Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis.

BACKGROUND: Different therapeutic strategies are available for the treatment of people with relapsing-remitting multiple sclerosis (RRMS), including immunomodulators, immunosuppressants and biological agents. Although each one of these therapies reduces relapse frequency and slows disability accumulation compared to no treatment, their relative benefit remains unclear. This is an update of a Cochrane review published in 2015. OBJECTIVES: To compare the efficacy and safety, through network meta-analysis, of interferon beta-1b, interferon beta-1a, glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, pegylated interferon beta-1a, daclizumab, laquinimod, azathioprine, immunoglobulins, cladribine, cyclophosphamide, diroximel fumarate, fludarabine, interferon beta 1-a and beta 1-b, leflunomide, methotrexate, minocycline, mycophenolate mofetil, ofatumumab, ozanimod, ponesimod, rituximab, siponimod and steroids for the treatment of people with RRMS. SEARCH METHODS: CENTRAL, MEDLINE, Embase, and two trials registers were searched on 21 September 2021 together with reference checking, citation searching and contact with study authors to identify additional studies. A top-up search was conducted on 8 August 2022. SELECTION CRITERIA: Randomised controlled trials (RCTs) that studied one or more of the available immunomodulators and immunosuppressants as monotherapy in comparison to placebo or to another active agent, in adults with RRMS. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies and extracted data. We considered both direct and indirect evidence and performed data synthesis by pairwise and network meta-analysis. Certainty of the evidence was assessed by the GRADE approach. MAIN RESULTS: We included 50 studies involving 36,541 participants (68.6% female and 31.4% male). Median treatment duration was 24 months, and 25 (50%) studies were placebo-controlled. Considering the risk of bias, the most frequent concern was related to the role of the sponsor in the authorship of the study report or in data management and analysis, for which we judged 68% of the studies were at high risk of other bias. The other frequent concerns were performance bias (34% judged as having high risk) and attrition bias (32% judged as having high risk). Placebo was used as the common comparator for network analysis. Relapses over 12 months: data were provided in 18 studies (9310 participants). Natalizumab results in a large reduction of people with relapses at 12 months (RR 0.52, 95% CI 0.43 to 0.63; high-certainty evidence). Fingolimod (RR 0.48, 95% CI 0.39 to 0.57; moderate-certainty evidence), daclizumab (RR 0.55, 95% CI 0.42 to 0.73; moderate-certainty evidence), and immunoglobulins (RR 0.60, 95% CI 0.47 to 0.79; moderate-certainty evidence) probably result in a large reduction of people with relapses at 12 months. Relapses over 24 months: data were reported in 28 studies (19,869 participants). Cladribine (RR 0.53, 95% CI 0.44 to 0.64; high-certainty evidence), alemtuzumab (RR 0.57, 95% CI 0.47 to 0.68; high-certainty evidence) and natalizumab (RR 0.56, 95% CI 0.48 to 0.65; high-certainty evidence) result in a large decrease of people with relapses at 24 months. Fingolimod (RR 0.54, 95% CI 0.48 to 0.60; moderate-certainty evidence), dimethyl fumarate (RR 0.62, 95% CI 0.55 to 0.70; moderate-certainty evidence), and ponesimod (RR 0.58, 95% CI 0.48 to 0.70; moderate-certainty evidence) probably result in a large decrease of people with relapses at 24 months. Glatiramer acetate (RR 0.84, 95%, CI 0.76 to 0.93; moderate-certainty evidence) and interferon beta-1a (Avonex, Rebif) (RR 0.84, 95% CI 0.78 to 0.91; moderate-certainty evidence) probably moderately decrease people with relapses at 24 months. Relapses over 36 months findings were available from five studies (3087 participants). None of the treatments assessed showed moderate- or high-certainty evidence compared to placebo. Disability worsening over 24 months was assessed in 31 studies (24,303 participants). Natalizumab probably results in a large reduction of disability worsening (RR 0.59, 95% CI 0.46 to 0.75; moderate-certainty evidence) at 24 months. Disability worsening over 36 months was assessed in three studies (2684 participants) but none of the studies used placebo as the comparator. Treatment discontinuation due to adverse events data were available from 43 studies (35,410 participants). Alemtuzumab probably results in a slight reduction of treatment discontinuation due to adverse events (OR 0.39, 95% CI 0.19 to 0.79; moderate-certainty evidence). Daclizumab (OR 2.55, 95% CI 1.40 to 4.63; moderate-certainty evidence), fingolimod (OR 1.84, 95% CI 1.31 to 2.57; moderate-certainty evidence), teriflunomide (OR 1.82, 95% CI 1.19 to 2.79; moderate-certainty evidence), interferon beta-1a (OR 1.48, 95% CI 0.99 to 2.20; moderate-certainty evidence), laquinimod (OR 1.49, 95 % CI 1.00 to 2.15; moderate-certainty evidence), natalizumab (OR 1.57, 95% CI 0.81 to 3.05), and glatiramer acetate (OR 1.48, 95% CI 1.01 to 2.14; moderate-certainty evidence) probably result in a slight increase in the number of people who discontinue treatment due to adverse events. Serious adverse events (SAEs) were reported in 35 studies (33,998 participants). There was probably a trivial reduction in SAEs amongst people with RRMS treated with interferon beta-1b as compared to placebo (OR 0.92, 95% CI 0.55 to 1.54; moderate-certainty evidence). AUTHORS' CONCLUSIONS: We are highly confident that, compared to placebo, two-year treatment with natalizumab, cladribine, or alemtuzumab decreases relapses more than with other DMTs. We are moderately confident that a two-year treatment with natalizumab may slow disability progression. Compared to those on placebo, people with RRMS treated with most of the assessed DMTs showed a higher frequency of treatment discontinuation due to AEs: we are moderately confident that this could happen with fingolimod, teriflunomide, interferon beta-1a, laquinimod, natalizumab and daclizumab, while our certainty with other DMTs is lower. We are also moderately certain that treatment with alemtuzumab is associated with fewer discontinuations due to adverse events than placebo, and moderately certain that interferon beta-1b probably results in a slight reduction in people who experience serious adverse events, but our certainty with regard to other DMTs is lower. Insufficient evidence is available to evaluate the efficacy and safety of DMTs in a longer term than two years, and this is a relevant issue for a chronic condition like MS that develops over decades. More than half of the included studies were sponsored by pharmaceutical companies and this may have influenced their results. Further studies should focus on direct comparison between active agents, with follow-up of at least three years, and assess other patient-relevant outcomes, such as quality of life and cognitive status, with particular focus on the impact of sex/gender on treatment effects.

Childbirth delivery mode and the risk of multiple sclerosis: a prospective population-based study.

BACKGROUND: Caesarean section (CS) may affect the risk of developing multiple sclerosis (MS) in the offspring, possibly through changes in gut microbiota composition, but findings from previous studies are inconsistent. We investigated whether birth by CS was associated with the risk of adult-onset MS. METHODS: We conducted a prospective population-based cohort study, including all individuals born in Norway between 1967 and 2003, using the Medical Birth Registry of Norway linked with the Norwegian Multiple Sclerosis Registry and Biobank. The follow-up was until 2021. We used multivariable Cox models to estimate HRs for MS risk with 95% CIs. RESULTS: Among 2 046 637 individuals in the cohort, 4954 MS cases were identified. Being born by CS was associated with a modest increase in MS risk (HR=1.18, 95% CI 1.05 to 1.32). In the sibling-matched analysis, we found no association between CS and MS risk. We found an interaction between CS and gestational age (p=0.03): CS was associated with an increased risk of MS in individuals born preterm (HR=1.62, 95% CI 1.18 to 2.24), whereas there was no association in individuals born at term (HR=1.13, 95% CI 0.99 to 1.27). In a subgroup analysis of individuals born in 1988 and onwards, emergency CS was related to an elevated MS risk (HR=1.40, 95% CI 1.07 to 1.83), whereas planned CS was not (HR: 1.10, 95% CI 0.77 to 1.58). CONCLUSIONS: CS was associated with a modestly higher risk of developing MS. However, the stronger associations seen in subgroups who likely experienced a more complicated pregnancy/delivery may point to confounding underlying these associations.

Validation of Administrative Health Data Algorithms for Identifying Persons with Parkinson's Disease and the 10-Year Prevalence Trend in Bologna, Italy.

INTRODUCTION: Health administrative databases are widely used for the estimation of the prevalence of Parkinson's disease (PD). Few in general, and none used in Italy, have been validated by testing their diagnostic accuracy. The primary objective was to validate two algorithms for the identification of persons with PD using clinical diagnosis as the reference standard on an Italian sample of people with PD. The second objective was to estimate 10-year trends in PD prevalence in the Bologna Local Health Trust from 2010 to 2019. METHODS: Two algorithms (index tests) applied to health administrative databases (hospital discharge, drug prescriptions, exemptions for medical costs) were validated against clinical diagnosis of PD by an expert neurologist (reference standard) in a cohort of consecutive outpatients. Sensitivity and specificity with relative 95% confidence intervals (CIs) were calculated. The prevalence of PD in a specific year was estimated as the ratio between the number of subjects fulfilling any criteria of the algorithm with better diagnostic accuracy and the total population in the same year (×1,000), stratified by age, sex, and district of residence. RESULTS: The two algorithms showed high accuracy for identifying patients with PD: one with greater sensitivity of 94.2% (CI: 88.4-97.6) and the other with greater specificity of 98.1% (CI: 97.7-98.5). For the estimation of prevalence, we chose the most specific algorithm with the fewest total number of misclassified cases. We identified 3,798 people with PD as of December 31, 2019, corresponding to a prevalence of 4.3 per 1,000 inhabitants (CI: 4.2-4.4). Prevalence was higher in males (4.7, CI: 4.5-5.0) than females (3.8, CI: 3.7-4.0) and increased with age. The crude prevalence over time was slightly elevated as it followed a progressive aging of the population. When stratifying the prevalence for age groups, we did not observe a trend except in the 45-64 year category where we observed an increasing trend over time. CONCLUSION: Algorithms based on administrative data are accurate when detecting people with PD in the Italian public health system. In a large northern Italian population, increased prevalence of about 10% was observed in the decade 2010-2019 and is explained by increased life expectancy. These data may be useful in planning the allocation of health care resources for people with PD.

Impact of regulatory restrictions on the use of valproic acid in women of childbearing age: An Italian study.

OBJECTIVE: Due to significant risks to the offspring after intrauterine exposure, the European Medicines Agency issued recommendations in 2014 and 2018 restricting the use of valproate (VPA) in women of childbearing age (WOCA). We aimed to evaluate their impact in the Emilia-Romagna region (ERR) of Northern Italy. METHODS: Using administrative databases, we identified all the ERR residents who received antiseizure medication (ASM) prescriptions from 2010 to 2020. Time series of incidence rates by sex and age group were evaluated for all ASMs. Focusing on VPA, an interrupted time series analysis was applied to assess the impact of the restrictions in WOCA with epilepsy (WOCA-E) and WOCA with psychiatric disorders (WOCA-P). We then evaluated the chronological order of ASM prescriptions with regard to the position of VPA. RESULTS: Incidence rates of VPA prescriptions overall decreased over time. A significant decrease was observed only for females. The effect was stronger for WOCA, after both the first (incidence rate ratio [IRR] = .85, 95% confidence interval [CI] = .75-.96) and the second restriction (IRR = .67, 95% CI = .55-.82). The decrease was significant after the second restriction both for WOCA-E (IRR = .43, 95% CI = .27-.68) and for WOCA-P (IRR = .49, 95% CI = .35-.70), as well as VPA as a first prescription in both populations. VPA prescriptions as further choice did not show the same trend. SIGNIFICANCE: After the regulatory restrictions, an overall significant decline in the use of VPA in WOCA was observed in ERR. The second restriction has been effective in consolidating the prescription trend. However, VPA appears still to be a commonly used drug in WOCA when other ASMs have failed.

Gut Microbiota Changes during Dimethyl Fumarate Treatment in Patients with Multiple Sclerosis.

The gut microbiota is involved in the development of the immune system and can modulate the risk for immune-mediated disorders such as multiple sclerosis (MS). Dysbiosis has been demonstrated in MS patients and its restoration by disease-modifying treatments (DMTs) is hypothesized. We aimed to study the changes in gut microbiota composition during the first 6 months of treatment with dimethyl fumarate (DMF), an oral DMT, and to identify the microorganisms associated with DMF side effects. We collected and analyzed the gut microbiota of 19 MS patients at baseline and after 1, 3, and 6 months of DMF treatment. We then cross-sectionally compared gut microbiota composition according to the presence of gastrointestinal (GI) symptoms and flushing. Overall, the gut microbiota biodiversity showed no changes over the 6-month follow-up. At the genus level, DMF was associated with decreased Clostridium abundance after 6 months. In subjects reporting side effects, a higher abundance of Streptococcus, Haemophilus, Clostridium, Lachnospira, Blautia, Subdoligranulum, and Tenericutes and lower of Bacteroidetes, Barnesiella, Odoribacter, Akkermansia, and some Proteobacteria families were detected. Our results suggest that gut microbiota may be involved in therapeutic action and side effects of DMF, representing a potential target for improving disease course and DMT tolerability.

Risk of SARS-CoV-2 infection, hospitalization and death for COVID-19 in people with Parkinson's disease or parkinsonism over a 15-month period: a cohort study.

BACKGROUND: The patterns of long term risk of SARS-CoV-2 infection, hospitalization for COVID-19 and related death are uncertain in people with Parkinson's disease (PD) or parkinsonism (PS). The aim of the study was to quantify these risks compared to a control population cohort, during the period March 2020-May 2021, in Bologna, northern Italy. METHOD: ParkLink Bologna cohort (759 PD; 192 PS) and controls (9,226) anonymously matched (ratio 1:10) for sex, age, district, comorbidity were included. Data were analysed in the whole period and in the two different pandemic waves (March-May 2020 and October 2020-May 2021). RESULTS: Adjusted hazard ratio of SARS-CoV-2 infection was 1.3 (95% CI 1.04-1.7) in PD and 1.9 (1.3-2.8) in PS compared to the controls. The trend was detected in both the pandemic waves. Adjusted hazard ratio of hospitalization for COVID-19 was 1.1 (95% CI 0.8-1.7) in PD and 1.8 (95% CI 0.97-3.1) in PS. A higher risk of hospital admission was detected in PS only in the first wave. The 30-day mortality risk after hospitalization was higher (p=0.048) in PS (58%) than in PD (19%) and controls (26%). CONCLUSIONS: Compared with controls, after adjustment for key covariates, people with PD and PS showed a higher risk of SARS-CoV-2 infection throughout the first 15 months of the pandemic. COVID-19 hospitalization risk was increased only in people with PS and only during the first wave. This group of patients was burdened by a very high risk of death after infection and hospitalization.

Risk of Hospitalization and Death for COVID-19 in People with Parkinson's Disease or Parkinsonism.

BACKGROUND: The risk of COVID-19 and related death in people with Parkinson's disease or parkinsonism is uncertain. The aim of the study was to assess the risk of hospitalization for COVID-19 and death in a cohort of patients with Parkinson's disease or parkinsonism compared with a control population cohort, during the epidemic bout (March-May 2020) in Bologna, northern Italy. METHODS: Participants of the ParkLink study with the clinical diagnosis of Parkinson's disease or parkinsonism and people anonymously matched (ratio 1:10) for sex, age, district, and Charlson Index were included. The hospital admission rate for COVID-19 (February 26-May 31, 2020) and the death rate for any cause were the outcomes of interest. RESULTS: The ParkLink cohort included 696 subjects with Parkinson's disease and 184 with parkinsonism, and the control cohort had 8590 subjects. The 3-month hospitalization rate for COVID-19 was 0.6% in Parkinson's disease, 3.3% in parkinsonism, and 0.7% in controls. The adjusted hazard ratio (age, sex, district, Charlson Index) was 0.8 (95% CI, 0.3-2.3, P = 0.74) in Parkinson's disease and 3.3 (1.4-7.6, P = 0.006) in parkinsonism compared with controls. Twenty-nine of the infected subjects died; 30-day fatality rate was 35.1%, without difference among the 3 groups. Six of 10 Parkinson's disease/parkinsonism patients had the infection during hospitalization or in a nursing home. CONCLUSIONS: Parkinson's disease per se probably is not a risk factor for COVID-19 hospitalization. Conversely, parkinsonism is an independent risk factor probably because of a more severe health status, entailing higher care dependence and placement in high-infection-risk accommodations. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Antibiotic Use and Risk of Multiple Sclerosis: A Nested Case-Control Study in Emilia-Romagna Region, Italy.

INTRODUCTION: Known risk factors for multiple sclerosis (MS) include smoking, a low vitamin D status, obesity, and EBV, while the inflammatory feature of the disease strongly suggests the presence of additional infectious agents. The association between use of antibiotics and MS risk that could shed light on these factors is still undetermined. We aimed to evaluate the association between antibiotics and MS risk, in the Emilia-Romagna region (RER), Italy. METHODS: All adult patients with MS seen at any RER MS center (2015-2017) were eligible. For each of the 877 patients included, clinical information was collected and matched to 5 controls (RER residents) (n = 4,205) based on age, sex, place of residence, and index year. Information on antibiotic prescription was obtained through the linkage with the RER drug prescription database. RESULTS: Exposure to any antibiotic 3 years prior to the index year was associated with an increased MS risk (OR = 1.52; 95% CI = 1.29-1.79). Similar results were found for different classes. No dose-response effect was found. DISCUSSION/CONCLUSIONS: Our results suggest an association between the use of antibiotics and MS risk in RER population. However, further epidemiological studies should be done with information on early life and lifestyle factors.

European guideline and expert statements on the management of narcolepsy in adults and children.

BACKGROUND AND PURPOSE: Narcolepsy is an uncommon hypothalamic disorder of presumed autoimmune origin that usually requires lifelong treatment. This paper aims to provide evidence-based guidelines for the management of narcolepsy in both adults and children. METHODS: The European Academy of Neurology (EAN), European Sleep Research Society (ESRS), and European Narcolepsy Network (EU-NN) nominated a task force of 18 narcolepsy specialists. According to the EAN recommendations, 10 relevant clinical questions were formulated in PICO format. Following a systematic review of the literature (performed in Fall 2018 and updated in July 2020) recommendations were developed according to the GRADE approach. RESULTS: A total of 10,247 references were evaluated, 308 studies were assessed and 155 finally included. The main recommendations can be summarized as follows: (i) excessive daytime sleepiness (EDS) in adults-scheduled naps, modafinil, pitolisant, sodium oxybate (SXB), solriamfetol (all strong); methylphenidate, amphetamine derivatives (both weak); (ii) cataplexy in adults-SXB, venlafaxine, clomipramine (all strong) and pitolisant (weak); (iii) EDS in children-scheduled naps, SXB (both strong), modafinil, methylphenidate, pitolisant, amphetamine derivatives (all weak); (iv) cataplexy in children-SXB (strong), antidepressants (weak). Treatment choices should be tailored to each patient's symptoms, comorbidities, tolerance and risk of potential drug interactions. CONCLUSION: The management of narcolepsy involves non-pharmacological and pharmacological approaches with an increasing number of symptomatic treatment options for adults and children that have been studied in some detail.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): Position paper on diagnosis, prognosis, and treatment by the MNGIE International Network.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by TYMP mutations and thymidine phosphorylase (TP) deficiency. Thymidine and deoxyuridine accumulate impairing the mitochondrial DNA maintenance and integrity. Clinically, patients show severe and progressive gastrointestinal and neurological manifestations. The onset typically occurs in the second decade of life and mean age at death is 37 years. Signs and symptoms of MNGIE are heterogeneous and confirmatory diagnostic tests are not routinely performed by most laboratories, accounting for common misdiagnosis. Factors predictive of progression and appropriate tests for monitoring are still undefined. Several treatment options showed promising results in restoring the biochemical imbalance of MNGIE. The lack of controlled studies with appropriate follow-up accounts for the limited evidence informing diagnostic and therapeutic choices. The International Consensus Conference (ICC) on MNGIE, held in Bologna, Italy, on 30 March to 31 March 2019, aimed at an evidence-based consensus on diagnosis, prognosis, and treatment of MNGIE among experts, patients, caregivers and other stakeholders involved in caring the condition. The conference was conducted according to the National Institute of Health Consensus Conference methodology. A consensus development panel formulated a set of statements and proposed a research agenda. Specifically, the ICC produced recommendations on: (a) diagnostic pathway; (b) prognosis and the main predictors of disease progression; (c) efficacy and safety of treatments; and (f) research priorities on diagnosis, prognosis, and treatment. The Bologna ICC on diagnosis, management and treatment of MNGIE provided evidence-based guidance for clinicians incorporating patients' values and preferences.

European guideline and expert statements on the management of narcolepsy in adults and children.

BACKGROUND AND AIM: Narcolepsy is an uncommon hypothalamic disorder of presumed autoimmune origin that usually requires lifelong treatment. This paper aims to provide evidence-based guidelines for the management of narcolepsy in both adults and children. METHODS: The European Academy of Neurology (EAN), European Sleep Research Society (ESRS) and European Narcolepsy Network (EU-NN) nominated a task force of 18 narcolepsy specialists. According to the EAN recommendations, 10 relevant clinical questions were formulated in PICO format. Following a systematic review of the literature (performed in Fall 2018 and updated in July 2020) recommendations were developed according to the GRADE approach. RESULTS: A total of 10,247 references were evaluated, 308 studies were assessed and 155 finally included. The main recommendations can be summarized as follows: (i) excessive daytime sleepiness in adults-scheduled naps, modafinil, pitolisant, sodium oxybate (SXB), solriamfetol (all strong), methylphenidate, amphetamine derivates (both weak); (ii) cataplexy in adults-SXB, venlafaxine, clomipramine (all strong) and pitolisant (weak); (iii) excessive daytime sleepiness in children-scheduled naps, SXB (both strong), modafinil, methylphenidate, pitolisant, amphetamine derivates (all weak); (iv) cataplexy in children-SXB (strong), antidepressants (weak). Treatment choices should be tailored to each patient's symptoms, comorbidities, tolerance and risk of potential drug interactions. CONCLUSION: The management of narcolepsy involves non-pharmacological and pharmacological approaches with an increasing number of symptomatic treatment options for adults and children that have been studied in some detail.

Awakening to sleep disorders in Europe: Survey on education, knowledge and treatment competence of European residents and neurologists.

OBJECTIVES: Sleep-wake disorders are common in the general population and in most neurological disorders but are often poorly recognized. With the hypothesis that neurologists do not get sufficient training during their residency, the Young European Sleep Neurologist Association (YESNA) of the European Academy of Neurology (EAN) performed a survey on postgraduate sleep education. METHODS: A 16-item questionnaire was developed and distributed among neurologists and residents across European countries. Questions assessed demographic, training and learning preferences in sleep disorders, as well as a self-evaluation of knowledge based on five basic multiple-choice questions (MCQs) on sleep-wake disorders. RESULTS: The questionnaire was completed by 568 participants from 20 European countries. The mean age of participants was 31.9 years (SD 7.4 years) and was composed mostly of residents (73%). Three-quarters of the participants reported undergraduate training in sleep medicine, while fewer than 60% did not receive any training on sleep disorders during their residencies. Almost half of the participants (45%) did not feel prepared to treat neurological patients with sleep problems. Only one-third of the participants correctly answered at least three MCQs. Notably, 80% of participants favoured more education on sleep-wake disorders during the neurology residency. CONCLUSIONS: Education and knowledge on disorders in European neurological residents is generally insufficient, despite a strong interest in the topic. The results of our study may be useful for improving the European neurology curriculum and other postgraduate educational programmes.

Liver injury with drugs used for multiple sclerosis: A contemporary analysis of the FDA Adverse Event Reporting System.

BACKGROUND: Drug-induced liver injury (DILI) has been observed in patients with multiple sclerosis (MS), raising concerns on the liver safety of MS drugs. OBJECTIVE: To describe DILI events with MS drugs by analyzing the FDA Adverse Event Reporting System. METHODS: DILI reports were extracted and classified in overall liver injury (OLI), including asymptomatic elevation of liver enzymes, and severe liver injury (SLI). We performed disproportionality analysis by calculating adjusted reporting odds ratios (RORs) with 95% confidence interval (CI) and case-by-case evaluation for concomitant drugs with hepatotoxic potential. RESULTS: Fampridine showed statistically significant ROR for both OLI and SLI, whereas teriflunomide and fingolimod generated solid disproportionality (ROR > 2) only for OLI (ROR, 2.31; 95% CI, 2.12-2.52; and 2.53; 2.40-2.66, respectively). Among monoclonal antibodies, only alemtuzumab generated higher-than-expected ROR for OLI (1.34; 1.09-1.65). We also detected the expected hepatotoxic potential of beta interferon and mitoxantrone. Concomitant reporting of hepatotoxic drugs ranged from 26% (dimethyl fumarate) to 90% (mitoxantrone). CONCLUSION: These real-world pharmacovigilance findings suggest that DILI might be a common feature of MS drugs and call for (1) formal population-based study to verify the risk of fampridine and (2) awareness by clinicians, who should assess the possible responsibility of MS drugs when they diagnose DILI.

Health-related quality of life in clinically isolated syndrome and risk of conversion to multiple sclerosis.

BACKGROUND AND OBJECTIVES: A few studies have found that low scores on self-rated health and quality of life measures are associated with following worsening disability in multiple sclerosis (MS). We wanted to estimate the association between self-rated quality of life scores among patients with clinically isolated syndrome (CIS) and the risk of subsequent conversion to definite MS. METHODS: One hundred sixty-two patients from the GERONIMUS cohort with a symptom or sign suggestive of MS and without a definite diagnosis of MS at the time of inclusion were asked to evaluate their health-related quality of life according to MSQoL-54 scale. They were clinically assessed and mood and depression scales were applied. The association between the scores of these scales and the risk of converting to definite MS during a 5-year follow-up was estimated using the Cox- proportional hazard regression model. RESULTS: Quality of life at examination was significantly lower compared to those of an age- and sex-adjusted general Italian population. During the follow-up, 116 patients (72%) converted to definite MS. No significant predictive effects were found for the summary scales of MSQol-54 or other scales. The estimates did not change after adjusting for age, sex, BMI, education, MRI findings, Expanded Disability Status Scale (EDSS) score, and treatment at time of examination. CONCLUSION: Persons with CIS in this cohort reported reduced self-rated quality of life compared to the general population, but variation in these scores was not associated with subsequent conversion from CIS to clinical definite MS.

Stress is associated with an increased risk of recurrent seizures in adults.

OBJECTIVE: The literature is sparse on the complex interrelationships between stressors, depression, anxiety disorders, and epilepsy. We hypothesized that a relationship exists between stress and epilepsy. We evaluated whether markers of stress are associated with seizure recurrence in a low income community-based cohort of adults with single unprovoked seizure or newly diagnosed epilepsy. METHODS: We ascertained adult residents of Northern Manhattan and Harlem, New York City, with a first unprovoked seizure or newly diagnosed epilepsy, between December 2010 and January 2013. At enrollment, we collected information about seizure phenomenology, demographics, clinical information, and measures of stress (environmental stress, stressful life events, facets of allostatic load-i.e., the cumulative effect of adaptation to stress, psychiatric disorders, and low collective efficacy). Collective efficacy assesses neighborhood characteristics and incorporates social cohesion and informal social control. All subjects were followed for 2 years for further seizures. Cox proportional hazard regression models were used to estimate the hazard ratios of seizure recurrence during the 2 years of follow-up. RESULTS: We identified 52 subjects (64.2%) with a single unprovoked seizure and 29 (35.9%) with newly diagnosed epilepsy. Seizure recurrence was recorded in 38.5% (N = 20) of subjects with a single unprovoked seizure and in 69% of those with epilepsy (N = 20) (p = 0.01). In the overall sample, the hazard of seizure recurrence was increased by lifetime generalized anxiety disorder (3.0-fold) and by low collective efficacy (2.7-fold). In a second model, the hazard was increased by lifetime mood disorder (2.1-fold) and low collective efficacy (2.5-fold). SIGNIFICANCE: Markers of stress (i.e., low collective efficacy, lifetime mood disorder, and lifetime generalized anxiety disorder) were associated with an increased risk for seizure recurrence in adults with a single unprovoked seizure or newly diagnosed epilepsy. Stress-reducing interventions, such as mindfulness, may be a useful, safe, and inexpensive adjunctive treatment for epilepsy.

Incidence of neuroepithelial primary brain tumors among adult population of Emilia-Romagna Region, Italy.

Incidence of neuroepithelial Primary Brain Tumors (nPBT) varies, ranging from 7.3 to 11.6 cases/100,000/year across Europe. We present incidence and survival of nPBT in the Emilia-Romagna region (ER), Italy. This study is the largest in Southern Europe. Specialists in neurosurgery, neurology, neuroradiology, oncology, radiotherapy, genetics, and pathology of ER notified all suspected nPBT adult cases residing in ER (4,337,966 inhabitants) observed during 2009. Furthermore, through ICD-9 discharge codes, we identified and reviewed all possible cases. Neuroepithelial PBT diagnosis was based on histological or radiological findings. We included 400 incident nPBT cases, of which 102 (25%) were retrospectively identified. These latter were significantly older. The standardized incidence was 10.5/100,000/year (95% CI 9.4-11.5), higher for men. It was 9.2/100,000/year (95% CI 8.3-10.2) for astrocytic tumors, 0.6/100,000/year (95% CI 0.4-0.9) for oligodendroglial tumors, and 7.1 (95% CI 6.3-8.0) for glioblastoma (GBM). Among GBM patients, median survival was 249 days if prospectively identified vs. 132 days when identified through ICD-9 codes (p < 0.0001). The incidence of nPBT in the ER region is among the highest in the literature. Older patients were more likely to escape an active surveillance system. This should be considered when comparing incidence rates across studies, giving the increasing number of elderly people in the general population.

Assessing subjective quality of life domains after multiple sclerosis diagnosis disclosure.

BACKGROUND AND OBJECTIVE: An investigation of the domains Italian patients with multiple sclerosis (MS) named as constituting their quality of life over time. DESIGN: We assessed, in 68 patients, QoL domains using the Schedule for the Evaluation of Individual QoL: (a) before MS diagnosis disclosure, (b) thirty days after disclosure, and (c) after one and (d) four years' follow-up. RESULTS: The life domains most frequently named by patients were as follows: Family, Work and Finance, Hobbies, Health, Relationship with Friends and Job Effectiveness. Only Health and Job Effectiveness domains varied with time. The Health domain became a critical dimension when MS diagnosis was revealed. In addition, patients tended to be more satisfied with their health after disclosure compared to pre-diagnosis. Job Effectiveness seemed to be an important aspect until 1 year after diagnosis disclosure, but it tended to become less crucial over time. Family seems to be the most important domain over time, and psychological adaptation to MS seems to be characterized by a reconceptualization of aspects that revolve around oneself, such as professional success, rather than relational or affective factors. CONCLUSIONS: Evaluating the most relevant life domains for patients and their alteration over time may provide practitioners with an important tool in making health-related decisions, thus improving health outcomes and QoL.

Psychiatric disorders and suicidal behavior in neurotypical young adults with childhood-onset epilepsy.

OBJECTIVES: We examined the associations of lifetime and current histories of psychiatric disorders and of suicidal thoughts and behaviors with childhood-onset epilepsies in a community-based cohort of young adults. METHODS: Cases were neurotypical (normal neurologic, cognitive, and imaging examinations and no evidence of a brain insult responsible for the epilepsy) young adults with childhood-onset epilepsy followed since the onset of their epilepsy approximately 15 years earlier and recruited as part of a community-based study. They were compared to two different control groups: siblings and external controls from the National Comorbidity Survey-Replication (NCS-R). The Diagnostic Interview Survey assessed lifetime and current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) diagnoses of mood disorders and anxiety disorders. Suicidal thoughts and suicide attempt were assessed using the Diagnostic Interview Survey for Children-IV and the Diagnostic Interview Survey (DIS-IV). RESULTS: Two hundred fifty-seven cases and 134 sibling controls participated in the DIS-IV portion of the young adult assessment. Comparing cases both to their sibling controls and to the controls drawn from the NCS-R, we did not find any evidence to suggest a higher prevalence of lifetime and current mood or anxiety disorders, suicidal thoughts, and suicide attempt in young adults with childhood-onset epilepsies. SIGNIFICANCE: Our findings from a community-based sample of neurotypical young adults do not suggest a substantial or lasting association between childhood epilepsy and psychiatric disorders and suicidal behavior.

Yield of epileptiform electroencephalogram abnormalities in incident unprovoked seizures: a population-based study.

OBJECTIVE: The yield of epileptiform abnormalities in serial electroencephalography (EEG) studies has not been addressed in a population-based setting for subjects with incident epilepsy or a single unprovoked seizure, raising the possibility of methodologic limitations such as selection bias. Our aim was to address these limitations by assessing the yield and predictors of epileptiform abnormalities for the first and subsequent EEG recording in a study of incident epilepsy or single unprovoked seizure in Rochester, Minnesota. METHODS: We used the resources of the Rochester Epidemiology Project to identify all 619 residents of Rochester, Minnesota, born in 1920 or later with a diagnosis of incident epilepsy (n = 478) or single unprovoked seizure (n = 141) between 1960 and 1994, who had at least one EEG study. Information on all EEG studies and their results was obtained by comprehensive review of medical records. RESULTS: Among subjects with epilepsy, the cumulative yield of epileptiform abnormalities was 53% after the first EEG study and 72% after the third. Among subjects with a single unprovoked seizure, the cumulative yield was 39% after the first EEG study and 68% after the third. Young age at diagnosis and idiopathic etiology were risk factors for finding epileptiform abnormalities across all EEG recordings. SIGNIFICANCE: Although the cumulative yield of epileptiform abnormalities increases over successive EEG recordings, there is a decrease in the increment for each additional EEG study after the first EEG study. This is most evident in incident epilepsy and in younger subjects. Clinically it may be worthwhile to consider that the probability of finding an epileptiform abnormality after the third nonepileptiform EEG recording is low.

How do we measure psychiatric diagnoses? Implications of the choice of instruments in epilepsy.

We evaluated several commonly used screening instruments for the detection of mood disorders, anxiety disorders, and attention-deficit hyperactivity disorder (ADHD). These were compared to a criterion-based standardized questionnaire, the Diagnostic Interview Survey (DIS)-IV, designed to make DSM-IV-TR diagnoses in the community-based study of childhood-onset epilepsy. The DIS-IV was administered to young adult cases with epilepsy at a 15-year follow-up assessment and compared to symptom screens administered at the same visit, and at a previous 9-year assessment. Among cases, the specificity of the DIS-IV ranged from 0.77 to 0.99 and the predictive value of a negative psychiatric diagnosis was similarly high. Sensitivity was lower, ranging from 0 to 0.77, with correspondingly low predictive value of a positive diagnosis. Symptom-based instruments assess current symptom burden and are useful for determining associations with ongoing seizures or quality of life. Criterion-based standardized interviews, such as the DIS-IV, provide psychiatric diagnoses over the lifetime, which is most useful in studies of epilepsy genetics and studies of comorbidities and prognosis of epilepsy.