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Background Administrative databases have become an important tool to monitor diseases. Patients with epilepsy could be traced using disease-specific codes and prescriptions, but formal validation is required to obtain an accurate case definition. The aim of the study was to correlate administrative data on epilepsy with an independent source of patients with epilepsy in a district of Lombardy, Northern Italy, from 2000 to 2008. Methods Data of nearly 320 600 inhabitants in the district of Lecco collected from the Drug Administrative Database of the Lombardy Region were analysed. Among them were included patients who fulfilled the International Classification of Diseases 9 (ICD-9) codes and/or the disease-specific exemption code for epilepsy and those who had at least one EEG record and took antiepileptic drugs (AEDs) as monotherapy or in variable combinations. To ascertain epilepsy cases, 11 general practitioners (GPs) with 15 728 affiliates were contacted. Multiple versions of the diagnostic algorithm were developed using different logistic regression models and all combinations of the four independent variables. Results Among the GP affiliates, 71 (4.5/1000) had a gold standard diagnosis of epilepsy. The best and most conservative algorithm included EEG and selected treatment schedules and identified 61/71 patients with epilepsy (sensitivity 85.9%, CI 76.0% to 92.2%) and 15 623/15 657 patients without epilepsy (specificity 99.8%,CI 99.7% to 99.8%). The positive and negative predictive values were 64.2% and 99.9%. Sensitivity (86.7%) and the positive predictive value (68.4%) increased only slightly when patients with single seizures were included. Conclusions A diagnostic algorithm including EEG and selected treatment schedules is only moderately sensitive for the detection of epilepsy and seizures. These findings apply only to the Northern Italian scenario. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Geographical differences in the incidence of amyotrophic lateral sclerosis (ALS) have been reported in the literature but comparisons across previous studies are limited by different methods in case ascertainment and by the relatively small size of the studied populations. To address these issues, the authors undertook a pooled analysis of European population based ALS registries.Methods: All new incident ALS cases in subjects aged 18 years old and older were identified prospectively in six population based registries in three European countries (Ireland, UK and Italy) in the 2 year period 1998-1999, with a reference population of almost 24 million.Results: Based on 1028 identified incident cases, the crude annual incidence rate of ALS in the general European population was 2.16 per 100 000 person years; 95% CI 2.0 to 2.3), with similar incidence rates across all registries. The incidence was higher among men (3.0 per 100 000 person years; 95% CI 2.8 to 3.3) than among women (2.4 per 100 000 person years; 95% CI 2.2 to 2.6). Spinal onset ALS was more common among men compared with women, particularly in the 70-80 year age group. Disease occurrence decreased rapidly after 80 years of age.Conclusions: ALS incidence is homogeneous across Europe. Sex differences in incidence may be explained by the higher incidence of spinal onset ALS among men, and the age related disease pattern suggests that ALS occurs within a susceptible group within the population rather than being a disease of ageing. [ABSTRACT FROM AUTHOR]

Objective: To measure survivorship and predictors of prognosis of amyotrophic lateral sclerosis (ALS). Methods: Incident cases, diagnosed in the 1998-1999 period and classified according to the El Escorial criteria, were enrolled from a prospective population based registry established in Puglia, Southern Italy, with a reference population of 4 025 329. Cases were followed up until death or 30 June 2004. Results: We identified 130 incident cases of ALS while four were lost to follow-up. Median survival was 28 months from first symptoms and 16 months from diagnosis, while cumulative survivorship at 4 years was approximately 30%. Advanced age (>75 years: hazard ratio (HR) 7.5; 95% CI 1.9 to 29.6; p = 0.004) and bulbar or generalised (HR 1.8; 95% CI 1.1 to 3.0; p = 0.01) onset of symptoms were independent predictors of adverse survival. After stratifying patients according to site of first symptoms, age was a predictor of death among spinal (HR for patients aged >75 years compared with patients aged 45 years or less: HR 11; 95% CI 1.5 to 78.5; p = 0.01) but not among bulbar ALS (HR 4.5; 95% CI 0.4 to 46.5; p = 0.2). Among spinal onset cases, cases with predominant upper motoneuronal (UMN) involvement presented with a borderline significant better survivorship (HR 0.5; 95% CI 0.2 to 1.3; p = 0.1) Conclusions: Bulbar signs and advanced age among subjects with spinal onset were indicators of poor prognosis while El Escorial category at entry did not predict survival. Among subjects with spinal onset of the disease, a trend for a better survivorship of subjects with UMN signs was noted. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a relatively rare disease with a reported population incidence of between 1.5 and 2.5 per 100 000 per year. Over the past 10 years, the design of ALS epidemiological studies has evolved to focus on a prospective, population based methodology, employing the El Escorial criteria and multiple sources of data to ensure complete case ascertainment. Five such studies, based in Europe and North America, have been published and show remarkably consistent incidence figures among their respective Caucasian populations. Population based studies have been useful in defining clinical characteristics and prognostic indicators in ALS. However, many epidemiological questions remain that cannot be resolved by any of the existing population based datasets. The working hypotheses is that ALS, like other chronic diseases, is a complex genetic condition, and the relative contributions of individual environmental and genetic factors are likely to be relatively small. Larger studies are required to characterise risks and identify subpopulations that might be suitable for further study. This current paper outlines the contribution of the various population based registers, identifies the limitations of the existing datasets and proposes a mechanism to improve the future design and output of descriptive epidemiological studies. [ABSTRACT FROM AUTHOR]

Objective: To assess the prevalence of peripheral neuropathy (PN) and its correlation with cryoglobulinemia (CG) in an unselected, untreated referral hepatitis C virus (HCV) population. Patients and Methods: Two hundred and thirty four patients (120 women and 114 men) with untreated HCV infection were consecutively enrolled by seven Italian centres. Clinical neuropathy was diagnosed when symptoms and signs of peripheral sensory or motor involvement were present. Median, ulnar, peroneal, and sural nerves were explored in all patients and distal symmetric polyneuropathy was diagnosed when all explored nerves or both lower limb nerves were affected. Mononeuropathy and mononeuropathy multiplex were diagnosed when one nerve or two non-contiguous nerves with asymmetrical distribution were affected. Screening for CG was done in 191 unselected patients. Results: Clinical signs of PN were observed in 25 of the 234 patients (10.6%). Electrophysiological PN was found in 36 (15.3%). CG was present in 56/191 patients (29.3%). The prevalence of CG increased significantly with age (p < 0.001) and disease duration (p < 0.05). PN was present in 12/56 (21%) patients with CG and 18/135 (13%) without CG (p = NS). PN increased significantly with age (p < 0.001) and logistic regression analysis confirmed age as the only independent predictor of PN (OR 1.10 for each year; 95% CI 1.04 to 1.15; p < 0.001). Conclusions: Electrophysiological examination detected subclinical neuropathy in 11 patients (4.7%). Statistical analysis showed that CG was not a risk factor for PN whereas PN prevalence increased significantly with age. [ABSTRACT FROM AUTHOR]

Background: While the incidence of amyotrophic lateral sclerosis (ALS) is similar across the world (range, 1.0 to 2.5/100,000), a latitude gradient from north to south has been observed.Objective: To determine the incidence of ALS in Puglia, a region of south eastern Italy, and to test the latitude gradient hypothesis comparing the present study with findings in studies conducted with the same design in a northern latitude.Methods: Puglia (4,086,613 residents in 2001) is the site of a multicentre-multisource prospective population based registry established in 1997. All incident ALS cases during the period 1998-99 were enrolled and followed up. Cases were classified using the first and the revised El Escorial criteria.Results: During the study period 130 cases were enrolled. The annual crude incidence for ALS in Puglia for the two year period 1998-99 was 1.6/100,000 (95% confidence interval, 1.3 to 1.9). The incidence was higher for men (incidence rate (IR) = 2.1 (1.7 to 2.7) than for women (IR = 1.2 (0.9 to 1.5)) in all age groups, with a male to female ratio of 1.6. For both men and women, the incidence increased through age 75 and declined rapidly afterwards. The mean annual incidence adjusted by age and sex to the 2001 Italian population was 1.7/100,000 (1.4 to 2.0).Conclusions: ALS incidence is within a narrow range across countries, with a peak between 65 and 75 years and a higher incidence in men. A north to south latitude gradient of ALS incidence is not supported by the results of cohort studies. [ABSTRACT FROM AUTHOR]

Objective: To establish whether chronic alcoholism and alcohol consumption are risk factors for developing a first symptomatic epileptic seizure.Methods: Multicentre case-control study of 293 patients (160 men, 133 women) with a first seizure symptomatic (either acute or remote) of head trauma, stroke, or brain tumour, matched to 444 hospital controls for centre, sex, age (+/-5 years), and underlying pathology.Results: The risk of first seizure in alcoholics was no higher than in non-alcoholics for men (odds ratio 1.2, 95% confidence interval 0.4 to 3.2) or women (1.5, 0.1 to 54.4). The odds ratio (both sexes) was 1.2 (0.8 to 1.7) for an average intake of absolute alcohol of 1-25 g/day, 0.9 (0.5 to 1.5) for 26-50 g/day, 1.6 (0.8 to 3.0) for 51-100 g/day, and 1.4 (0.5 to 3.5) for >100 g/day.Conclusions: We found no evidence of an association between alcohol use or alcoholism and a first symptomatic seizure. [ABSTRACT FROM AUTHOR]

Objectives: To assess the recurrence rate of epilepsy attributable to discontinuation of treatment in seizure free patients and to identify the risk factors for recurrence.Methods: 330 patients referred to an epilepsy centre who were seizure free for at least 2 years while on stable monotherapy were the study population. Discontinuation of antiepileptic drugs (AEDs) was proposed to all eligible patients or to their carers after discussion of the risks and benefits. Depending on whether they accepted or refused treatment withdrawal, the patients were stratified into two cohorts and followed up until seizure relapse or 31 March 1999, whichever came first. For each patient, records were taken of the main demographic and clinical variables.Results: The sample comprised 225 patients who entered the discontinuation programme and 105 who decided to continue treatment. Twenty nine patients (28%) continuing treatment had a relapse, compared with 113 (50%) of those entering the withdrawal programme. For patients continuing treatment, the probability of remission was 95% at 6 months, 91% at 12 months, 82% at 24 months, 80% at 36 months, and 68% at 60 months. The corresponding values for patients discontinuing treatment were 88%, 74%, 57%, 51%, and 48%. After adjusting for the principal prognostic factors, in patients discontinuing AEDs the risk of seizure relapse was 2.9 times that of patients continuing treatment. A relation was also found between relapse and duration of active disease, number of years of remission while on treatment, and abnormal psychiatric findings.Conclusions: Seizure free referral patients on stable monotherapy who elect to withdraw drug treatment are at higher risk of seizure relapse compared with patients continuing treatment. Severity of disease and seizure free period are significant prognostic factors. [ABSTRACT FROM AUTHOR]

The prevalence and characteristics of polyneuropathy were assessed using standard clinical and electrophysiological criteria in 39 consecutive outpatients with primary hypothyroidism, 15 of whom were previously untreated. Subjective complaints, mainly paraesthesiae, were recorded from 25 cases (64%) and objective findings supporting a clinical diagnosis of polyneuropathy were present in 13 (33%). Using standard electrophysiological criteria, a definite diagnosis of polyneuropathy was made in 28 cases (72%). The commonest sites of abnormal nerve conduction were the sensory nerves, especially the sural nerve. Polyneuropathy was generally mild. None of the clinical and biochemical indicators of hypothyroidism were significantly correlated with the electrophysiological signs of peripheral nerve impairment or the diagnosis of polyneuropathy. [ABSTRACT FROM AUTHOR]

BACKGROUND: The prevalence of tic disorders in children varies from 1% to 29% depending on the characteristics of the study population, the diagnostic criteria, and the study design and methods. AIMS: To calculate the prevalence of tic disorders among primary school children in Italy. METHODS: The study population comprised 2347 primary school children from the city of Pavia (pop. 80 073), Northern Italy. Using trained school teachers as the source of cases, all children with motor or vocal tics occurring intermittently and unpredictably out of a background of normal motor activity were accepted. The type, frequency, and circumstances of tic disorders were noted. School performance was correlated to the presence of tics. RESULTS: A total of 68 children (56 boys, 12 girls) aged 6-11 years were identified with tic disorders. The period prevalence was 2.9% (95% CI 2.3 to 3.7). The prevalence was 4.4% in boys and 1.1% in girls, with no detectable trends at age 6-11. Motor tics were present in 46 cases, vocal tics in 6, and motor and vocal tics in 16. Situation related tics were noted in 37 cases. A significant correlation was found between the presence of tic disorders and impaired school performance. DISCUSSIONS: Tic disorders are a fairly uncommon but disabling clinical disorder among primary school children from an urban community. The fairly low prevalence of this clinical condition, as compared to other reports, can be explained by the choice of stringent diagnostic criteria and the exclusion of patients with other movement disorders. [ABSTRACT FROM AUTHOR]

Objectives: To compare mortality, comorbidities and causes of death in people with psychogenic non-epileptic seizures (PNES), epilepsy and the general population., Methods: Using linkage of multiple Swedish national registers, we identified individuals with incident diagnosis of PNES, epilepsy and conversion disorder with motor symptoms or deficits, and 10 controls for each. Main outcome was all-cause mortality. Causes of death were categorised into non-natural (eg, suicide, injuries) and natural. Conditional Cox regression models were used to estimate HRs and 95% CIs for mortality. HRs were adjusted for socioeconomic factors and psychiatric comorbidities., Results: Included were 885 individuals with PNES, 50 663 with epilepsy and 1057 with conversion disorder and motor symptoms or deficits. We found 32 (3.6%) deaths among individuals with PNES, compared with 46 (0.5%) deaths in controls, giving an adjusted HR of 5.5 (95% CI 2.8 to 10.8). Patients with epilepsy had a 6.7 times higher risk of death (95% CI 6.4 to 7.0) compared with individuals without epilepsy. The association between conversion disorder with motor symptoms or deficits was non-significant after adjusting for psychiatric comorbidities. PNES carried a higher risk of natural (HR 8.1, 95% CI 4.0 to 16.4) and non-natural causes of death (HR 15.3, 95% CI 3.0 to 78.6). Suicide ranked high in patients with PNES (18.8%) and conversion disorder with motor symptoms and deficits. The association between PNES diagnosis and all-cause mortality varied with age and time since diagnosis., Conclusion: Like epilepsy, PNES carries a higher than expected risk of both natural and non-natural causes of death. The high proportion of suicides requires further investigation., Competing Interests: Competing interests: EB reports grants from Italian Ministry of Health, grants from Swedish Orphan Biovitrum, personal fees from Arvelle Therapeutics, grants from American ALS Association, outside the submitted work. TT reports grants form EISAI, GSK, UCB, Bial, personal fees from EISAI, Sanofi, Sun Pharma, UCB, Sandoz, grants from EU, grants from Stockholm County Council, grants from CURE, outside the submitted work. The remaining authors have nothing to disclose., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To determine the prevalence of different comorbidities in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and their impact on outcome, treatment choice and response., Methods: Using a structured questionnaire, we collected information on comorbidities from 393 patients with CIDP fulfilling the European Federation of Neurological Societies and Peripheral Nerve Society criteria included in the Italian CIDP database., Results: One or more comorbidities were reported by 294 patients (75%) and potentially influenced treatment choice in 192 (49%) leading to a less frequent use of corticosteroids. Response to treatment did not differ, however, from that in patients without comorbidities. Diabetes (14%), monoclonal gammopathy of undetermined significance (MGUS) (12%) and other immune disorders (16%) were significantly more frequent in patients with CIDP than expected in the general European population. Patients with diabetes had higher disability scores, worse quality of life and a less frequent treatment response compared with patients without diabetes. Patients with IgG-IgA or IgM MGUS had an older age at CIDP onset while patients with other immune disorders had a younger age at onset and were more frequently females. IgM MGUS was more frequent in patients with motor CIDP than in patients with typical CIDP., Conclusions: Comorbidities are frequent in patients with CIDP and in almost 50% of them have an impact on treatment choice. Diabetes, MGUS and other immune diseases are more frequent in patients with CIDP than in the general population. Only diabetes seems, however, to have an impact on disease severity and treatment response possibly reflecting in some patients a coexisting diabetic neuropathy., Competing Interests: Competing interests: PED has received travel grants to attend scientific meetings from CSL Behring and Kedrion. DC has received honoraria for lecturing from Shire, CSL Behring and Kedrion and travel grants to attend scientific meeting from Shire, Kedrion, and CSL Behring. FM reports personal fees for scientific events from CSL Behring and has received travel grants to attend scientific meetings from CSL Behring and Kedrion. RF has served on scientific advisory boards for CSL Behring and has received travel grants from Kedrion and CSL Behring to attend scientific meeting. Chiara Briani has served on scientific advisory boards for Pfizer, Alnylam, and Akcea, and has received travel grants from Kedrion and CSL Behring to attend scientific meeting. MF has served on scientific advisory boards for CSL Behring and has received travel grants from Kedrion, Baxter and CSL Behring to attend scientific meeting. SJ has received research grants from Grifols, outside this work, and travel grants from Grifols and Kedrion. Anna Mazzeo has received travel grants from Kedrion and CSL Behring to attend scientific meeting. GC has received travel grants to attend scientific meetings from CSL Behring and Kedrion. AC has received travel grants to attend scientific meetings from Kedrion. MC has received travel grants to attend scientific meetings from Kedrion. ML has received travel grants to attend scientific meetings from Kedrion. GC has received honoraria for lecturing and travel grants to attend scientific meetings from Kedrion. E Beghi reports grants from UCB-Pharma, grants from Shire, grants from EISAI, personal fees from Viropharma, grants from Italian Ministry of Health, grants from Fondazione Borgonovo, grants from Associazione IDIC 15, grants from European Union, outside the submitted work. Giuseppe Liberatore has received travel grants to attend scientific meetings from CSL Behring and Kedrion. Lucio Santoro reports personal fees for scientific events from CSL Behring and has received travel grants to attend scientific meetings from CSL Behring and Kedrion. EP has received travel grants to attend scientific meetings from CSL Behring. Eduardo Nobile Orazio reports personal fees for Advisory or Scientific Board from Kedrion, Italy, Baxter, Italy, Novartis, Switzerland, CSL-Behring, Italy, Astellas, the Netherlands, outside the submitted work and travel grants to attend Scientific Meeting from Baxter, Grifols, Kedrion, and Novartis, Italy. The other authors declare no conflict of interest., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: We investigated the association between cigarette smoking and risk of amyotrophic lateral sclerosis (ALS) in a pooled analysis of population-based case-control studies and explored the independent effects of intensity, duration and time-since-quitting., Methods: ALS cases and controls, matched by age, sex and region, were recruited in the Netherlands, Italy and Ireland (*Euro-MOTOR project). Demographics and detailed lifetime smoking histories were collected through questionnaires. Effects of smoking status, intensity (cigarettes/day), duration (years), pack-years and time-since-quitting (years) on ALS risk were estimated using logistic regression models, adjusting for age, sex, alcohol, education and centre. We further investigated effect modification of the linear effects of pack-years by intensity, duration and time-since-quitting using excess OR (eOR) models., Results: Analyses were performed on 1410 cases and 2616 controls. Pack-years were positively associated with ALS risk; OR=1.26 (95% CI: 1.03 to 1.54) for the highest quartile compared with never smokers. This association appeared to be predominantly driven by smoking duration (p trend =0.001) rather than intensity (p trend =0.86), although the trend for duration disappeared after adjustment for time-since-quitting. Time-since-quitting was inversely related to ALS (p trend <0.0001). The eOR decreased with time-since-quitting smoking, until about 10 years prior to disease onset. High intensity smoking with shorter duration appeared more deleterious than lower intensity for a longer duration., Conclusions: Our findings provide further support for the association between smoking and ALS. Pack-years alone may be insufficient to capture effects of different smoking patterns. Time-since-quitting appeared to be an important factor, suggesting that smoking may be an early disease trigger., Competing Interests: Competing interests: EB reports grants from UCB-PHARMA, personal fees from MA-Provider, grants from American ALS Association, grants from EISAI, grants from Shire. AC reports personal fees from Biogen, grants from Italfarmaco, personal fees from Roche, personal fees from Cytokinetics, personal fees from Mitsubishi Tanabe. OH has received speaking honoraria from Novartis, Biogen Idec, Sanofi Aventis and Merck-Serono; and has been a member of advisory panels for Biogen Idec, Allergen, Ono Pharmaceuticals, Novartis, Cytokinetics and Sanofi Aventis. LvdB serves on scientific advisory boards for the Prinses Beatrix Spierfonds, Thierry Latran Foundation, Biogen, Cytokinetics, Orion and Sarepta. SP, AEV, FD, JV, LP, GL, EP, JHV and RV report no potential conflicts of interest., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To describe the long-term prognosis of epilepsy and prognostic patterns in a large cohort of newly diagnosed patients and identify prognostic factors., Methods: Study participants were 13 Italian epilepsy centres with accessible records dating back to 2005 or earlier, complete data on seizure outcome and treatments, precise epilepsy diagnosis, and follow-up of at least 10 years. Records were examined by trained neurology residents for demographics, seizure characteristics, neurological signs, psychiatric comorbidity, first electroencephalogram (EEG) and MRI/CT, epilepsy type and aetiology, antiepileptic drugs (AEDs), and 1-year, 2-year, 5-year and 10-year seizure remissions. Five predefined prognostic patterns were identified: early remission, late remission, relapsing-remitting course, worsening course and no remission. Prognostic factors were assessed using multinomial logistic regression models., Results: 1006 children and adults were followed for 17 892 person-years (median 16 years; range 10-57). During follow-up, 923 patients (91.7%) experienced 1-year remission. 2-year, 5-year and 10-year remissions were present in 89.5%, 77.1% and 44.4% of cases. 5-year remission was associated with one to two seizures at diagnosis, generalised epilepsy, no psychiatric comorbidity, and treatment with one or two AEDs during follow-up. 10-year remission was associated with one or two AEDs. The most common prognostic pattern was relapsing-remitting (52.2%), followed by early remission (24.5%). 8.3% of cases experienced no remission. Predictors of a relapsing-remitting course were <6 seizures at diagnosis, (presumed) genetic aetiology and no psychiatric comorbidity., Conclusions: Few seizures at diagnosis, generalised epilepsy and no psychiatric comorbidity predict early or late seizure freedom in epilepsy. Achieving remission at any time after the diagnosis does not exclude further relapses., Competing Interests: Competing interests: EB reports grants from UCB Pharma and from the Italian Ministry of Health. CF is a consultant of Biogen, Roche and OCM., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To investigate whether exposure to particulates and combustion products may explain the association between certain occupations and amyotrophic lateral sclerosis (ALS) risk in a large, multicentre, population-based, case-control study, based on full job histories, using job-exposure matrices, with detailed information on possible confounders., Methods: Population-based patients with ALS and controls were recruited from five registries in the Netherlands, Ireland and Italy. Demographics and data regarding educational level, smoking, alcohol habits and lifetime occupational history were obtained using a validated questionnaire. Using job-exposure matrices, we assessed occupational exposure to silica, asbestos, organic dust, contact with animals or fresh animal products, endotoxins, polycyclic aromatic hydrocarbons and diesel motor exhaust. Multivariate logistic regression models adjusting for confounding factors were used to determine the association between these exposures and ALS risk., Results: We included 1557 patients and 2922 controls. Associations were positive for all seven occupational exposures (ORs ranging from 1.13 to 1.73 for high vs never exposed), and significant on the continuous scale for silica, organic dust and diesel motor exhaust (p values for trend ≤0.03). Additional analyses, adding an exposure (one at a time) to the model in the single exposure analysis, revealed a stable OR for silica. We found similar results when patients with a C9orf72 mutation were excluded., Conclusion: In a large, multicentre study, using harmonised methodology to objectively quantify occupational exposure to particulates and combustion products, we found an association between ALS risk and exposure to silica, independent of the other occupational exposures studied., Competing Interests: Competing interests: EB reports grants from UCB-Pharma, Shire, EISAI; personal fees from Viropharma; grants from the Italian Ministry of Health, the European Union and Fondazione Borgonovo; grants from Associazione IDIC 15, outside the submitted work. AC reports personal fees from Biogen Idec and Cytokinetics; grants from Italfarmaco; personal fees from Mitsubishi, outside the submitted work. OH reports grants from Framework 7 EUROMOTOR project, Health Research Board Ireland and Science Foundation Ireland, during the conduct of the study; personal fees from ALS FTD Journal, outside the submitted work. JHV reports other from Vertex Pharmaceuticals, outside the submitted work. LHvdB reports grants from Netherlands ALS Foundation and the Netherlands Organization for Health Research and Development, during the conduct of the study; grants from Baxalta, Prinses Beatrix Spierfonds, European Community’s Health Seventh Framework Programme, outside the submitted work; and LHvdB serves on scientific advisory boards for the Prinses Beatrix Spierfonds, Thierry Latran Foundation, Biogen and Cytokinetics. Serves on the editorial board of Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration and The Journal of Neurology, Neurosurgery, and Psychiatry. AEV, FD, SMP, RCHV and GL report no disclosures., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: A few variants of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) have been described, but their frequency and evolution to typical CIDP remain unclear. To determine the frequency and characteristics of the CIDP variants, their possible evolution to typical CIDP, and treatment response., Methods: We applied a set of diagnostic criteria to 460 patients included in a database of Italian patients with CIDP. Clinical characteristics and treatment response were reviewed for each patient. The Kaplan-Meier curve was used to estimate the progression rate from atypical to typical CIDP., Results: At the time of inclusion, 376 (82%) patients had a diagnosis of typical CIDP while 84 (18%) had atypical CIDP, including 34 (7%) with distal acquired demyelinating symmetric neuropathy (DADS), 17 (4%) with purely motor, 17 (4%) with Lewis-Sumner syndrome (LSS) and 16 (3.5%) with purely sensory CIDP. Based on retrospective review of the symptoms and signs present at onset and for at least 1 year, 180 (39%) patients had an initial diagnosis compatible with atypical CIDP that in 96 (53%) patients evolved to typical CIDP. Mean disease duration was longer in patients evolving to typical CIDP than in those not evolving (p=0.0016). Patients with DADS and LSS had a less frequent response to immunoglobulin than those with typical CIDP, while patients with purely motor and sensory CIDP had a similar treatment response., Conclusions: The proportion of patients with atypical CIDP varies during the disease course. DADS and LSS have a less frequent response to intravenous immunoglobulin compared with typical CIDP, raising the possibility of a different underlying pathogenetic mechanism., Competing Interests: Competing interests: EN-O reports personal fees for Advisory or Scientific Board from Kedrion, Italy, Baxter, Italy, Novartis, Switzerland, CSL Behring, Italy, Astellas, the Netherlands, outside the submitted work and travel grants to attend scientific meeting from Baxter, Grifols, Kedrion and Novartis, Italy. PED has received travel grants to attend scientific meetings from CSL Behring and Kedrion. GLib has received travel grants to attend scientific meetings from CSL Behring and Kedrion. DC has received honoraria for lecturing from Shire, CSL Behring and Kedrion and travel grants to attend scientific meeting from Shire, Kedrion and CSL Behring. EP has received travel grants to attend scientific meetings from CSL Behring. RF has served on scientific advisory boards for CSL Behring and has received travel grants from Kedrion and CSL Behring to attend scientific meeting. MC has received travel grants to attend scientific meetings from Kedrion. AM has received travel grants from Kedrion and CSL Behring to attend scientific meeting. CB has served on scientific advisory boards for Pfizer and has received travel grants from Kedrion and CSL Behring to attend scientific meeting. GC has received travel grants to attend scientific meetings from CSL Behring and Kedrion. BF has received travel grants to attend scientific meetings from CSL Behring and liberal contribution from CSL Behring for the neuromuscular diseases centre, outside the submitted work. EB reports grants from UCB-Pharma, grants from Shire, grants from EISAI, personal fees from Viropharma, grants from Italian Ministry of Health, grants from Fondazione Borgonovo, grants from Associazione IDIC 15, grants from European Union, outside the submitted work. AC has received travel grants to attend scientific meetings from Kedrion. ML has received honoraria for scientific board from Pfeizer and Alnylam and travel grants from Grifols and Kedrion to attend scientific meeting. LS reports personal fees for scientific events from CSL Behring and has received travel grants to attend scientific meetings from CSL Behring and Kedrion. FM reports personal fees for scientific events from CSL Behring and has received travel grants to attend scientific meetings from CSL Behring and Kedrion. GC has received honoraria for lecturing and travel grants to attend scientific meetings from Kedrion. MF has served on scientific advisory boards for CSL Behring and has received travel grants from Kedrion, Baxter and CSL Behring to attend scientific meeting. SJ has received research grants from Grifols, outside this work, and travel grants from Grifols and Kedrion., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Several studies focused on the association between alcohol consumption and amyotrophic lateral sclerosis (ALS), although with inconsistent findings. Antioxidants may play a role since lyophilised red wine was found to prolong SOD1 mice lifespan. The aim of this international population-based case-control study performed in Ireland, The Netherlands and Italy was to assess the role of alcohol, and red wine in particular, in developing ALS., Methods: Euro-MOTOR is a case-control study where patients with incident ALS and controls matched for gender, age and area of residency were recruited in a population-based design. Logistic regression models adjusted for sex, age, cohort, education, leisure time physical activity, smoking, heart problems, hypertension, stroke, cholesterol and diabetes were performed., Results: 1557 patients with ALS and 2922 controls were enrolled in the study. Exposure to alcohol drinking was not significantly associated with ALS risk. A stratified analysis of exposure to alcohol by cohort revealed significant ORs in The Netherlands and in Apulia, with opposite directions (respectively 0.68 and 2.38). With regard to red wine consumption, only in Apulia the double-fold increased risk (OR 2.53) remained significant. A decreased risk was found for current alcohol drinkers (OR 0.83), while a significantly increased risk was detected among former drinkers (OR 1.63). Analysis of cumulative exposure to alcohol revealed no significant associations with ALS risk., Conclusion: With few exceptions, no significant association was found between alcohol consumption and ALS. The study of the association between alcohol and ALS requires a thorough exploration, especially considering the role of different type of alcoholic beverages., Competing Interests: Competing interests: JPKR was funded by the Health Research Board Clinical Fellowship Programme (HPF-2014-527). EB reports grants from UCB-Pharma, grants from Shire, grants from EISAI, personal fees from Viropharma, grants from Italian Ministry of Health, grants from Fondazione Borgonovo, grants from Associazione IDIC 15, grants from European Union, outside the submitted work. OH is funded by the Health Research Board Clinician Scientist Programme and Science Foundation Ireland; has received speaking honoraria from Novartis, Biogen Idec, Sanofi Aventis and Merck-Serono; has been a member of advisory panels for Biogen Idec, Allergen, Ono Pharmaceuticals, Novartis, Cytokinetics and Sanofi Aventis; and serves as editor-in-chief of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. LHvdB reports grants from European Union Health Seventh Framework Programme (EUROMOTOR project), Netherlands ALS Foundation and The Netherlands Organization for Health Research and Development (Vici scheme), serves on scientific advisory boards for the Prinses Beatrix Spierfonds, Thierry Latran Foundation, Biogen, Cytokinetics, Orion and Sarepta; serves on the editorial board of Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration and The Journal of Neurology, Neurosurgery, and Psychiatry. AC serves on the editorial advisory board of Amyotrophic Lateral Sclerosis; receives research support from the Italian Ministry of Health (Ricerca Finalizzata), Regione Piemonte (Ricerca Finalizzata), University of Turin, Fondazione Vialli e Mauro onlus and the European Commission (Health Seventh Framework Programme); and serves on scientific advisory boards for Biogen Idec, Cytokinetics, Italfarmaco, Neuraltus and Mitsubishi Tanabe. FD, AEV, UM, RCHV, GL and JHV report no disclosures relevant to the manuscript., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To investigate the association between physical activity (PA) and amyotrophic lateral sclerosis (ALS) in population-based case-control studies in three European countries using a validated and harmonised questionnaire., Methods: Patients with incident ALS and controls were recruited from five population-based registers in The Netherlands, Ireland and Italy. Demographic and data regarding educational level, smoking, alcohol habits and lifetime PA levels in both leisure and work time were gathered by questionnaire, and quantified using metabolic equivalent of task scores. Logistic regression models adjusting for PA-related factors were used to determine the association between PA and ALS risk, and forest plots were used to visualise heterogeneity between regions., Results: 1557 patients and 2922 controls were included. We found a linear association between ALS and PA in leisure time (OR 1.07, P=0.01) and occupational activities (OR 1.06, P<0.001), and all activities combined (OR 1.06, P<0.001), with some heterogeneity between regions: the most evident association was seen in the Irish and Italian cohorts. After adjustment for other occupational exposures or exclusion of patients with a C9orf72 mutation, the ORs remained similar., Conclusion: We provide new class I evidence for a positive association between PA and risk of ALS in a large multicentre study using harmonised methodology to objectively quantify PA levels, with some suggestions for population differences., Competing Interests: Competing interests: AEV, FD, HJW, RCHV and GL report no disclosures. JPKR reports grants from health research board, during the conduct of the study. EB reports grants from UCB-Pharma, grants from Shire, grants from EISAI, personal fees from Viropharma, grants from Italian Ministry of Health, grants from European Union, grants from Fondazione Borgonovo, grants from Associazione IDIC 15, outside the submitted work. AC reports personal fees from Biogen Idec, personal fees from Cytokinetics, grants from Italfarmaco, personal fees from Mitsubishi, outside the submitted work. OH reports grants from framework 7 EUROMOTOR project, grants from Health Research Board Ireland, grants from Science Foundation Ireland, during the conduct of the study; personal fees from ALS FTD Journal, outside the submitted work. JHV reports other from Vertex Pharmaceuticals, outside the submitted work. LHvdB reports grants from Netherlands ALS Foundation, grants from The Netherlands Organisation for Health Research and Development, during the conduct of the study; grants from Baxalta, grants from Prinses Beatrix Spierfonds, grants from European Community’s Health Seventh Framework Programme, outside the submitted work; LHvdB serves on scientific advisory boards for the Prinses Beatrix Spierfonds, Thierry Latran Foundation, Biogen and Cytokinetics and serves on the editorial board of amyotrophic lateral sclerosis and frontotemporal degeneration and the journal of neurology, neurosurgery and psychiatry., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Prospective population based-registers of amyotrophic lateral sclerosis (ALS) have operated in Europe for over two decades, and have provided important insights into our understanding of ALS. Here, we review the benefits that population registers have brought to the understanding of the incidence, prevalence, phenotype and genetics of ALS and outline the core operating principles that underlie these registers and facilitate international collaboration. Going forward, we offer lessons learned from our collective experience of operating population-based ALS registers in Europe for over two decades, focusing on register design, maintenance, identification and management of bias and the value of cross-national harmonisation and integration., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: We reported that 6-month therapy with intravenous immunoglobulin (IVIg) was more frequently effective or tolerated than intravenous methylprednisolone (IVMP) in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We now retrospectively compared the proportion of patients who eventually worsened after discontinuing therapy and the median time to clinical worsening., Methods: By March 2013, data were available from 41 of the 45 patients completing the trial with a median follow-up after therapy discontinuation of 42 months (range 1-60). Three patients withdrew during the original study and one failed to respond to either of the therapies. No patient received a diagnosis alternative to CIDP during the follow-up., Results: Twenty-eight of the 32 patients treated with IVIg (as primary or secondary therapy after failing to respond to IVMP) improved after therapy (87.5%) as compared with 13 of the 24 patients treated with IVMP as primary or secondary therapy (54.2%). After a median follow-up of 42 months (range 1-57), 24 out of 28 patients responsive to IVIg (85.7%) worsened after therapy discontinuation. The same occurred in 10 out of 13 patients (76.9%) responsive to IVMP (p=0.659) after a median follow-up of 43 months (range 7-60). Worsening occurred 1-24 months (median 4.5) after IVIg discontinuation and 1-31 months (median 14) after IVMP discontinuation (p=0.0126)., Conclusions: A similarly high proportion of patients treated with IVIg or IVMP eventually relapse after therapy discontinuation but the median time to relapse was significantly longer after IVMP than IVIg. This difference may help to balance the more frequent response to IVIg than to IVMP in patients with CIDP., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: The impact of educational strategies in the management of adverse treatment effects and drug interactions in adult patients with epilepsy with comorbidities remains undetermined., Objective: The EDU-COM study is a randomised, pragmatic trial investigating the effect of a patient-tailored educational plan in patients with epilepsy with comorbidity., Methods: 174 adult patients with epilepsy with chronic comorbidities, multiple-drug therapy and reporting at least one adverse treatment effect and/or drug interaction at study entry were randomly assigned to the educational plan or usual care. The primary endpoint was the number of patients becoming free from adverse treatment events and/or drug interactions after a 6-month follow-up. The number of adverse treatment events and drug interactions, health-related quality of life (HRQOL) summary score changes and the monetary costs of medical contacts and drugs were assessed as secondary outcomes., Results: The primary endpoint was met by 44.0% of patients receiving the educational plan versus 28.9% of those on usual care (p=0.0399). The control group reported a significantly higher risk not to meet successfully the primary endpoint at the end of the study: OR (95% CI) of 2.29 (1.03 to 5.09). A separate analysis on drug adverse effects and drug interactions showed that the latter were more sensitive to the effect of educational treatment. Quality of life and costs were not significantly different in the two groups., Conclusions: A patient-tailored educational strategy is effective in reducing drug-related problems (particularly drug interactions) in epilepsy patients with chronic comorbidities, without adding significant monetary costs. Registered at ClinicalTrials.gov, identifier NCT01804322, (http://www.clinicaltrials.gov)., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Purpose: To study prognosis and prognostic predictors of sporadic non-lesional temporal lobe epilepsy (TLE)., Method: 474 patients with TLE were consecutively seen from April 1987 to April 2004. 190 had a sporadic non-lesional TLE and a follow-up longer than 2 years. 284 patients were excluded because of family history for TLE, incomplete history, poor compliance with treatment, psychogenic seizures, no brain MRI study, presence of intracranial lesions except for scattered T2 hyperintense spots on hemispheric white matter or mesial temporal sclerosis (MTS). The following prognostic predictors were considered: age at onset of epilepsy, gender, family history of non-TLE or febrile seizures, perinatal factors, history of febrile seizures, ictal phenomena, MTS and interictal EEG. The end point was time to 24 month seizure freedom after treatment onset. The χ(2) test, Student's t test, Kaplan-Meier survival curves with log rank test (univariate analysis) and Cox proportional hazards regression models (multivariate analysis) were used to assess seizure prognosis and prognostic predictors., Results: At univariate analysis, patients achieving 24 month seizure freedom had a significantly older age at onset of epilepsy (33.5 ± 19.9 vs 17.2 ± 14.4 years), and lower occurrence of febrile seizures (11.0% vs 24.4%) and MTS (19.0% vs 35.6%). The chance of remission was directly correlated to age at onset of seizures and inversely correlated to a history of febrile seizures and to the presence of MTS. At multivariate analysis, age at onset of epilepsy was the only significant prognostic predictor., Conclusion: Older age at onset predicts better prognosis in sporadic non-lesional TLE.