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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.

Amyotrophic lateral sclerosis is a fatal progressive disease with a still unclear multi-factorial etiology. This study focused on the potential relationship between drug exposure and the development of amyotrophic lateral sclerosis by performing a detailed analysis of events reported in the FDA Adverse Event Reporting System database.The FDA Adverse Event Reporting System quarterly data (January 2004-June 2020) were downloaded and deduplicated. The reporting odds ratios and their 95% confidence intervals were calculated as a disproportionality measure. The robustness of the disproportion was assessed accounting for major confounders (i.e., using a broader query, restricting to suspect drugs, and excluding reports with amyotrophic lateral sclerosis as an indication). Disproportionality signals were prioritized based on their consistency across analyses (reporting odds ratio stability).We retained 1188 amyotrophic lateral sclerosis cases. Sixty-two drugs showed significant disproportionality for amyotrophic lateral sclerosis onset in at least one analysis, and 31 had consistent reporting odds ratio stability, including tumor necrosis factor-alpha inhibitors and statins. Disproportionality signals from ustekinumab, an immunomodulator against interleukins 12-23 used in autoimmune diseases, and the anti-IgE omalizumab were consistent among analyses and unexpected.For each drug emerging as possibly associated with amyotrophic lateral sclerosis onset, biological plausibility, underlying disease, and reverse causality could be argued. Our findings strengthened the plausibility of a precipitating role of drugs primarily through immunomodulation (e.g., tumor necrosis factor-alpha, ustekinumab, and omalizumab), but also by impacting metabolism and the musculoskeletal integrity (e.g., statins and bisphosphonates). Complement and NF-kB dysregulation could represent interesting topics for planning translational mechanistic studies on amyotrophic lateral sclerosis as an adverse drug effect.

Introduction: Multiple Sclerosis (MS) is an immune-mediated, complex, chronic inflammatory, and neurodegenerative disease of the central nervous system. Among the several therapeutic options developed over the last decade for relapsing MS (RMS), fingolimod, a sphingosine 1-phosphate receptor (S1PR) modulator, was the first oral treatment. The adverse events associated with fingolimod have limited its use in certain populations, thus further stimulating the search for other S1PR modulators. Areas covered: The authors reviewed the English-published literature on ponesimod using the PubMed database. The search terms used were ‘ponesimod’ or ‘ACT-128,800’ and ‘multiple sclerosis.’ Available data on the pharmacological profile of ponesimod and the information on clinical efficacy and safety drawn from clinical trials in comparison with other S1PR modulators are presented and discussed. Expert opinion: Published peer-reviewed data on long-term safety and efficacy are still lacking but have been collected and regulatory authorities expressed a favorable opinion to market access. At present, we believe that ponesimod has little chance of becoming a leading treatment for RMS due to the availability of many alternative options and the timing of market access. Given its favorable risk-benefit and convenience profile, however, ponesimod might become a leading option among S1P receptor modulators used for RMS.

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: The objectives of the review are to estimate the benefits and harms of: azathioprine (AZA) compared with placebo or other disease ‐modifying treatments (DMTs) as first‐choice treatment for relapsing forms of multiple sclerosis (MS); AZA compared with placebo or other DMTs for relapsing forms of MS when switching from another DMT; AZA compared with placebo or other DMTs as first‐choice treatment for progressive forms of MS; and AZA compared with placebo or other DMTs for progressive forms of MS when switching from another DMT.

International audience; 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.

Background A total of 2.8 million people are living with multiple sclerosis and due to disparities in access to medicines, the ability to treat this condition varies widely. Off-label disease-modifying therapies are sometimes more available or affordable in different health systems. Appropriate methodology is integral in creating high-quality and trustworthy guidelines. In this article, we outline Multiple Sclerosis International Federation’s (MSIF) approach to creating guidelines for off-label treatments for multiple sclerosis. Methods We use the Guidelines International Network (GIN)-McMaster Guideline Development Checklist and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) Evidence-to-Decision (EtD) framework. We developed detailed health descriptors for health outcomes and the panel drafted PICO (Population, Intervention, Comparator, Outcome) questions and prioritised outcomes. We collaborate with independent organisations, which systematically review and collate the information. We are actively engaging stakeholders and consulting with relevant organisations, boards, working groups and individuals. Results The draft guideline recommendations will be published for open comment and stakeholders will be encouraged to endorse and disseminate the guidelines. Our methodology ensures integrity and transparency in the criteria, evidence and judgement used to make recommendations. Conclusions This approach will facilitate transparent creation of high-quality and trustworthy guidelines, and allow the global guidelines to be adopted or adapted into national settings.

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.

IntroductionEpilepsy is a chronic condition requiring consistent follow-up aimed at seizure control, and monitoring of anti-seizure medication (ASM) levels and side effects. Telemedicine (TM) offers invaluable support to patient follow-up, guaranteeing the prompt availability of a team of experts for persons with epilepsy (PWE) widely distributed across the country. Although many health institutions have endorsed the use of TM, robust data on effectiveness, safety and costs of TM applied to epilepsy are lacking. TELEmedicine for EPIlepsy Care (TELE-EPIC) will evaluate the effectiveness of video consultation (VC) via TM compared with usual care (UC) for the monitoring of PWE (TELE-EPIC_RCT). Moreover, TELE-EPIC will apply an innovative Volumetric Absorptive Microsampling (VAMS) device for quantitation of ASM through finger prick blood sampling as an alternative to venipuncture sampling (TELE-EPIC_VAMS).Methods and analysisTELE-EPIC_RCT is a multicentre, open, pragmatic two-arm randomised controlled trial prospectively including adult and paediatric outpatients with established diagnosis of epilepsy consecutively attending the Epilepsy Centres of Bologna and Rome, respectively. The primary outcome is the non-inferiority of VC on seizure control compared with UC after an 18-month follow-up. Secondary outcomes are adherence to treatment, ASM-related adverse events, quality of life, mood disorders, patient and caregiver satisfaction, safety and costs. TELE-EPIC_VAMS is a cross-validation study for blood ASM quantitation through a novel, VAMS-based device, comparing (1) VAMS versus plasma samples (reference standard method); and (2) nurse-collected versus self-collected blood by VAMS device.Ethics and disseminationThe study has been approved by the local ethics committee (349-2019-SPER-AUSLBO). Complete information about the state of project, relevant events and results will be regularly updated on the project’s webpage on ClinicalTrials.gov. The project’s results and data on the potential impact of TM in epilepsy will be disseminated on social media. A closeout meeting will be convened for the communication and dissemination of the project, highlighting its main achievements and impacts.Trial registration numberNCT04496310

Background Depression is more frequently associated with akinetic-rigid/postural instability gait difficulty subtypes of Parkinson's disease than with tremor-dominant subtype. Objectives The aim of the study is to investigate the frequency of exposure to antidepressant drugs, as proxy of depression, before motor onset according to Parkinson's disease subtypes. Method Based on a historical cohort design, the exposure to antidepressant drugs before Parkinson's disease motor onset was obtained from the drug prescription database and assessed in the resident population of the Local Healthcare Trust of Bologna (443,117 subjects older than 35 years). Diagnosis of Parkinson's disease and subtype (tremor dominant, non-tremor dominant) at onset were recorded by neurologists and obtained from the “ParkLink Bologna” record linkage system. Exposure to antidepressants was compared both to the general population and between the two subtypes. Results From 2006 to 2018, 198 patients had a tremor dominant subtype at onset whereas 450 did not. Comparison with the general population for antidepressant exposure showed an adjusted hazard ratio of 0.86 (95% CI 0.44–1.70) for the tremor dominant subtype and 1.66 (1.16–2.39) for the non-tremor dominant subtype. Comparison of non-tremor dominant with tremor dominant subtypes showed an adjusted odds ratio of 1.86 (1.05–3.95) for antidepressant exposure. Conclusions In our study, non-tremor dominant Parkinson's disease at onset was significantly associated with exposure to antidepressants in comparison to the general population and in comparison with the tremor dominant subtype. These results support the hypothesis of different biological substrates for different Parkinson's disease subtypes even before motor onset.

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.

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.

Background: Eliciting the research priorities of people affected by a condition, carers and health care professionals can increase research value and reduce research waste. The Cochrane Multiple Sclerosis and Rare Disease of CNS Group, in collaboration with the Cochrane Neurological Sciences Field, launched a priority setting exercise with the aim of prioritizing pressing questions toensure that future systematic reviews are as useful as possible to the people who need them, in all countries, regardless of their economic status. Method: Sixteen high priority questions on different aspects of MS were developed by members of a multistakeholder priority setting Steering Group (SG). In an anonymous online survey translated into 12 languages researchers, clinicians, people with MS (PwMS) and carers were asked to identify andrank, 5 out of 16 questions as high priority and to provide an explanation for their choice. An additional free-text priority research topic suggestion was allowed. Results: The survey was accessible through MS advocacy associations’ social media and Cochrane webpages from October 20, 2020 to February 6, 2021. 1.190 responses (86.73% of all web contacts) were evaluable and included in the analysis. Responses came from 55 countries worldwide, 7 ofwhich provided >75% of respondents and 95% of which were high and upper-middle income countries. 58.8% of respondents live in the EU, 23% in the Americas, 8.9% in the Western Pacific, 2.8% in the Eastern Mediterranean and 0.3% in South Eastern Asia. About 75% of the respondents were PwMS. The five research questions to be answered with the highest priority were: Question (Q)1 “Does MRI help predict disability worsening of PwMS?” (19.9%), Q5 “What are the benefits and harms of treating PwMS with one disease-modifying drug compared to another?” (19.3%), Q3 “Does multidisciplinary care by teams of different social and health professionals improve health outcomes and experiences for PwMS?” (11.9%), Q16 “Does psychological health affect disease progression in PwMS?” (9.2%) and Q10 “What are the benefits and harms of exercise for PwMS?” (7.2%). The multivariable logistic regression analysis indicated a significant influence of geographic area and income level on the ranking of Q1 and a marginal for Q16 as top a priority after accounting for the effect of all other predictors. Approximately 50% of the respondents indicated that they had an important additional suggestion to be considered. Conclusion: This international collaborative initiative in the field of MS offers a worldwide perspective on the research questions perceived as pivotal by a geographically representative sample of multiple stakeholders in the field of MS. The results of the survey could guide the prioritization of research on pharmacological and non-pharmacological interventions which could be meaningful and useful for PwMS and carers, avoiding the duplication of efforts and research waste. High quality systematic reviews elicited by priority setting exercises may offer the best available evidence and inform decisions by healthcare providers and policy-makers which can be adapted to the different realities around the world.

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.

Background Early-life factors are reported to modulate the risk of developing multiple sclerosis (MS) among adults. The association between exposure to breastfeeding and the risk of MS is debated. We aimed to disclose whether past exposure to breastfeeding and its duration are associated with the risk of developing MS. Methods We used a cohort design linking prospectively collected information on breastfeeding from the Cohort of Norway community-based surveys on health status (CONOR) with the Norwegian MS Registry and the population-based Medical Birth Registry of Norway that includes information on all births in Norway since 1967. MS clinical onset was collected throughout 2016. A total of 95 891 offspring born between 1922 and 1986 to mothers participating in CONOR were included. We identified 215 offspring within this cohort who developed adult-onset MS. Associations between breastfeeding and MS risk were estimated as hazard ratios using Cox proportional hazard models adjusting for maternal factors including education. Results We found no association between having been breastfed for ≥4 months and MS risk, also after adjusting for various maternal factors (hazard ratio = 0.90; 95% confidence interval 0.68–1.19). The estimates did not change for different durations of breastfeeding. The results were similar when adjusting for other perinatal factors. Conclusion Our study could not confirm previous findings of an association between breastfeeding and risk of MS. Breastfeeding information was less likely to be biased by knowledge of disease compared with case–control studies.

International audience; Objectives: Mortality data have been used as a proxy for amyotrophic lateral sclerosis (ALS) incidence. However, the accuracy of death certificates (DCs) needs to be validated. This study aims to assess the accuracy of DCs in the identification of ALS cases. Methods: This is a retrospective population-based validation study. DC information, provided by the "Centre d'épidémiologie sur les causes médicales de décès", including ICD10 codes for specific cause of death for patients recorded in the French register of ALS cases in the Limousin region (FRALim) and deceased between 2000 and 2011, was assessed. The FRALim register was used as gold standard. Results: In the study period, DCs were available for 197 patients diagnosed with ALS, of whom 185 (93.9%) were correctly identified with an ICD10 code (G12.2) corresponding to ALS. The overall sensitivity was 93.9% (95% CI 89.6-96.8) and the positive predictive value (PPV) was 64.9 (59.1-70.4), with higher values in the period 2004-2011 (75.0-78.9). Stratification for sex, age, and year at death did not show difference in accuracy, except a lower PPV during the first years of observation. Conclusions: DCs identifying subjects with a diagnosis of ALS in the Limousin region, France showed an overall good sensitivity and moderate PPV. The absence of ALS diagnosis as the main and underlying cause of death on DCs highlights the need to use DC in combination with other administrative data to create algorithms with higher accuracy performances.

Background: Possible relationship between drug exposure and multiple sclerosis (MS) development is insufficiently investigated, and further challenged by the incomplete understanding of MS etiopathogenesis. The study aims to investigate whether drug exposure could contribute to MS, by analyzing worldwide spontaneous reporting archives of adverse drug reaction (ADRs). Research design and methods: We retrieved information from the US Food and Drug Administration Adverse Event Reporting System (FAERS) over a 13-year period. Reporting odds ratio (ROR) for MS was calculated for each single substance. Disproportionality signals were considered when at least 10 cases were retrieved with a lower limit of the 95% confidence interval (CI) >1. Results: After a customized data-mining process, 3,226 reports of MS were retrieved. ‘Antineoplastic and immunomodulating drugs’ (33% of total reports) were the most frequently reported, with 10 disproportionality signals, including etanercept (445 cases; ROR: 2.48; 95% Cl: 2.24–2.74), adalimumab (329; 2.05; 1.83–2.30), and infliximab (119; 2.25; 1.87–2.70). We also observed signals for drugs acting on hormone balance, bone density, and central nervous system. Conclusion: Our findings suggest that immunomodulatory drugs increase the risk of MS and point out that some other drug classes should be further investigated for this risk.

Background and purpose Receiving clear, complete and up-to-date information and having a satisfying relationship with the health professional (HP) are of primary importance for MS patients. Healthcare organization plays a key role in promoting an effective relationship and communication between patients and HPs. The present study aims to explore which care organization and service characteristics provided by Italian MS centres best predict patients’ satisfaction with healthcare. Methods Eighty-one centres and 707 patients (502 women, mean age 40.5 years, SD 10.2; mean education 12.2 years, SD 3.6; time since diagnosis 5.9 years, SD 1.5) were included in the analysis. The care organization and service provided by each centre were evaluated in comparison with the National Institute for Health and Care Excellence (NICE) guidelines on management of MS. Patients’ satisfaction with care was measured using the patient self-assessed questionnaire ‘Comunicazione medico-paziente nella Sclerosi Multipla, revised’ section 2 (COSM-R section 2). Results The clinical characteristics of patients significantly affected their satisfaction. A multivariate regression model showed that higher patients’ satisfaction (COSM-R score) was inversely associated with hospital size (number of patients under care) (β = −0.21, 95% confidence interval −0.35; −0.07) and directly associated with psychological interventions (β = 2.44, 95% confidence interval 0.29; 4.59). Conclusions Multiple sclerosis patients from larger hospitals are less satisfied with the information received and the relationship with HPs. Building an individualized relationship between patients and HPs and tailoring the communication of information improve patients’ satisfaction. Such a goal is probably less likely to be accomplished in larger centres with many incoming patients. Moreover, when the centres also provide structured psychological interventions, the patients are more satisfied.

Background Depression is considered one of the prodromal symptoms of Parkinson's disease (PD) along with sleep disorders, hyposmia and constipation. Prodromal symptoms refer to the stage wherein early motor symptoms and signs allowing a diagnosis of PD are not yet present. The objective of this study was to investigate the association between the use of antidepressants, as indirect measure of depression, and subsequent PD onset, clinically diagnosed, in the Local Health Trust of Bologna, Italy. Methods Historical cohort study with use of antidepressants as exposure and PD onset as outcome. The cohort considered consisted of inhabitants of Bologna aged ≥35 years in 2005; those who had used antidepressants in the previous 3 years were excluded. Subjects were followed up from 2006 and until PD onset, migration out of Bologna, death or end of the study period (2017), whichever came first. “The ParkLink Bologna” system was used to detect disease onset. “ParkLink Bologna” is a research study including patients with a clinical diagnosis of PD residing in Bologna. Residents that used antidepressants for at least 180 consecutive days within 1 year were considered exposed. Hazard ratios (HR) and 95% confidence interval (CI) were estimated with Cox proportional hazards models, using exposure as time-dependent variable and adjusting for potential confounders: age, gender, use of medical care and comorbidities. Results From 2006 to 2017 199,093 person-years were exposed and 4,286,470 not exposed. Fifty-one subjects with PD were identified in the exposed group and 556 subjects in the non-exposed showing an association of adjusted HR = 1.7 (CI 1.3–2.3). The association was stronger for males (HR 2.2, CI 1.5–3.2) compared to females (HR 1.2, CI 0.8–1.9), for subjects ≤65 years of age (HR 2.4, CI 1.6–3.6) vs. >65 years (HR 1.3, CI 0.8–1.9) and for those with less comorbidities. Age and gender were confounders in the associations between antidepressant use and PD onset. Conclusions The use of antidepressants as indirect measure of depression is associated with the subsequent development of PD. Our findings confirm that depression may precede the onset of motor symptoms in PD. The association is stronger for younger subjects, who are males and with fewer comorbidities.

This is a cross-sectional, quantitative and descriptive study, carried out in Uberaba-MG, Brazil, from August 2016 to February 2017. It aims to evaluate and correlate sociodemographic and clinical aspects with the quality of life of individuals with chronic kidney disease undergoing hemodialysis. The following instruments were applied to 51 participants: questionnaires with sociodemographic/clinical information and the Kidney Disease and Quality of Life Short Form 1.3, punctuated by the “Scoring Program (v2.0)”. Normality tests and inferential correlation analysis were performed. The domains with the best results were "Sexual Function", "Cognitive Function" and "Support of the dialysis team", and the worst were "Work situation", "Role of physical limitation" and "Physical Health". The domains Physical Functionality" and "Physical Health" were negatively correlated with age (r = -0.521 and r = -0.380, respectively) and "General Health" and "Effects of Kidney Disease" with dry weight (r = -0.319 er = -0.502, respectively). These results indicate a compromised quality of life, requiring general attention to these individuals in conjunction with actions that promote better general health conditions.

Introduction: Chronic kidney disease and hemodialysis normally have an impact on the functioning. Objective: To validate the Brazilian version of the World Health Organization Disability Assessment Schedule 2.0 in individuals with chronic kidney disease on hemodialysis treatment. Methods: The 36-item version was applied to interview 51 individuals with chronic kidney disease undergoing dialysis treatment. To ascertain the instrument’s applicability, its internal consistency and test-retest stability were studied. To check the validity, a convergent/divergent analysis was performed. Results: The participants answered the questions on the main instrument at two timepoints and on the World Health Organization Quality of Life Abbreviated instrument and the Kidney Disease Quality of Life - Short FormTM 1.3 once each. Cronbach’s α coefficient was appropriate in all domains except the “Getting along” domain. The test-retest coefficients were above the recommended value (> 0.70). Convergent and divergent validity analysis also showed consistent results by correlation coefficient assessment. Conclusion: The instrument is valid and reliable. This study supports the use of the questionnaire by presenting its appropriate psychometric properties. We suggest that some care should be taken specifically in the sexual questions of the “Getting along” domain.

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. Language: en

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.

No previous population-based study has addressed the contribution of activation procedures to the yield of epileptiform abnormalities on serial EEGs. We assessed yield of activation-related epileptiform abnormalities and predictors of finding an activation-related abnormality with multiple EEGs in a population-based study of newly diagnosed epilepsy.We used the resources of the Rochester Epidemiology Project to identify 449 residents of Rochester, Minnesota with a diagnosis of newly diagnosed epilepsy at age 1 year or older, between 1960 and 1994, who had at least one EEG. Information on all activation procedures (i.e., sleep, hyperventilation, and photic activation) and seizure/epilepsy characteristics was obtained by comprehensive review of medical records.At the first EEG, the yield of epileptiform abnormalities was greatest for individuals 1 to 19 years of age at diagnosis, for each activation procedure. The yield in patients aged 1 to 19 versus ≥20 years was 21.6% versus 10.3% for sleep, 6.5% versus 3.3% for photic stimulation, and 10.3% versus 5% for hyperventilation. Among young people (aged 1-19 years), sleep was associated with an increased likelihood of finding an activation-related abnormality on any EEG. The likelihood of finding an activation-related abnormality on any EEG was decreased for postnatal symptomatic and for unknown etiology.Among activation procedures, sleep showed the highest yield of epileptiform abnormalities. There was a low yield for photic stimulation and hyperventilation. Within each activation procedure, younger age at diagnosis had the greatest yield. Sleep is the most effective activation procedure, especially in younger patients, and should be performed when possible.

Introduction: The role of drugs in the occurrence of multiple sclerosis (MS) is perceived to be insufficiently investigated. Objective: The aim of this study was to map and assess the evidence on MS occurrence after drug exposure, in order to identify possible signals of causal association. Methods: A search strategy was performed in MEDLINE and Embase as of July 2016; references consistent with the aim of the study were analysed to extract relevant measures of causal association between drugs and MS. The Newcastle-Ottawa Scale and appropriate guidelines from the International Society for Pharmacoepidemiology (ISPE) and the International Society of Pharmacovigilance (ISoP) were used to assess the quality of included studies. Results: After screening 832 articles, 58 were selected (of which 14 were found by checking the reference lists of reviews): 30 case reports and case series, 24 longitudinal studies and four randomized controlled trials. Seven longitudinal studies had good (at least 7 out of 9) quality scores, whereas case reports/case series presented several limitations. Half of included articles focused on immunomodulatory drugs (etanercept, infliximab and adalimumab), especially in case reports/series, suggesting an association with MS occurrence. Contraceptives and antibacterials were investigated in some population-based studies, without definite results. Conclusion: A heterogeneous pharmacological profile of identified classes emerged. Low strength of evidence and conflicting results highlighted the difficulties in addressing the possible contribution of drugs in MS occurrence. Methodological advances are needed, especially to control the confounding role of underlying disease for specific drug classes.

SummaryObjective 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.

SUMMARY Background: In the light of the new diagnostic criteria for multiple sclerosis (MS) and currently available early treatment, this study aimed to explore whether, and to what extent, disclosure of the diagnosis of MS or clinically isolated syndrome (CIS) affects patients’ anxiety, mood and quality of life (QoL). Methods: Eligible participants were all patients referred for the first time to the Neurological Unit who had manifested symptoms suggestive of MS for no more than 6 months. All patients were evaluated for (i) QoL (SEIQoL and MS-QoL54), (ii) Anxiety (STAI) and Depression (CMDI) on study inclusion (T0), 30 days after diagnosis disclosure (T30), and after 1 (T1y) and 2 (T2y) years’ follow-up. Results: Two hundred and twenty-nine patients were enrolled; 93 of these were unaware of their diagnosis. Patients who already knew their diagnosis (100 with CIS and 22 with MS) were excluded from the main analyses and used to perform control analyses. At the end of the screening, an MS diagnosis was disclosed to 18 of the 93 patients, whereas a CIS diagnosis was disclosed to 62 patients (12 patients received a diagnosis other than MS or CIS). Thirty days after diagnosis disclosure, irrespective of the diagnosis disclosed, both QoL and Anxiety and Depression were significantly rated as better compared to the start of screening, (ps < 0.03), and this improvement remained stable over the two annual follow-ups. However, as suggested by a significant ‘Time’ · ‘Diagnosis’ interaction with regard to both QoL and Anxiety and Depression (ps < 0.02), the effect of the disclosure in the short term differed depending on CIS or MS diagnosis. Specifically, on MSQoL, which is a healthrelated QoL scale, we found a statically significant improvement, immediately after the diagnosis disclosure, in both the MS and CIS groups (ps < 0.01). Differently, on SEIQoL, which is a non health-related QoL measure, and on the anxiety scale, we observed a statistically significant improvement only in the group which received a MS diagnosis (ps < 0.03). Conclusions: This first prospective study provides objective data showing that early disclosure of MS diagnosis improves both the patient’s QoL and psychological well-being. In addition, the results seem to suggest that CIS disclosure does not lead to the same favourable effects. What’s known Very few studies have investigated the effect of MS diagnosis disclosure on psychological well-being and QoL. It is suggested that there is a significant improvement in QoL and psychological well-being following disclosure, but the fact that the patients’ mood and QoL were assessed only when diagnosis disclosure had already taken place poses an important methodological limit to these studies. A comparison with the previous phase in which the patients were unaware of the diagnosis, therefore, is missing.

We determined the prevalence of common recurrent symptoms in a community-based study of children and investigated whether these symptoms were associated with epilepsy and febrile seizure. A questionnaire was developed and sent to parents of all children attending school in the Reykjavik school district, grades 1–10. The questions assessed personality traits, headache, epilepsy, febrile seizure, and recurrent symptoms. Of the 13,044 questionnaires distributed, 10,578 were returned (81%). We analyzed the subset of 9679 (91%) questionnaires with complete information on relevant factors. The prevalence of epilepsy was 7.7/1000; febrile seizures were reported in 5.1% of children. Prevalence estimates of recurrent symptoms were similar to the published literature. In our cohort, recurrent dizzy spells and recurrent visual disturbances were associated with epilepsy after adjustment for age, migraine and febrile seizure. This association could reflect, only in part, the occurrence of auras in children with epilepsy.

The members of the PERNO Study Group were not individually captured in the metadata of the original publication. They are included in the metadata of this publication.

Patients with high-grade gliomas usually have heterogeneous response to surgery and chemoirradiation. The objectives of this study were (1) to evaluate serial changes in tumor volume and perfusion imaging parameters and (2) to determine the value of these data in predicting overall survival (OS). Twenty-nine patients with World Health Organization grades III and IV gliomas underwent magnetic resonance (MR) and computed tomography (CT) perfusion examinations before surgery, and 1, 3, 6, 9, and 12 months after radiotherapy. Serial measurements of tumor volumes and perfusion parameters were evaluated by receiver operating characteristic analysis, Cox proportional hazards regression, and Kaplan-Meier survival analysis to determine their values in predicting OS. Higher trends in blood flow (BF), blood volume (BV), and permeability-surface area product in the contrast-enhancing lesions (CEL) and the non-enhancing lesions (NEL) were found in patients with OS < 18 months compared to those with OS ≥ 18 months, and these values were significant at selected time points (P < 0.05). Only CT perfusion parameters yielded sensitivities and specificities of ≥ 70% in predicting 18 and 24 months OS. Pre-surgery BF in the NEL and BV in the CEL and NEL 3 months after radiotherapy had sensitivities and specificities >80% in predicting 24 months OS in patients with grade IV gliomas. Our study indicated that CT perfusion parameters were predictive of survival and could be useful in assessing early response and in selecting adjuvant treatment to prolong survival if verified in a larger cohort of patients.

Summary 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.

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.

To present new information on the semiology and short-term evolution of seizures associated with primary brain tumors (PBTs) in a prospective study.This study is a section of the PERNO study--Project of Emilia Romagna Region on Neuro-Oncology, the main aim of which is to collect prospectively all cases of PBTs occurring in the Emilia-Romagna region, northeast Italy (3,983,346 population) from January 2009 to December 2011, to allow epidemiologic, clinical, and biomolecular studies. The epilepsy section of the PERNO study included all the patients who experienced seizures, either as first symptom of the tumor or appearing during the course of the disease. Each patient was interviewed by the referring neurologist with a specific interest in epilepsy. The patients who entered the study were followed up with visits on a quarterly basis.We collected 100 cases with full clinical, neuroradiologic, and pathologic data. The majority (79\%) had high grade PBTs (glioblastoma in 50 cases), whereas the remaining patients had low-grade gliomas, mostly localized in the frontal (60\%), temporal (38\%), and parietal (28\%) lobes. Seizures were the first symptom of the tumor in 72 cases. Overall, the initial seizures were tonic-clonic (48\%) (without clear initial focal signs in more than half of the patients), focal motor (26\%), complex partial (10\%), and somatosensitive (8\%). The majority of cases (60\%) had isolated seizures or a low seizure frequency at the onset of the disease, whereas a high seizure frequency or status epilepticus was observed in 18\% and 12\% of cases, respectively. Ninety-two patients underwent surgical removal of the tumor, which was either radical (38\%) or partial (53\%). Seven patients underwent only cerebral biopsy. In the 72 patients in whom seizures were the first symptom, the mean time to the surgical treatment was 174 days, with a significant difference between high grade (95 days) and low grade (481 days) gliomas. At the time of our first observation, the majority of patients (69\%) had already undergone surgical removal, with a mean follow-up of 3 months after the procedure. Overall, 39 patients (56\%) were seizure free after tumor removal. The good outcome did not depend on presurgical seizure frequency or tumor type, although there was a trend for better results with low-grade PBTs.These data provide evidence that seizures are strictly linked to the tumoral lesion: They are the initial symptom of the tumor, reflect the tumor location and type, are usually resistant to antiepileptic treatment, and may disappear after the treatment of the lesion.

The aim of the study was to estimate the rate of conversion from clinically isolated syndrome (CIS) to multiple sclerosis (MS) and to investigate variables predicting conversion in a cohort of patients presenting with symptoms suggestive of MS. Patients with a first symptom suggestive of MS in the preceding 6 months and exclusion of other diseases were enrolled in an observational prospective study from December 2004 through June 2007. Conversion from CIS to MS according to both McDonald and Clinically Defined Multiple Sclerosis (CDMS) criteria was prospectively recorded until March 2010. The multivariate Cox proportional hazard model was used to assess the best predictive factors of conversion from CIS to MS. Among 168 patients included in the analysis, 122 converted to MS according to McDonald criteria whereas 81 converted to MS according to CDMS criteria. The 2-year probability of conversion was 57 % for McDonald Criteria and 36 % for CDMS criteria. Variables at enrolment significantly associated with conversion according to McDonald criteria were age and positivity for Barkhof criteria, and according to Poser’s CDMS criteria, age, positivity for Barkhof criteria and no disease modifying therapy. In this large prospective cohort study the conversion rate from CIS to MS in patients presenting with recent symptoms suggestive of MS was within the range of previous observational studies and lower than that reported in the placebo arm of randomized trials. We confirm the prognostic value of MRI in addition to the previous experimental data on the protective role of disease-modifying therapies.

Objective The inflammatory myopathies (IMs) are a group of disorders characterised by weakness and inflammation of the skeletal muscles. Muscle biopsy is the most crucial test to confirm the clinical diagnosis, but also the most common cause of misdiagnosis. There are currently no markers specific or sensitive enough to distinguish IMs from other diseases with similar clinical and morphological features, and an international multidisciplinary effort is under way to develop new classification criteria for IMs. Methods Standards for Reporting of Diagnostic Accuracy recommendations to validate a diagnostic test based on the quantification of internal major histocompatibility complex class I (MHC-I) positive fibres were adopted. MHC-I immunostained specimens from 64 patients were scored by two independent blinded investigators, and the percentage of positive fibres was determined. Agreement between investigators was evaluated with the k-weighted statistic. The receiver operating characteristic curve, area under the curve, sensitivity, specificity, and positive and negative predictive values of each percentage range of positive fibres versus the diagnosis of IM were calculated. Results The main difference between IM and non-inflammatory samples was the number of internal MHC-I positive fibres. The k-weighted value was 0.89 for a percentage of MHC-I positive fibres above 50%; the positive predictive value was 100%, and the negative predictive value was 94%. Conclusions This is the first study on the validity of a quantitative analysis of internal MHC-I positive fibres for an IM diagnosis performed according to Standards for Reporting of Diagnostic Accuracy recommendations. The interobserver agreement was almost perfect, thus making the method reproducible. Applying an MHC-I cut-off above 50% is an optimal marker for polymyositis (PM) and dermatomyositis (DM) diagnosis.

Three cirrhotic patients with chronic acquired hepatocerebral degeneration (CAHD) received neurologic, neuropsychologic and neuroimaging assessment before and after liver transplantation (LT). Before transplantation, neurologic dysfunction consisted in severe bradykinesia, dystonia, dyskinesia, ataxia and dysarthria. Cognitive impairment affected mainly attentional and executive domains. Brain MRI showed bilateral hyperintensities of the basal ganglia on T1-weighted images. After transplantation, motor manifestations promptly resolved. Cognitive testing showed a major improvement in two patients, whereas cognitive performances were slightly worsened in the third, reasonably due to the effects of a head injury before LT and a tacrolimus-related encephalopathy arising early after LT. MRI images 12 months later showed a slight reduction of the previously disclosed abnormalities in all three patients. None of them experienced recurrence of CAHD. Our observation reinforces the assumption that surgery is the best treatment option for CAHD and that severe neurological impairment in CAHD should not be considered a contraindication for LT.

Epidemiological surveys on status epilepticus (SE) in adults in two Italian areas (Bologna and Lugo di Romagna) disclosed a major difference in 30-day case fatality (33% versus 7 %). Since suboptimal management was hypothesised in the first site, we compared the quality of treatment in the two cohorts and examined its contribution to prognosis.The Bologna and Lugo di Romagna cohorts of adults with incident SE were included. Patients with post-anoxic encephalopathy were excluded. Quality of treatment was independently classified by two experts. Clinical and treatment features were compared in the two sites. The contribution of variables collected to the 30-day case fatality was explored through multivariate logistic analysis in the whole group of patients.Fifty-seven patients were included. No differences were observed between Bologna and Lugo di Romagna either in clinical features or the time of management. The quality of global drug treatment significantly differed in disfavour of Bologna (p = 0.044). Independent predictors of a worse 30-day case fatality in the whole group of patients were the onset of SE in hospital (OR 9.67, p = 0.0095) and the poor global quality of treatment (partially correct versus correct OR 3.59, p = 0.55, and incorrect versus correct OR 21.09, p = 0.0084). By subgroup analysis, the site of onset factor encompasses the aetiologic background of patients.In addition to previously known prognostic factors, epidemiological comparison of mortality rates of SE between different regions must also consider the quality of treatment.

CNS involvement is frequent in patients with chronic liver disease, resulting in overt or subclinical (“minimal”) encephalopathy. Occasionally, patients liver cirrhosis may develop a progressive encephalopathy known as chronic acquired hepatocerebral degeneration (CAHD), presenting with neuropsychiatric changes and movement disorders. In patients affected by CAHD cognitive dysfunction is the rule, but to date this aspect has not been systematically studied. Our aim was to characterize the neuropsychological profile of cognitive impairment associated with CAHD. Eight patients with CAHD received extensive neuropsychological assessment, far from episodes of acute liver decompensation. Their cognitive performances were compared with those of 8 patients with cirrhosis free from CAHD or overt hepatic encephalopathy (HE) and with those of 8 healthy controls matched for age, sex and educational level. Patients with CAHD revealed a significant impairment of visuo-spatial attention compared to healthy controls, and a lower performance on a single task of visual search and sequencing when compared to cirrhotics without CAHD. Our findings support the hypothesis of a linear decline in attentional performances of patients with chronic liver disease, starting from cognitively intact patients, moving toward patients with minimal HE, and finally progressing to those with overt HE and CAHD.

Post-transplant headache is a recognized complication of organ transplantation. Its treatment can sometimes be problematic given the status of the patient and the risk of drug interference. Six organ-transplanted patients (5 liver and 1 heart) experiencing post-transplant headache were successfully treated with riboflavin 200 mg daily. The drug proved safe and well tolerated and its properties are unlikely to produce clinically relevant drug interactions in the transplant recipient. Awaiting specific trials, riboflavin is proposed as an option for the preventive treatment of post-transplant headache.

Sir, Fatal familial insomnia (FFI) is an autosomal dominant prion disease linked to the D178N/129M haplotype in the prion protein gene, PRNP, and is the third in frequency among the genetic transmissible spongiform encephalopathies (TSEs) [4]. FFI is characterized by sleep and behavioral disturbances, autonomic alterations, ataxia, pyramidal signs, myoclonus, and late development of mental deterioration. FFI has been reported in families from Italy, Germany, Austria, Spain, the UK, France, Finland, the United States, Australia, Japan, and China [4, 7]. Here we describe the occurrence of the disease in the African Continent. A 45-year-old man, born in Morocco (Greater Casablanca region), was admitted after a five-month history of diplopia, and worsening unsteady gait. When specifically asked he reported a nine-month history of insomnia with total sleep time decreasing from 7 to 5 h per night. In addition he had developed excessive sweating, erectile dysfunction, and a ‘‘gasping’’ breathing. He reported that a similar disease was present in several members of in his family (Fig. 1, genealogical tree) who died after about one year of a progressive neurological illness. He had directly observed the evolution of the disease of his mother and three uncles (III-3, III-1, III-2, III-7 in the figure) which was characterized by disequilibrium, diplopia, speech disorder, insomnia, and late cognitive deterioration. He also gave us clinical records of a cousin (IV-9 in the figure) who had suffered from the ‘‘disease of the family’’. Neurological examination at admission showed horizontal and vertical saccades of the eyes in primary position with horizontal and vertical diplopia. The finger-to-nose test showed mild dysmetria with irregular tremor. Spontaneous and evoked myoclonus was evident, either segmental or massive, at the extremities and at the trunk; tendon reflexes were brisk. Gait was severely ataxic with retropulsion and with a trunk-extremity dissinergy. Neuropsycological examination showed only a mild deficit in long-term verbal memory. EEG showed no periodic discharges. In the CSF the 14-3-3 protein was absent and total tau protein was 120 pg/ml (normal values:141 ± 107 pg/ml). Four consecutive 24-h polysomnographic recordings (PSG) revealed marked reduction of total sleep time (range: 229–340 min; NV: 440 min) and total nocturnal sleep time (range: 123–290 min; NV: 420 min). Sleep efficiency ranged between 26 and 60% (NV [ 85%). Sleep was fragmented by frequent and sometimes prolonged periods of wakefulness. All sleep phases were represented but typical sleep figures (K-complexes and sleep spindles) were markedly reduced. REM sleep was characterized by physiological muscle sleep atonia; both during the night and during daytime naps REM sleep latency was abnormally short. These features were consistent with previous reports on FFI [5]. Brain MRI with diffusion weighted imaging and with spectroscopy, was reported as normal. Analyses of DNA from peripheral leukocytes, revealed the D178N mutation and methionine/valine heterozygosity at the polymorphic 129 codon of the PRNP gene. The mutated allele had methionine at codon 129 and an R3-R4 24 bp deletion. E. Baldin S. Capellari F. Provini P. Corrado R. Liguori P. Parchi P. Montagna P. Cortelli (&) Department of Neurological Science, University of Bologna, via Ugo Foscolo, 7, Bologna, Italy e-mail: pietro.cortelli@unibo.it