Sex steroid hormones and epilepsy: Effects of hormonal replacement therapy on seizure frequency of postmenopausal women with epilepsy-A systematic review.

BACKGROUND AND PURPOSE: Hormonal replacement therapy (HRT) is used for symptomatic treatment of menopause. Some evidence suggests a proconvulsant effect of estrogen and an anticonvulsant role of progesterone. Thus, the use of exogenous sex steroid hormones might influence the course of epilepsy in peri- and postmenopausal women with epilepsy (WWE). We conducted a systematic review on the impact of HRT on the frequency of seizures of WWE. METHODS: PubMed and Scopus were searched for articles published from inception until August 2022. Abstracts from the past 5 years from the European Academy of Neurology and European Epilepsy Congresses were also reviewed. Article reference lists were screened, and relevant articles were retrieved for consultation. Interventional and observational studies on WWE and animal models of estrogen deficiency were included. Critical appraisal was performed using the revised Cochrane risk-of-bias tool for randomized trials and ROBINS-E tool. RESULTS: Of 497 articles screened, 13 studies were included, including three human studies. One cross-sectional study showed a decrease in seizure frequency in WWE using combined HRT, a case-control study showed an increase in comparison with controls, and a randomized clinical trial found a dose-dependent increase in seizure frequency in women with focal epilepsy taking combined HRT. Ten studies addressing the impact of HRT in rat models were also included, which showed conflicting results. CONCLUSIONS: There is scarce evidence of the impact of HRT in WWE. Further studies should evaluate the harmful potential, and prospective registries are needed for monitoring this population.

The involvement of palliative care with neurology - a comparison of UK, Switzerland and Italy.

OBJECTIVES: To ascertain the involvement of palliative care with neurology services in the care of people with amyotrophic lateral sclerosis (ALS) in the United Kingdom, Italy and Switzerland, in particular the collaboration with and referral from neurology, the involvement in multidisciplinary team care and in the respiratory support of ALS patients. METHODS: In 2019, two online surveys were undertaken of palliative care specialists, using specialist groups of the European Academy of Neurology, European Association of Palliative Care and the Association of Palliative Medicine for Great Britain and Ireland. RESULTS: The respondents were specialist palliative care professionals, predominantly senior doctors, involved in the care of people with ALS. As the numbers of respondents from many countries were in single figures the analysis was restricted to the United Kingdom, Italy and Switzerland. The time of involvement varied, with early involvement commonest in the UK. Barriers to referral included neurologists not referring and financial issues, particularly in Switzerland. The reluctance of patients and families to see palliative care services was reported as less than 20% in all countries. Respondents were often involved in the care of people receiving noninvasive ventilation (NIV), in all countries. and with tracheostomy ventilation (TV), particularly in Italy. CONCLUSIONS: Palliative care services are often involved in the care of people with ALS, but the extent and timing of involvement varies. The use of clinical guidelines and education on palliative care for neurology services may encourage collaboration, for the benefit of people with ALS and their families.

Is it really myositis? Mimics and pitfalls.

Idiopathic inflammatory myopathies are a heterogeneous set of systemic inflammatory disorders primarily affecting muscle. Signs and symptoms vary greatly between and within subtypes, requiring supportive laboratory and pathologic evidence to confirm the diagnosis. Several studies are typical assessments for patients with suspected inflammatory myopathy, including muscle enzymes, autoimmune markers, imaging, and muscle biopsy. Misdiagnoses of myositis are not only related to the overlap of clinical phenotype with non-inflammatory myopathies, but also due to the limitations of diagnostic tests employed. Since many of the investigative tests are non-specific, they share features with other disorders, including muscular dystrophies, endocrine, toxic, and metabolic myopathies, and other neuromuscular or rheumatologic conditions. Recognizing the limitations of tests and understanding the shared features between inflammatory and non-inflammatory myopathies can help prevent misdiagnosing myositis with one of its several mimics.

Clinical spectrum time course in non-Asian patients positive for anti-MDA5 antibodies.

OBJECTIVES: To define the clinical spectrum time-course and prognosis of non-Asian patients positive for anti-MDA5 antibodies. METHODS: We conducted a multicentre, international, retrospective cohort study. RESULTS: 149 anti-MDA5 positive patients (median onset age 53 years, median disease duration 18 months), mainly females (100, 67%), were included. Dermatomyositis (64, 43%) and amyopathic dermatomyositis (47, 31%), were the main diagnosis; 15 patients (10%) were classified as interstitial pneumonia with autoimmune features (IPAF) and 7 (5%) as rheumatoid arthritis. The main clinical findings observed were myositis (84, 56%), interstitial lung disease (ILD) (108, 78%), skin lesions (111, 74%), and arthritis (76, 51%). The onset of these manifestations was not concomitant in 74 cases (50%). Of note, 32 (21.5%) patients were admitted to the intensive care unit for rapidly progressive-ILD, which occurred in median 2 months from lung involvement detection, in the majority of cases (28, 19%) despite previous immunosuppressive treatment. One-third of patients (47, 32% each) was ANA and anti-ENA antibodies negative and a similar percentage was anti-Ro52 kDa antibodies positive. Non-specific interstitial pneumonia (65, 60%), organising pneumonia (23, 21%), and usual interstitial pneumonia-like pattern (14, 13%) were the main ILD patterns observed. Twenty-six patients died (17%), 19 (13%) had a rapidly progressive-ILD. CONCLUSIONS: The clinical spectrum of the anti-MDA5 antibodies-related disease is heterogeneous. Rapidly-progressive ILD deeply impacts the prognosis also in non-Asian patients, occurring early during the disease course. Anti-MDA5 antibody positivity should be considered even when baseline autoimmune screening is negative, anti-Ro52 kDa antibodies are positive, and radiology findings show a NSIP pattern.

OptimisAtion of Diagnostic Accuracy in idioPathic inflammaTory myopathies (ADAPT study): a protocol for a prospective diagnostic accuracy study of multimodality testing in patients suspected of a treatable idiopathic inflammatory myopathy.

INTRODUCTION: Idiopathic inflammatory myopathies (IIMs) excluding inclusion body myositis (IBM) are a group of heterogeneous autoimmune disorders characterised by subacute-onset and progressive proximal muscle weakness, which are frequently part of a multisystem autoimmune disorder. Reaching the diagnosis can be challenging, and no gold standard for the diagnosis of IIM exists. Diagnostic modalities include serum creatine kinase activity, muscle imaging (MRI or ultrasound (US)), electromyography (EMG), myositis autoantibody testing and muscle biopsy. Several diagnostic criteria have been developed for IIMs, varying in reported sensitivity and specificity. HYPOTHESIS: We hypothesise that an evidence-based diagnostic strategy, using fewer and preferably the least invasive diagnostic modalities, can achieve the accuracy of a complete panel of diagnostic tests, including MRI, US, EMG, myositis-specific autoantibody testing and muscle biopsy. METHODS AND ANALYSIS: The OptimizAtion of Diagnostic Accuracy in idioPathic inflammaTory myopathies study is a prospective diagnostic accuracy study with an over-complete study design. 100 patients suspected of an IIM excluding IBM will be included. A reference diagnosis will be assigned by an expert panel using all clinical information and all results of all ancillary tests available, including 6 months of follow-up. Several predefined diagnostic strategies will be compared against the reference diagnosis to find the optimal diagnostic strategy. ETHICS AND DISSEMINATION: Ethical approval was obtained from the medical ethics committee of the Academic Medical Centre, University of Amsterdam, The Netherlands (2019-814). The results will be distributed through conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: Netherlands trial register; NL8764.

A double-blind, placebo-controlled, randomized trial of PXT3003 for the treatment of Charcot-Marie-Tooth type 1A.

BACKGROUND: Charcot-Marie-Tooth disease type 1A (CMT1A) is a rare, orphan, hereditary neuromuscular disorder with no cure and for which only symptomatic treatment is currently available. A previous phase 2 trial has shown preliminary evidence of efficacy for PXT3003 in treating CMT1A. This phase 3, international, randomized, double-blind, placebo-controlled study further investigated the efficacy and safety of high- or low-dose PXT3003 (baclofen/naltrexone/D-sorbitol [mg]: 6/0.70/210 or 3/0.35/105) in treating subjects with mild to moderate CMT1A. METHODS: In this study, 323 subjects with mild-to-moderate CMT1A were randomly assigned in a 1:1:1 ratio to receive 5 mL of high- or low-dose PXT3003, or placebo, orally twice daily for up to 15 months. Efficacy was assessed using the change in Overall Neuropathy Limitations Scale total score from baseline to months 12 and 15 (primary endpoint). Secondary endpoints included the 10-m walk test and other assessments. The high-dose group was discontinued early due to unexpected crystal formation in the high-dose formulation, which resulted in an unanticipated high discontinuation rate, overall and especially in the high-dose group. The statistical analysis plan was adapted to account for the large amount of missing data before database lock, and a modified full analysis set was used in the main analyses. Two sensitivity analyses were performed to check the interpretation based on the use of the modified full analysis set. RESULTS: High-dose PXT3003 demonstrated significant improvement in the Overall Neuropathy Limitations Scale total score vs placebo (mean difference: - 0.37 points; 97.5% CI [- 0.68 to - 0.06]; p = 0.008), and consistent treatment effects were shown in the sensitivity analyses. Both PXT3003 doses were safe and well-tolerated. CONCLUSION: The high-dose group demonstrated a statistically significant improvement in the primary endpoint and a good safety profile. Overall, high-dose PXT3003 is a promising treatment option for patients with Charcot-Marie-Tooth disease type 1A.

Advanced Care Planning in Parkinson's Disease: In-depth Interviews With Patients on Experiences and Needs.

Introduction: Advance care planning (ACP) is an iterative process of discussing the needs, wishes, and preferences of patients regarding disease-specific and end-of-life issues. There is ample evidence that ACP improves the quality of life and promotes the autonomy of patients with cancer and motor neuron disease who have a high disease burden and shortened life expectancy. In Parkinson's disease (PD) though, knowledge about the experiences and preferences of patients regarding ACP is scarce, despite the major disease burden associated with PD. Aim: This study aims to explore the experiences, needs, and preferences of PD patients regarding the content and timing of ACP. Methods: In-depth interviews were conducted with a purposively selected sample of patients diagnosed with PD. Using a semi-structured topic list, the participants were asked about their prospects for a future living with PD and with whom they wanted to discuss this. Qualitative analysis was performed in parallel with data collection using a data-driven constant comparative approach. The transcribed interviews were coded and analyzed by two researchers using MAXQDA software. Results: Of all 20 patients (13 males; age 47-82; disease duration 1-27 years), most expressed a wish to talk about ACP with a healthcare provider, enabling them to anticipate the uncertain future. The majority of patients preferred their healthcare provider to initiate the discussion on ACP, preferably at an early stage of the disease. Nearly all patients expressed the wish to receive more information regarding the long-term impact of PD, although, the preferred timing varied between patients. They also perceived that their neurologist was primarily focused on medication and had little time to address their need for a more holistic approach toward living with PD. Conclusion: Our results suggest that PD patients are in need of discussing ACP with their healthcare provider (HCP), even in the early stages of the disease. In addition, PD patients perceive a lack of information on their disease course and miss guidance on available supportive care. We recommend HCPs to inquire the information requirements and preferences of patients regarding ACP regularly, starting soon after diagnosis.

Intravenous immunoglobulins as first-line treatment in idiopathic inflammatory myopathies: a pilot study.

OBJECTIVES: We explored efficacy and safety of IVIg as first-line treatment in patients with an idiopathic inflammatory myopathy. METHODS: In this investigator-initiated phase 2 open-label study, we included 20 adults with a newly diagnosed, biopsy-proven idiopathic inflammatory myopathy, and a disease duration of less than 9 months. Patients with IBM and prior use of immunosuppressants were excluded. The standard treatment regimen consisted of IVIg (Privigen) monotherapy for 9 weeks: a loading dose (2 g/kg body weight) and two subsequent maintenance doses (1 g/kg body weight) with a 3-week interval. The primary outcome was the number of patients with at least moderate improvement on the 2016 ACR/EULAR Total Improvement Score. Secondary outcomes included time to improvement, the number of patients requiring rescue medication and serious adverse events. RESULTS: We included patients with DM (n = 9), immune-mediated necrotizing myopathy (n = 6), non-specific myositis/overlap myositis (n = 4) and anti-synthetase syndrome (n = 1). One patient was excluded from analyses because of minimal weakness resulting in a ceiling effect. Eight patients (8/19 = 42.0%; Clopper-Pearson 95% CI: 19.6, 64.6) had at least moderate improvement by 9 weeks. Of these, six reached improvement by 3 weeks. Seven patients required rescue medication due to insufficient efficacy and prematurely ended the study. Three serious adverse events occurred, of which one was pulmonary embolism. CONCLUSION: First-line IVIg monotherapy led to at least moderate improvement in nearly half of patients with a fast clinical response in the majority of responders. TRIAL REGISTRATION: Netherlands Trial Register identifier, NTR6160.

The clinical, histologic, and genotypic spectrum of SEPN1-related myopathy: A case series.

OBJECTIVE: To clarify the prevalence, long-term natural history, and severity determinants of SEPN1-related myopathy (SEPN1-RM), we analyzed a large international case series. METHODS: Retrospective clinical, histologic, and genetic analysis of 132 pediatric and adult patients (2-58 years) followed up for several decades. RESULTS: The clinical phenotype was marked by severe axial muscle weakness, spinal rigidity, and scoliosis (86.1%, from 8.9 ± 4 years), with relatively preserved limb strength and previously unreported ophthalmoparesis in severe cases. All patients developed respiratory failure (from 10.1±6 years), 81.7% requiring ventilation while ambulant. Histopathologically, 79 muscle biopsies showed large variability, partly determined by site of biopsy and age. Multi-minicores were the most common lesion (59.5%), often associated with mild dystrophic features and occasionally with eosinophilic inclusions. Identification of 65 SEPN1 mutations, including 32 novel ones and the first pathogenic copy number variation, unveiled exon 1 as the main mutational hotspot and revealed the first genotype-phenotype correlations, bi-allelic null mutations being significantly associated with disease severity (p = 0.017). SEPN1-RM was more severe and progressive than previously thought, leading to loss of ambulation in 10% of cases, systematic functional decline from the end of the third decade, and reduced lifespan even in mild cases. The main prognosis determinants were scoliosis/respiratory management, SEPN1 mutations, and body mass abnormalities, which correlated with disease severity. We propose a set of severity criteria, provide quantitative data for outcome identification, and establish a need for age stratification. CONCLUSION: Our results inform clinical practice, improving diagnosis and management, and represent a major breakthrough for clinical trial readiness in this not so rare disease.

Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT): a randomised, double-blind, placebo-controlled phase 2b trial.

BACKGROUND: Inclusion body myositis is an idiopathic inflammatory myopathy and the most common myopathy affecting people older than 50 years. To date, there are no effective drug treatments. We aimed to assess the safety, efficacy, and tolerability of bimagrumab-a fully human monoclonal antibody-in individuals with inclusion body myositis. METHODS: We did a multicentre, double-blind, placebo-controlled study (RESILIENT) at 38 academic clinical sites in Australia, Europe, Japan, and the USA. Individuals (aged 36-85 years) were eligible for the study if they met modified 2010 Medical Research Council criteria for inclusion body myositis. We randomly assigned participants (1:1:1:1) using a blocked randomisation schedule (block size of four) to either bimagrumab (10 mg/kg, 3 mg/kg, or 1 mg/kg) or placebo matched in appearance to bimagrumab, administered as intravenous infusions every 4 weeks for at least 48 weeks. All study participants, the funder, investigators, site personnel, and people doing assessments were masked to treatment assignment. The primary outcome measure was 6-min walking distance (6MWD), which was assessed at week 52 in the primary analysis population and analysed by intention-to-treat principles. We used a multivariate normal repeated measures model to analyse data for 6MWD. Safety was assessed by recording adverse events and by electrocardiography, echocardiography, haematological testing, urinalysis, and blood chemistry. This trial is registered with ClinicalTrials.gov, number NCT01925209; this report represents the final analysis. FINDINGS: Between Sept 26, 2013, and Jan 6, 2016, 251 participants were enrolled to the study, of whom 63 were assigned to each bimagrumab group and 62 were allocated to the placebo group. At week 52, 6MWD change from baseline did not differ between any bimagrumab dose and placebo (least squares mean treatment difference for bimagrumab 10 mg/kg group, 17·6 m, SE 14·3, 99% CI -19·6 to 54·8; p=0·22; for 3 mg/kg group, 18·6 m, 14·2, -18·2 to 55·4; p=0·19; and for 1 mg/kg group, -1·3 m, 14·1, -38·0 to 35·4; p=0·93). 63 (100%) participants in each bimagrumab group and 61 (98%) of 62 in the placebo group had at least one adverse event. Falls were the most frequent adverse event (48 [76%] in the bimagrumab 10 mg/kg group, 55 [87%] in the 3 mg/kg group, 54 [86%] in the 1 mg/kg group, and 52 [84%] in the placebo group). The most frequently reported adverse events with bimagrumab were muscle spasms (32 [51%] in the bimagrumab 10 mg/kg group, 43 [68%] in the 3 mg/kg group, 25 [40%] in the 1 mg/kg group, and 13 [21%] in the placebo group) and diarrhoea (33 [52%], 28 [44%], 20 [32%], and 11 [18%], respectively). Adverse events leading to discontinuation were reported in four (6%) participants in each bimagrumab group compared with one (2%) participant in the placebo group. At least one serious adverse event was reported by 21 (33%) participants in the 10 mg/kg group, 11 (17%) in the 3 mg/kg group, 20 (32%) in the 1 mg/kg group, and 20 (32%) in the placebo group. No significant adverse cardiac effects were recorded on electrocardiography or echocardiography. Two deaths were reported during the study, one attributable to subendocardial myocardial infarction (secondary to gastrointestinal bleeding after an intentional overdose of concomitant sedatives and antidepressants) and one attributable to lung adenocarcinoma. Neither death was considered by the investigator to be related to bimagrumab. INTERPRETATION: Bimagrumab showed a good safety profile, relative to placebo, in individuals with inclusion body myositis but did not improve 6MWD. The strengths of our study are that, to the best of our knowledge, it is the largest randomised controlled trial done in people with inclusion body myositis, and it provides important natural history data over 12 months. FUNDING: Novartis Pharma.

Idiopathic inflammatory myopathy: Interrater variability in muscle biopsy reading.

OBJECTIVE: To determine interrater variability in diagnosing individual muscle biopsy abnormalities and diagnosis. METHODS: We developed a scoring tool to analyze consensus in muscle biopsy reading of an ad hoc workgroup of international experts. Twenty-four samples from patients with suspected idiopathic inflammatory myopathy (IIM) were randomly selected, providing sections that were stained with standard histologic and immunohistochemical methods. Sections were made available on an online platform, and experts were queried about myopathologic features within 4 pathologic domains: muscle fibers, inflammation, connective tissue, and vasculature. A short clinical presentation of cases was included, and experts were asked to give a tentative diagnosis of polymyositis, dermatomyositis, inclusion-body myositis, antisynthetase syndrome-related myositis, immune-mediated necrotizing myopathy, nonspecific myositis, or other disease. Fleiss κ values, scoring interrater variability, showed the highest agreement within the muscle fiber and connective tissue domains. RESULTS: Despite overall low κ values, moderate agreement was achieved for tentative diagnosis, supporting the idea of using holistic muscle biopsy interpretation rather than adding up individual features. CONCLUSION: The assessment of individual pathologic features needs to be standardized and harmonized and should be measured for sensitivity and specificity for subgroup classification. Standardizing the process of diagnostic muscle biopsy reading would allow identification of more homogeneous patient cohorts for upcoming treatment trials.

Autosomal recessive limb-girdle and Miyoshi muscular dystrophies in the Netherlands: The clinical and molecular spectrum of 244 patients.

In this retrospective study, we conducted a clinico-genetic analysis of patients with autosomal recessive limb-girdle muscular dystrophy (LGMD) and Miyoshi muscular dystrophy (MMD). Patients were identified at the tertiary referral centre for DNA diagnosis in the Netherlands and included if they carried two mutations in CAPN3, DYSF, SGCG, SGCA, SGCB, SGCD, TRIM32, FKRP or ANO5 gene. DNA was screened by direct sequencing and multiplex ligand-dependent probe amplification (MLPA) analysis. A total of 244 patients was identified; 68 LGMDR1/LGMD2A patients with CAPN3 mutations (28%), 67 sarcoglycanopathy patients (LGMDR3-5/LGMD2C-E) (27%), 64 LGMDR12/LGMD2L and MMD3 patients with ANO5 mutations (26%), 25 LGMDR2/LGMD2B and MMD1 with DYSF mutations (10%), 21 LGMDR9/LGMD2I with FKRP mutations (9%) and one LGMDR8/LGMD2H patient with TRIM32 mutations (<1%). The estimated minimum prevalence of AR-LGMD and MMD in the Netherlands amounted to 14.4 × 10-6 . Thirty-three novel mutations were identified. A wide range in age of onset (0-72 years) and loss of ambulation (5-74 years) was found. Fifteen patients (6%) initially presented with asymptomatic hyperCKemia. Cardiac abnormalities were found in 35 patients (17%). Non-invasive ventilation was started in 34 patients (14%). Both cardiac and respiratory involvement occurs across all subtypes, stressing the need for screening in all included subtypes.

Seronegative patients form a distinctive subgroup of immune-mediated necrotizing myopathy.

Objectives: To investigate the characteristics of different clinico-serologic subgroups of immune-mediated necrotizing myopathy (IMNM). Methods: We retrospectively reviewed data from medical charts of 64 patients diagnosed with IMNM between 2012 and 2017 in 3 neuromuscular referral centers in The Netherlands and 1 in Belgium. Results: Seventeen patients had anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) autoantibodies (Abs), of whom 11 had a history of statin use, 15 had anti-signal recognition particle (SRP) Abs, 2 had anti-melanoma differentiation-associated protein 5 (MDA5) Abs, 22 patients were seronegative, and 9 patients did not have a complete Ab assessment. Moderate to severe disability in HMGCR Ab-positive and anti-SRP Ab-positive IMNM was common (71% and 60%, respectively) despite multimodality treatment. Compared with statin-associated anti-HMGCR Ab-positive IMNM, statin-naive anti-HMGCR Ab-positive IMNM patients were more often men (67% vs 45%), had lower rates of dysphagia (17% vs 45%), and more frequently had third-line therapy (50% vs 9%) and poor to fatal outcome (50% vs 0%). Compared with seropositive IMNM, seronegative IMNM was characterized by female predominance (1:3), frequent occurrence of associated connective tissue disorders (22% vs 9%), and significantly higher rates of extramuscular disease activity (50% vs 16%, p 0.014; 2-sided Fisher exact), also after excluding patients with an associated connective tissue disease (35% vs 7%, p 0.038; 2-sided Fisher exact). Conclusions: Our findings indicate that seronegative IMNM forms a subgroup with distinctive features from seropositive IMNM.

The Role of Palliative Care in Chronic Progressive Neurological Diseases-A Survey Amongst Neurologists in the Netherlands.

Background: Chronic progressive neurological diseases like high grade glioma (HGG), Parkinson's disease (PD), and multiple sclerosis (MS) are incurable, and associated with increasing disability including cognitive impairment, and reduced life expectancy. Patients with these diseases have complex care needs. Therefore, timely advance care planning (ACP) is required. Our aim was to investigate timing and content of discussions on treatment restrictions, i.e., to initiate, withhold, or withdraw treatment in patients with HGG, PD, and MS, from the neurologists' perspective. Methods: We performed a national online survey amongst consultants in neurology and residents in The Netherlands. The questionnaire focused on their daily practice concerning timing and content of discussions on treatment restrictions with patients suffering from HGG, PD or MS. We also inquired about education and training in discussing these issues. Results: A total of 125 respondents [89 neurologists (71%), 62% male, with a median age of 44 years, and 36 residents (29%), 31% male with a median age of 29 years] responded. Initial discussions on treatment restrictions were said to take place during the first year after diagnosis in 28% of patients with HGG, and commonly no earlier than in the terminal phase in patients with PD and MS. In all conditions, significant cognitive decline was the most important trigger to advance discussions, followed by physical decline, and initiation of the terminal phase. Most discussed issues included ventilation, resuscitation, and admission to the intensive care unit. More than half of the consultants in neurology and residents felt that they needed (more) education and training in having discussions on treatment restrictions. Conclusion: In patients with HGG discussions on treatment restrictions are initiated earlier than in patients with PD or MS. However, in all three diseases these discussions usually take place when significant physical and cognitive decline has become apparent and commonly mark the initiation of end-of-life care. More than half of the responding consultants in neurology and residents feel the need for improvement of their skills in performing these discussions.

2017 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Adult and Juvenile Idiopathic Inflammatory Myopathies and Their Major Subgroups.

OBJECTIVE: To develop and validate new classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIM) and their major subgroups. METHODS: Candidate variables were assembled from published criteria and expert opinion using consensus methodology. Data were collected from 47 rheumatology, dermatology, neurology, and pediatric clinics worldwide. Several statistical methods were utilized to derive the classification criteria. RESULTS: Based on data from 976 IIM patients (74% adults; 26% children) and 624 non-IIM patients with mimicking conditions (82% adults; 18% children), new criteria were derived. Each item is assigned a weighted score. The total score corresponds to a probability of having IIM. Subclassification is performed using a classification tree. A probability cutoff of 55%, corresponding to a score of 5.5 (6.7 with muscle biopsy) "probable IIM," had best sensitivity/specificity (87%/82% without biopsies, 93%/88% with biopsies) and is recommended as a minimum to classify a patient as having IIM. A probability of ≥90%, corresponding to a score of ≥7.5 (≥8.7 with muscle biopsy), corresponds to "definite IIM." A probability of <50%, corresponding to a score of <5.3 (<6.5 with muscle biopsy), rules out IIM, leaving a probability of ≥50-<55% as "possible IIM." CONCLUSION: The European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for IIM have been endorsed by international rheumatology, dermatology, neurology, and pediatric groups. They employ easily accessible and operationally defined elements, and have been partially validated. They allow classification of "definite," "probable," and "possible" IIM, in addition to the major subgroups of IIM, including juvenile IIM. They generally perform better than existing criteria.

Palliative care in neuromuscular diseases.

PURPOSE OF REVIEW: Palliative care is an approach that improves the quality of life of patients and their families facing the problem associated with life-threatening illness. Neuromuscular disorders (NMDs) are characterized by progressive muscle weakness, leading to pronounced and incapacitating physical disabilities. Most NMDs are not amenable to curative treatment and would thus qualify for palliative care. Amyotrophic lateral sclerosis is a relentlessly progressive disease, which leads to death about 2 years after onset due to respiratory muscle weakness. Increasingly, neurologists caring for these patients learn to apply the principles of palliative care. However, this does not yet apply to other well known and frequently occurring NMDs. RECENT FINDINGS: There is sparse literature on palliative care in NMDs such as Duchenne muscular dystrophy, spinal muscular atrophy, muscular dystrophies, some congenital myopathies, Pompe's disease and myotonic dystrophy type 1. These NMDs are often associated with imminent respiratory insufficiency and/or heart failure leading to a reduced life expectancy. Reasons for underutilization may include misconceptions about palliative care amongst patients, family carers and healthcare professionals or lack of awareness of the usefulness of this approach in these severely affected patients and the possibilities of integration of palliative principles into care for children and adults with NMDs. SUMMARY: There is an urgent need for increased attention to the development of palliative care in chronic progressive neuromuscular diseases associated with increasing functional incapacities and premature death. This will require education and training of the healthcare professionals, involvement of patient associations and funding to perform research.

Long-Term Air Pollution Exposure and Amyotrophic Lateral Sclerosis in Netherlands: A Population-based Case-control Study.

BACKGROUND: Recently, there has been increasing evidence that exposure to air pollution is linked to neurodegenerative diseases, but little is known about the association with amyotrophic lateral sclerosis (ALS). OBJECTIVES: We investigated the association between long-term exposure to air pollution and risk of developing ALS. METHODS: A population-based case-control study was conducted in Netherlands from 1 January 2006 to 1 January 2013. Data from 917 ALS patients and 2,662 controls were analyzed. Annual mean air pollution concentrations were assessed by land use regression (LUR) models developed as part of the European Study of Cohorts for Air Pollution Effects (ESCAPE). Exposure estimates included nitrogen oxides (NO2, NOx), particulate matter (PM) with diameters of <2.5 µm (PM2.5), <10 µm (PM10), between 10 µm and 2.5 µm (PMcoarse), and PM2.5 absorbance. We performed conditional logistic regression analysis using two different multivariate models (model 1 adjusted for age, gender, education, smoking status, alcohol use, body mass index, and socioeconomic status; model 2 additionally adjusted for urbanization degree). RESULTS: Risk of ALS was significantly increased for individuals in the upper exposure quartile of PM2.5 absorbance [OR=1.67; 95% confidence interval (CI): 1.27, 2.18], NO2 (OR=1.74; 95% CI: 1.32, 2.30), and NOx concentrations (OR=1.38; 95% CI: 1.07, 1.77). These results, except for NOx, remained significant after adjusting additionally for urbanization degree. CONCLUSIONS: Based on a large population-based case-control study, we report evidence for the association between long-term exposure to traffic-related air pollution and increased susceptibility to ALS. Our findings further support the necessity for regulatory public health interventions to combat air pollution levels and provide additional insight into the potential pathophysiology of ALS. https://doi.org/10.1289/EHP1115.

Myasthenia gravis with muscle specific kinase antibodies mimicking amyotrophic lateral sclerosis.

Muscle-specific kinase (MuSK) myasthenia gravis (MG) is hallmarked by the predominant involvement of bulbar muscles and muscle atrophy. This might mimic amyotrophic lateral sclerosis (ALS) presenting with bulbar weakness. We encountered four cases of MuSK MG patients with an initial misdiagnosis of ALS. We analyzed the clinical data of the four misdiagnosed MuSK MG patients, and investigated the presence of MuSK autoantibodies in a group of 256 Dutch bulbar-onset ALS patients using a recombinant MuSK ELISA and a standard MuSK radioimmunorecipitation assay. Clues for changing the diagnosis were slow progression, clinical improvement, development of diplopia and absence of signs of upper motor neuron involvement. No cases of MuSK MG were identified among a group of 256 bulbar ALS patients diagnosed according to the revised El Escorial criteria. A misdiagnosis of ALS in patients with MuSK MG is rare. We recommend to carefully consider the diagnosis of MuSK MG in patients presenting with bulbar weakness without clear signs of upper motor neuron dysfunction.