. Mazzini 18-28100 Novara, Italy.

Background And Purpose: We aimed to evaluate validity and reliability of the Barthel Index administered telephonically compared with face-to-face assessment in clinically stable patients with stroke.

Methods: One hundred thirty-one patients were interviewed twice by 2 registered nurses with identical training. Half of the patients were randomized to receive the telephone interview followed by the face-to-face interview and half the contrary. The sequence of interviewers was randomized.

Results: The median value of the Barthel Index score was 30 (first to third interquartile range, 15 to 80) by telephone and 35 (15 to 75) by face-to-face (P=0.29). The weighted κ was 0.90 (95% CI, 0.85 to 0.94); κ values ranged from 0.70 (0.58 to 0.82) for bowel control to 0.91 (0.83 to 0.99) for bathing.

Conclusions: Telephone assessment of stroke disability with the Barthel Index is reliable in comparison to direct face-to-face assessment.
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http://dx.doi.org/10.1161/STROKEAHA.111.613521DOI Listing
July 2011

Risk factors for a first epileptic seizure symptomatic of brain tumour or brain vascular malformation. A case control study.

Swiss Med Wkly 2011 28;141:w13155. Epub 2011 Jan 28.

Clinica Neurologica, Ospedale Maggiore della Carità, C. Mazzini 18, 28100 Novara, Italy.

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.
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http://dx.doi.org/10.4414/smw.2011.13155DOI Listing
June 2011
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