Clinical practice guidelines on the management of status epilepticus in adults: A systematic review.

OBJECTIVE: Status epilepticus (SE) is the second most common neurological emergency in adults. Despite improvements in the management of acute neurological conditions over the last decade, mortality is still durably high. Because a gap has emerged between SE management based on clinical practice guidelines (CPGs) and actual clinical practice, we conducted a systematic review of CPGs, assessing their quality, outlining commonalities and discrepancies in recommendations, and highlighting research gaps. METHODS: We searched the PubMed and EMBASE databases and other gray literature sources (nine among guideline registries, evidence-based medicine databases, point-of-care tools; seven websites of governmental organizations and international neurologic societies) in December 2021 (updated in November 2023). The units of analysis were CPGs that included recommendations on the diagnostic and/or therapeutic management of SE in adults. The quality of the CPGs was assessed using the AGREE II tool. RESULTS: Fifteen CPGs were included. The "Applicability" domain was assigned the lowest median score of 10%. The domains "Stakeholder Involvement", "Rigor of Development," and "Editorial Independence" were as well generally underrated. Recommendations on general and diagnostic management and on organizational interventions were fragmented and scattered. Recommendations on pre-hospital and hospital treatment of early-onset and refractory SE were broadly agreed, whereas there was less agreement on the treatment model and medications for established SE and super-refractory SE. SIGNIFICANCE: The CPGs for the management of SE developed in recent years are flawed by several methodological issues and discrepancies in the coverage of important topics. The gap between CPG-based management of SE and actual clinical practice may be due in part to the inherent limitations of the CPGs produced so far.

Sex disparities in clinical features and burden of narcolepsy type 1.

To investigate potential sex-related differences in patients with narcolepsy type 1, we carried out an analysis of baseline data from 93 women and 89 men with narcolepsy type 1 who participated in the TElemedicine for NARcolepsy (TENAR) trial. The following data were considered: sociodemographics; diagnostic (disease history, polysomnography, orexin, human leukocyte antigen) and clinical features, including sleepiness (Epworth Sleepiness Scale), cataplexy and other narcolepsy symptoms; disease severity (Narcolepsy Severity Scale); pharmacological treatment; depressive symptoms (Beck Depression Inventory); and self-reported relevance of eight narcolepsy-related issues. We found that, compared with men, significantly more women reported automatic behaviours (55.4% versus 40%) and had higher Epworth Sleepiness Scale (median 10 versus 9) and Beck Depression Inventory scores (median 10.5 versus 5), and there was a trend for a higher Narcolepsy Severity Scale total score in women (median 19 versus 18, p = 0.057). More women than men were officially recognized as having a disability (38% versus 22.5%) and considered 5/8 narcolepsy-related issues investigated as a relevant problem. More severe sleepiness and a greater narcolepsy-related burden in women could mirror sex differences present in the general population, or may be related to suboptimal management of narcolepsy type 1 or to more severe depressive symptoms in women. Future studies and guidelines should address these aspects.

Tuberous sclerosis complex in adulthood: focus on epilepsy prognosis.

OBJECTIVE: Typically diagnosed in early childhood or adolescence, TSC is a chronic, multisystemic disorder with age-dependent manifestations posing a challenge for transition and for specific surveillance throughout the lifetime. Data on the clinical features and severity of TSC in adults and on the prognosis of epilepsy are scarce. We analyzed the clinical and genetic features of a cohort of adult patients with TSC, to identify the prognostic predictors of seizure remission after a long follow-up. METHOD: We conducted a retrospective analysis of patients diagnosed with TSC according to the updated international diagnostic criteria. Pearson's chi-square or Fisher's exact test and Mann Whitney U test were used to compare variables among the Remission (R) and Non-Remission (NR) group. Univariate and multivariate logistic regression analyses were performed. RESULTS: We selected 43 patients with TSC and neurological involvement in terms of epilepsy and/or brain lesions, attending the Epilepsy Center of our Institute: of them, 16 (37.2%) were transitioning from the pediatric care and 6 (13.9%) were referred by other specialists. Multiorgan involvement includes cutaneous (86.0%), nephrological (70.7%), hepatic (40.0%), ocular (34.3%), pneumological (28.6%) and cardiac (26.3%) manifestations. Thirty-nine patients (90.7 %) had epilepsy. The mean age at seizure onset was 4 ± 7.3 years: most patients (29, 76.3 %) presented with focal seizures or spasms by age 3 years; only 2 (5.3 %) had seizure onset in adulthood. Twenty-seven patients (69.2 %) experienced multiple seizure types overtime, 23 (59.0 %) had intellectual disability (ID). At last assessment, 14 (35.9 %) were seizure free (R group) and 25 (64.1 %) had drug-resistant seizures (NR group). At logistic regression univariate analysis, ID (OR 7.9, 95 % CI 1.8--34.7), multiple seizure types lifelong (OR 13.2, 95 % CI 2.6- 67.2), spasms/tonic seizures at presentation (OR 6.5, 95 % CI 1.2--35.2), a higher seizure frequency at onset (OR 5.4, 95 % CI 1.2--24.3), abnormal neurological examination (OR 9.8, 95 % CI 1.1--90.6) and pathogenic variants in TSC2 (OR 5.4, 95 % CI 1.2--24.5) were significantly associated with non-remission. In the multivariate analysis, both ID and multiple seizure types lifelong were confirmed as independent predictors of poor seizure outcome. CONCLUSIONS: In our cohort of adult patients with TSC, epilepsy remains one of the main neurological challenges with only 5.3% of cases manifesting in adulthood. Approximately 64% of these patients failed to achieve seizure remission. ID and multiple seizure types were the main predictors of poor outcome. Nephrological manifestations require continuous specific follow-up in adults.

Magnetic resonance imaging scoring system of the lower limbs in adult patients with suspected idiopathic inflammatory myopathy.

PURPOSE: We aim to propose a visual quantitative score for muscle edema in lower limb MRI to contribute to the diagnosis of idiopathic inflammatory myopathy (IIM). MATERIAL AND METHODS: We retrospectively evaluated 85 consecutive patients (mean age 57.4 ± 13.9 years; 56.5% female) with suspected IIM (muscle weakness and/or persistent hyper-CPK-emia with/without myalgia) who underwent MRI of lower limbs using T2-weighted fast recovery-fast spin echo images and fat-sat T2 echo planar images. Muscle inflammation was evaluated bilaterally in 11 muscles of the thigh and eight muscles of the leg. Edema in each muscle was graded according to a four-point Likert-type scale adding up to 114 points ([11 + 8)] × 3 × 2). Diagnostic accuracy of the total edema score was explored by assessing sensitivity and specificity using the area under the ROC curve. Final diagnoses were made by a multidisciplinary Expert Consensus Panel applying the Bohan and Peter diagnostic criteria whenever possible. RESULTS: Of the 85 included patients, 34 (40%) received a final diagnosis of IIM (IIM group) while 51 (60%) received an alternative diagnosis (non-IIM group). A cutoff score ≥ 18 was able to correctly classify patients having an IIM with an area under the curve of 0.85, specificity of 96%, and sensitivity of 52.9%. CONCLUSION: Our study demonstrates that a quantitative MRI score for muscle edema in the lower limbs (thighs and legs) aids in distinguishing IIM from conditions that mimic it.

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.

Work productivity and activity impairment in patients with narcolepsy type 1.

The aim of this study was to assess work productivity and activity impairments and to explore their association with excessive daytime sleepiness, body mass index (BMI), depression, and anxiety in patients with narcolepsy type 1. We carried out a cross-sectional study in which patients with narcolepsy type 1 and matched controls for sex, age, and education were assessed for occupational features, EDS (Epworth Sleepiness Scale), BMI, depression (Beck Depression Inventory), anxiety (State-Trait Anxiety Inventory), and Work Productivity and Activity Impairment (WPAI). Different statistical approaches were used to investigate differences between groups and correlations between WPAI scores and clinical features. The 127 patients with narcolepsy type 1 (mean age 38.2 ± 15.5, 91.3% taking drugs for narcolepsy) and 131 controls (mean age of 37.4 ± 14.3) included did not differ in terms of occupational features, except for hours worked/week (29.9 in patients vs. 34.9 in controls) and officially recognised disability (30.7% vs. 5.3%). Impairment in all WPAI scores was approximately three times greater in patients. Narcolepsy was associated with work time missed in 27.4% of patients, while 93.2% to 95.5% of them had some impairment while working or during daily activities (vs. 37.5-46.8% of controls). Correlations with WPAI scores were found for excessive daytime sleepiness only in patients, and for both depression and anxiety in patients and controls, with a stronger correlation for activity impairment in patients. These results suggest that, despite treatment, narcolepsy type 1 was associated with extensive impairment especially regarding job effectiveness and daily activities. Future studies should investigate risk factors and effects of interventions on these outcomes.

Prioritization process for European Academy of Neurology clinical practice guidelines.

BACKGROUND AND PURPOSE: The development of high-quality clinical practice guidelines (CPGs) takes substantial time, effort, and resources. During the past years, the European Academy of Neurology (EAN) guideline production was significantly increased, so the need to develop clear, transparent, and methodologically solid criteria for prioritizing guideline topics became apparent. With this paper, we aim to define a set of criteria to be applied for prioritizing topics for future EAN guidelines, as well as the procedure for their implementation. METHODS: After review of the literature, we identified a recent systematic review that reported on the main prioritization criteria used by health organizations. Based on these, we developed a list of 20 preliminary criteria, which were voted on through a Delphi consensus procedure, including 160 stakeholders. Finally, we established a working procedure on how to submit and select new guideline topic proposals within the EAN. This procedure was reviewed by the EAN Scientific Committee and the Board. RESULTS: The first round, 61.3% of the participants voted, and 86% of them participated in the second round. Seven criteria were approved with this procedure. After the selection of the criteria, a prioritization procedure was launched, and the first 30 topics are reported in this paper. This bottom-up process that involved the whole EAN community was followed by a top-down process, using additional criteria for further selection by the EAN board members. CONCLUSIONS: We describe the development of prioritization criteria to be applied in the process of topic selection for future EAN CPGs. We will perform regular reviews and adjustments of the process.

The Movement Disorder Society Criteria for the Diagnosis of Multiple System Atrophy.

BACKGROUND: The second consensus criteria for the diagnosis of multiple system atrophy (MSA) are widely recognized as the reference standard for clinical research, but lack sensitivity to diagnose the disease at early stages. OBJECTIVE: To develop novel Movement Disorder Society (MDS) criteria for MSA diagnosis using an evidence-based and consensus-based methodology. METHODS: We identified shortcomings of the second consensus criteria for MSA diagnosis and conducted a systematic literature review to answer predefined questions on clinical presentation and diagnostic tools relevant for MSA diagnosis. The criteria were developed and later optimized using two Delphi rounds within the MSA Criteria Revision Task Force, a survey for MDS membership, and a virtual Consensus Conference. RESULTS: The criteria for neuropathologically established MSA remain unchanged. For a clinical MSA diagnosis a new category of clinically established MSA is introduced, aiming for maximum specificity with acceptable sensitivity. A category of clinically probable MSA is defined to enhance sensitivity while maintaining specificity. A research category of possible prodromal MSA is designed to capture patients in the earliest stages when symptoms and signs are present, but do not meet the threshold for clinically established or clinically probable MSA. Brain magnetic resonance imaging markers suggestive of MSA are required for the diagnosis of clinically established MSA. The number of research biomarkers that support all clinical diagnostic categories will likely grow. CONCLUSIONS: This set of MDS MSA diagnostic criteria aims at improving the diagnostic accuracy, particularly in early disease stages. It requires validation in a prospective clinical and a clinicopathological study. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Risk of hospitalization and death for COVID-19 in persons with epilepsy over a 20-month period: The EpiLink Bologna cohort, Italy.

OBJECTIVE: Data on COVID-19 outcomes in persons with epilepsy (PWE) are scarce and inconclusive. We aimed to study the risk of hospitalization and death for COVID-19 in a large cohort of PWE from March 1, 2020 to October 31, 2021. METHODS: The historical cohort design (EpiLink Bologna) compared adult PWE grouped into people with focal epilepsy (PFE), idiopathic generalized epilepsy (PIGE), and developmental and/or epileptic encephalopathy (PDEE), and a population cohort matched (ratio 1:10) for age, sex, residence, and comorbidity (assessed with the multisource comorbidity score), living in the local health trust of Bologna (approximately 800 000 residents). Clinical data were linked to health administrative data. RESULTS: In both cohorts (EpiLink: n = 1575 subjects, 1128 PFE, 267 PIGE, 148 PDEE, 32 other; controls: n = 15 326 subjects), 52% were females, and the mean age was 50 years (SD = 18). Hospital admissions for COVID-19 in the whole period were 49 (3.1%) in PWE and 225 (1.5%) in controls. The adjusted hazard ratio (aHR) in PWE was 1.9 (95% confidence interval [CI] = 1.4-2.7). The subgroups at higher risk were PFE (aHR = 1.9, 95% CI = 1.3-2.8) and PDEE (aHR = 3.9, 95% CI = 1.7-8.7), whereas PIGE had a risk comparable to the controls (aHR = 1.1, 95% CI = .3-3.5). Stratified analyses of the two main epidemic waves (March-May 2020, October 2020-May 2021) disclosed a higher risk of COVID-19-related hospitalization during the first epidemic wave (March-May 2020; aHR = 3.8, 95% CI = 2.2-6.7). Polytherapy with antiseizure medications contributed to a higher risk of hospital admission. Thirty-day risk of death after hospitalization was 14% in both PWE and controls. SIGNIFICANCE: During the first 20 months since the outbreak of COVID-19 in Bologna, PWE had a doubled risk of COVID-19 hospital admission compared to a matched control population. Conversely, epilepsy did not represent a risk factor for COVID-19-related death.

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.

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

BACKGROUND AND PURPOSE: Rare diseases affect up to 29 million people in the European Union, and almost 50% of them affect the nervous system or muscles. Delays in diagnosis and treatment onset and insufficient treatment choices are common. Clinical practice guidelines (CPGs) may improve the diagnosis and treatment of patients and optimize care pathways, delivering the best scientific evidence to all clinicians treating these patients. Recommendations are set for developing and reporting high-quality CPGs on rare neurological diseases (RNDs) within the European Academy of Neurology (EAN), through a consensus procedure. METHODS: A group of 27 experts generated an initial list of items that were evaluated through a two-step Delphi consensus procedure and a face-to-face meeting. The final list of items was reviewed by an external review group of 58 members. RESULTS: The consensus procedure yielded 63 final items. Items are listed according to the domains of the AGREE instruments and concern scope and purpose, stakeholder involvement, rigour of development, and applicability. Additional items consider reporting and ethical issues. Recommendations are supported by practical examples derived from published guidelines and are presented in two tables: (1) items specific to RND CPGs, and general guideline items of special importance for RNDs, or often neglected; (2) items for guideline development within the EAN. CONCLUSIONS: This guidance aims to provide solutions to the issues specific to RNDs. This consensus document, produced by many experts in various fields, is considered to serve as a starting point for further harmonization and for increasing the quality of CPGs in the field of RNDs.

Predictors of hyperkinetic seizures.

OBJECTIVE: To identify predisposing factors for hyperkinetic seizure occurrence in a representative cohort of surgically treated patients with drug-resistant focal epilepsy. METHODS: We retrospectively recruited all seizure-free patients after epilepsy surgery with a postoperative follow-up ≥12 months. Patients were classified as presenting with hyperkinetic seizures if at least 2 episodes occurred during their disease history, based on clear-cut anamnestic description and/or video-EEG/stereo-EEG recordings. We performed univariable and multivariable logistic regression models to study the association between the occurrence of hyperkinetic seizures and some predictors. RESULTS: From a pool of 1758 consecutive patients who underwent surgery from 1996 to 2017, we identified 974 seizure-free cases. Considering at least 1-year follow-up, 937 cases were included (511 males, 91 patients with hyperkinetic seizures). Variables significantly associated with an increased risk of hyperkinetic seizure occurrence were (1) presence of epilepsy with sleep-related seizures (SRE) (P < 0.001); (2) histological diagnosis of type II focal cortical dysplasia (FCD) (P < 0.001); (3) resection including the frontal lobe (P = 0.002) (4) duration of epilepsy at surgery (P < 0.001) and (5) high seizure frequency at surgery (weekly: P = 0.02 - daily: P = 0.05). A resection including the occipital lobe reduced the risk of hyperkinetic seizures (P = 0.05). About 63% of patients had hyperkinetic seizure onset before 12 years and it was rarely reported before 5 years of age. SIGNIFICANCE: Our findings underlie the role of SRE, type II FCD and frontal epileptogenic zone as predictors of hyperkinetic seizure occurrence and highlight an age-dependent effect in favoring hyperkinetic manifestations.

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.

If seizures left speechless: CA-P-S C-A-R-E, a proposal of a new ictal language evaluation protocol.

INTRODUCTION: We aimed to create standardized protocol for language examination in patients who underwent video-EEG recording and assessed its efficacy in the characterization of ictal language impairment, its ability to differentiate this from impaired awareness, and interobserver reliability in clinical practice. METHODS: From our database of video-EEG recordings, we selected a representative sample of 63 focal seizures with presumed language impairment. A multidisciplinary team of epileptologists, EEG technicians, and speech therapists analyzed the selected videos to highlight the critical issues of ordinary ictal language evaluation. We subsequently followed a multi-step process to develop the protocol and assess its interobserver reliability. RESULTS: A protocol based on seven tests in hierarchical succession was created, summed up in the acronym CA-P-S C-A-R-E (Closed Answers, Pro-speak question, Simple orders, Common object denomination, Audio repetition, Reading, Evoke). Following its preliminary administration for 5 months, we assessed the inter-observer reliability of 16 healthcare professionals in distinguishing between language impairment and impaired awareness among a sample of 10 seizures, finding a substantial agreement (kappa 0.61). CONCLUSION: The proposed protocol, made of simple and easy to memorize tests, is an effective tool that evaluates multiple domains beyond language. Its use could help to recognize ictal aphasia effectively and differentiate it from impaired awareness, minimizing inter-examiner variability.

EAN/ERS/ESO/ESRS statement on the impact of sleep disorders on risk and outcome of stroke.

Sleep disorders are highly prevalent in the general population and may be linked in a bidirectional fashion to stroke, which is one of the leading causes of morbidity and mortality.Four major scientific societies established a task force of experts in neurology, stroke, respiratory medicine, sleep medicine and methodology, to critically evaluate the evidence regarding potential links and the impact of therapy. 13 research questions were evaluated in a systematic literature search using a stepwise hierarchical approach: first, systematic reviews and meta-analyses; second, primary studies post-dating the systematic reviews/meta-analyses. A total of 445 studies were evaluated and 88 included. Statements were generated regarding current evidence and clinical practice.Severe obstructive sleep apnoea (OSA) doubles the risk for incident stroke, especially in young to middle-aged patients. Continuous positive airway pressure (CPAP) may reduce stroke risk, especially in treatment-compliant patients. The prevalence of OSA is high in stroke patients and can be assessed by polygraphy. Severe OSA is a risk factor for recurrence of stroke and may be associated with stroke mortality, while CPAP may improve stroke outcome. It is not clear if insomnia increases stroke risk, while pharmacotherapy of insomnia may increase it. Periodic limb movements in sleep (PLMS), but not restless limb syndrome (RLS), may be associated with an increased risk of stroke. Preliminary data suggest a high frequency of post-stroke insomnia and RLS and their association with a less favourable stroke outcome, while treatment data are scarce.Overall, the evidence base is best for OSA relationship with stroke and supports active diagnosis and therapy. Research gaps remain especially regarding insomnia and RLS/PLMS relationships with stroke.

Skin Biopsy May Help to Distinguish Multiple System Atrophy-Parkinsonism from Parkinson's Disease With Orthostatic Hypotension.

BACKGROUND: The differential diagnosis between multiple system atrophy parkinsonism type (MSA-P) and Parkinson's disease with orthostatic hypotension (PD+OH) is difficult because the 2 diseases have a similar clinical picture. The aim of this study is to distinguish MSA-P from PD+OH by immunostaining for abnormal phosphorylated α-synuclein at serine 129 (p-syn) in cutaneous nerves. METHOD: We recruited 50 patients with parkinsonism and chronic orthostatic hypotension: 25 patients fulfilled the diagnostic criteria for MSA-P and 25 patients for PD+OH. The patients underwent a skin biopsy from the cervical area, thigh, and leg to analyze somatic and autonomic skin innervation and p-syn in skin nerves. RESULTS: Intraneural p-syn positivity was found in 72% of patients with MSA-P, mainly in distal skin sites. More important, p-syn deposits in MSA-P differed from PD+OH because they were mainly found in somatic fibers of subepidermal plexi, whereas scant autonomic fiber involvement was found in only 3 patients. All patients with PD+OH displayed widely distributed p-syn deposits in the autonomic skin fibers of proximal and distal skin sites, whereas somatic fibers were affected only slightly in 4 patients with PD+OH. Skin innervation mirrored p-syn deposits because somatic innervation was mainly reduced in MSA-P. Sympathetic innervation was damaged in PD+OH but fairly preserved in MSA-P. CONCLUSIONS: The p-syn in cutaneous nerves allows the differentiation of MSA-P from PD+OH; MSA-P mainly shows somatic fiber involvement with relatively preserved autonomic innervation; and by contrast, PD+OH displays prevalent abnormal p-syn deposits and denervation in autonomic postganglionic nerves. © 2020 International Parkinson and Movement Disorder Society.