Publications by authors named "Marianne de Visser"

188 Publications

Genotype-phenotype correlations in valosin-containing protein disease: a retrospective muticentre study.

J Neurol Neurosurg Psychiatry 2022 Jul 27. Epub 2022 Jul 27.

Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Madrid, Spain.

Background: Valosin-containing protein (VCP) disease, caused by mutations in the gene, results in myopathy, Paget's disease of bone (PBD) and frontotemporal dementia (FTD). Natural history and genotype-phenotype correlation data are limited. This study characterises patients with mutations in gene and investigates genotype-phenotype correlations.

Methods: Descriptive retrospective international study collecting clinical and genetic data of patients with mutations in the gene.

Results: Two hundred and fifty-five patients (70.0% males) were included in the study. Mean age was 56.8±9.6 years and mean age of onset 45.6±9.3 years. Mean diagnostic delay was 7.7±6 years. Symmetric lower limb weakness was reported in 50% at onset progressing to generalised muscle weakness. Other common symptoms were ventilatory insufficiency 40.3%, PDB 28.2%, dysautonomia 21.4% and FTD 14.3%. Fifty-seven genetic variants were identified, 18 of these no previously reported. c.464G>A (p.Arg155His) was the most frequent variant, identified in the 28%. Full time wheelchair users accounted for 19.1% with a median time from disease onset to been wheelchair user of 8.5 years. Variant c.463C>T (p.Arg155Cys) showed an earlier onset (37.8±7.6 year) and a higher frequency of axial and upper limb weakness, scapular winging and cognitive impairment. Forced vital capacity (FVC) below 50% was as risk factor for being full-time wheelchair user, while FVC <70% and being a full-time wheelchair user were associated with death.

Conclusion: This study expands the knowledge on the phenotypic presentation, natural history, genotype-phenotype correlations and risk factors for disease progression of VCP disease and is useful to improve the care provided to patient with this complex disease.
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http://dx.doi.org/10.1136/jnnp-2022-328921DOI Listing
July 2022

Is it really myositis? Mimics and pitfalls.

Best Pract Res Clin Rheumatol 2022 Jun 22:101764. Epub 2022 Jun 22.

Department of Neurology, Amsterdam University Medical Centers, Amsterdam, the Netherlands. Electronic address:

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.
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http://dx.doi.org/10.1016/j.berh.2022.101764DOI Listing
June 2022

Mapping of European activities on the integration of sex and gender factors in neurology and neuroscience.

Eur J Neurol 2022 Jun 8. Epub 2022 Jun 8.

Grenoble Alpes University, Division of Neurology, CHU of Grenoble, Grenoble Institute o Neuroscience, INSERM, Grenoble, France.

Background: Neurological disorders pose a profound unmet medical need for which new solutions are urgently needed. The consideration of both biological (sex) and socio-cultural (gender) differences between men and women is necessary to identify more efficacious, safer and tailored treatments. Approaches for putting sex and gender medicine into practice have gathered momentum across Europe, but it is currently unclear to what extent they have been implemented in the field of neurology and neuroscience.

Methods: We mapped current activities in research, funding and education aimed at integrating sex and gender consideration in neuroscience and neurology in Europe. We examined and analyzed data gathered from (1) literature searches, (2) policy documents and reports by the European Commission and national funding agencies, (3) web-based searches, (4) "Web of Science", and (5) searches of project databases of funding agencies. An informative / non-systematic search was performed for sections on policies and funding, education, basic research, while a systematic literature and database review was conducted forquantitative analysis of research output and funded projects in terms of sex and gender analysis.

Results: Our mapping shows that there is a growing interest and attention towards sex and gender consideration in neurological fields, both from funding agencies and researchers. However, most activities, especially for education, are limited to the individual motivation of researchers and are not organically built within curricula and strategic research priorities.

Discussion: We recommend actions that might help increase the consideration of sex and gender specifically in the field of neuroscience and neurology.
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http://dx.doi.org/10.1111/ene.15439DOI Listing
June 2022

Greater Efficacy of Avalglucosidase vs Alglucosidase Alfa in Adult Pompe Disease? The Jury Is Still Out.

Neurology 2022 May 26. Epub 2022 May 26.

Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

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http://dx.doi.org/10.1212/WNL.0000000000200821DOI Listing
May 2022

Ultrasound and MR muscle imaging in new onset idiopathic inflammatory myopathies at diagnosis and after treatment: a comparative pilot study.

Rheumatology (Oxford) 2022 May 10. Epub 2022 May 10.

Department of Neurology, Amsterdam University Medical Centre,University of Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands.

Objectives: To prospectively compare ultrasound (US) and whole-body Magnetic Resonance Imaging (MRI) for detection of muscle abnormalities compatible with idiopathic inflammatory myopathies (IIM).

Methods: Newly diagnosed IIM patients underwent US (14 muscles) and MRI (36 muscles) at diagnosis and after nine weeks monotherapy with intravenous immunoglobulin. Muscles were compatible with IIM when quantitative US echo-intensity (EI) z-score was ≥1.5, semi-quantitative US Heckmatt score was ≥2, qualitative US was abnormal, or when MRI showed oedema on T2-weighted images. At patient level, findings were classified as abnormal when quantitative US EI z-score was >1.5 (n = 3 muscles), >2.5 (n = 2 muscles) or > 3.5 (n = 1 muscle), or if ≥ 3 muscles showed abnormalities as described above for the other diagnostic methods.

Results: At diagnosis, in 18 patients US of 252 muscles revealed abnormalities in 36 muscles (14%) with quantitative, in 153 (61%) with semi-quantitative and in 168 (67%) with qualitative analysis. MRI showed oedema in 476 out of 623 muscles (76%). Five patients (28%) reached abnormal classification with quantitative US, 16 (89%) with semi-quantitative and qualitative US, and all patients (100%) with MRI. Nine-week follow-up of 12 patients showed no change over time with quantitative US or MRI, and a decrease in abnormalities with semi-quantitative US (p < 0.01), and qualitative US (p < 0.01).

Conclusion: At diagnosis, MRI was more sensitive than US to detect muscle abnormalities compatible with IIM. Semi-quantitative US and qualitative US detected abnormalities in the majority of the patients while evaluating fewer muscles than MRI and showed change over time after nine weeks of treatment.
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http://dx.doi.org/10.1093/rheumatology/keac263DOI Listing
May 2022

Pathophysiological Mechanisms and Treatment of Dermatomyositis and Immune Mediated Necrotizing Myopathies: A Focused Review.

Int J Mol Sci 2022 Apr 13;23(8). Epub 2022 Apr 13.

Department of Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, 1100 DD Amsterdam, The Netherlands.

Idiopathic inflammatory myopathies (IIM), collectively known as myositis, are a composite group of rare autoimmune diseases affecting mostly skeletal muscle, although other organs or tissues may also be involved. The main clinical feature of myositis is subacute, progressive, symmetrical muscle weakness in the proximal arms and legs, whereas subtypes of myositis may also present with extramuscular features, such as skin involvement, arthritis or interstitial lung disease (ILD). Established subgroups of IIM include dermatomyositis (DM), immune-mediated necrotizing myopathy (IMNM), anti-synthetase syndrome (ASyS), overlap myositis (OM) and inclusion body myositis (IBM). Although these subgroups have overlapping clinical features, the widespread variation in the clinical manifestations of IIM suggests different pathophysiological mechanisms. Various components of the immune system are known to be important immunopathogenic pathways in IIM, although the exact pathophysiological mechanisms causing the muscle damage remain unknown. Current treatment, which consists of glucocorticoids and other immunosuppressive or immunomodulating agents, often fails to achieve a sustained beneficial response and is associated with various adverse effects. New therapeutic targets have been identified that may improve outcomes in patients with IIM. A better understanding of the overlapping and diverging pathophysiological mechanisms of the major subgroups of myositis is needed to optimize treatment. The aim of this review is to report on recent advancements regarding DM and IMNM.
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http://dx.doi.org/10.3390/ijms23084301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9030619PMC
April 2022

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

Eur J Neurol 2022 06 23;29(6):1571-1586. Epub 2022 Mar 23.

Neurology Department, Medical Faculty, University Hospital, Bern, Switzerland.

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.
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http://dx.doi.org/10.1111/ene.15267DOI Listing
June 2022

Editorial: Palliative Care in Neurology, Volume II.

Front Neurol 2022 16;13:840110. Epub 2022 Feb 16.

Department of Palliative Medicine, Faculty of Medicine and University Hospital, University of Cologne, Cologne, Germany.

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http://dx.doi.org/10.3389/fneur.2022.840110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8888924PMC
February 2022

Cortical and subcortical changes in resting-state neuronal activity and connectivity in early symptomatic ALS and advanced frontotemporal dementia.

Neuroimage Clin 2022 12;34:102965. Epub 2022 Feb 12.

Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Department of Clinical Neurophysiology, Magnetoencephalography Centre, Amsterdam Neuroscience, Amsterdam, the Netherlands.

The objective of this study was to examine if patterns of resting-state brain activity and functional connectivity in cortical and subcortical regions in patients with early symptomatic amyotrophic lateral sclerosis (ALS) resemble those of behavioural variant frontotemporal dementia (bvFTD). In a cross-sectional design, eyes-closed resting-state magnetoencephalography (MEG) data of 34 ALS patients, 18 bvFTD patients and 18 age- and gender-matched healthy controls (HCs) were projected to source-space using an atlas-based beamformer. Group differences in peak frequency, band-specific oscillatory activity and functional connectivity (corrected amplitude envelope correlation) in 78 cortical regions and 12 subcortical regions were determined. False discovery rate was used to correct for multiple comparisons. BvFTD patients, as compared to ALS and HCs, showed lower relative beta power in parietal, occipital, temporal and nearly all subcortical regions. Compared to HCs, patients with ALS and patients with bvFTD had a higher delta (0.5-4 Hz) and gamma (30-48 Hz) band resting-state functional connectivity in a high number of overlapping regions in the frontal lobe and in limbic and subcortical regions. Higher delta band connectivity was widespread in the bvFTD patients compared to HCs. ALS showed a more widespread higher gamma band functional connectivity compared to bvFTD. In conclusion, MEG in early symptomatic ALS patients shows resting-state functional connectivity changes in frontal, limbic and subcortical regions that overlap considerably with bvFTD. The findings show the potential of MEG to detect brain changes in early symptomatic phases of ALS and contribute to our understanding of the disease spectrum, with ALS and bvFTD at the two extreme ends.
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http://dx.doi.org/10.1016/j.nicl.2022.102965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8867127PMC
February 2022

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

Clin Exp Rheumatol 2022 Feb 16;40(2):274-283. Epub 2022 Feb 16.

Rheumatology, Hospital Universitario San Augustin, Aviles, Spain.

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.
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http://dx.doi.org/10.55563/clinexprheumatol/di1083DOI Listing
February 2022

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.

BMJ Open 2021 12 13;11(12):e053594. Epub 2021 Dec 13.

Department of Neurology and Clinical Neurophysiology, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam Neuroscience, Amsterdam UMC Locatie AMC, Amsterdam, The Netherlands.

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.
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http://dx.doi.org/10.1136/bmjopen-2021-053594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8671992PMC
December 2021

Assessment of disability in idiopathic inflammatory myopathy: a call for linearity.

Rheumatology (Oxford) 2022 Aug;61(8):3420-3426

Department of Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience.

Objectives: To evaluate the clinimetric properties of the Academic Medical Centre Disability Score (ALDS) in patients with idiopathic inflammatory myopathy (IIM).

Methods: We used prospectively collected data of IIM patients who completed a phase-2 study with first-line IVIG monotherapy. The ALDS is a patient-reported questionnaire which contains 25 items relevant for disability in myositis. ALDS and all core set measures (CSMs) for myositis [including HAQ-Disability Index (HAQ-DI)] were evaluated at baseline and 9 weeks follow-up. In addition, the 2016 ACR/EULAR myositis response criteria outcome called Total Improvement Score (TIS) was evaluated at 9 weeks. We examined floor/ceiling effects, reliability and construct validity of the ALDS. To examine known-group validity, ALDS change scores over time were compared with TIS and physician impression of clinical response.

Results: Nineteen patients with IIM [median age 59 years, 12 (63%) female] were enrolled. At baseline, ALDS showed a median score of 65.4 (IQR 58.2-73.5), good Cronbach's alpha (α = 0.84) and a small ceiling effect (11%). Construct validity was confirmed by moderate to strong correlations between ALDS and HAQ-DI [rs = -0.57 (baseline); -0.86 (follow-up)]. ALDS change score correlated with TIS (rs = 0.70), discriminated between responders and non-responders (TIS ≥ 40; P = 0.001), between groups based on physician impression of clinical response (P = 0.03), and detected deterioration.

Conclusion: The ALDS showed promising clinimetric properties and detected relevant changes in disability in patients with myositis. These results warrant further investigations.
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http://dx.doi.org/10.1093/rheumatology/keab906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9348770PMC
August 2022

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

Orphanet J Rare Dis 2021 10 16;16(1):433. Epub 2021 Oct 16.

Department of Neuromuscular Medicine, Hospital for Special Care, New Britain, USA.

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.
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http://dx.doi.org/10.1186/s13023-021-02040-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8520617PMC
October 2021

High-resolution breakpoint junction mapping of proximally extended D4Z4 deletions in FSHD1 reveals evidence for a founder effect.

Hum Mol Genet 2022 03;31(5):748-760

Department of Human Genetics, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands.

Facioscapulohumeral muscular dystrophy (FSHD) is an inherited myopathy clinically characterized by weakness in the facial, shoulder girdle and upper a muscles. FSHD is caused by chromatin relaxation of the D4Z4 macrosatellite repeat, mostly by a repeat contraction, facilitating ectopic expression of DUX4 in skeletal muscle. Genetic diagnosis for FSHD is generally based on the sizing and haplotyping of the D4Z4 repeat on chromosome 4 by Southern blotting (SB), molecular combing or single-molecule optical mapping, which is usually straight forward but can be complicated by atypical rearrangements of the D4Z4 repeat. One of these rearrangements is a D4Z4 proximally extended deletion (DPED) allele, where not only the D4Z4 repeat is partially deleted, but also sequences immediately proximal to the repeat are lost, which can impede accurate diagnosis in all genetic methods. Previously, we identified several DPED alleles in FSHD and estimated the size of the proximal deletions by a complex pulsed-field gel electrophoresis and SB strategy. Here, using the next-generation sequencing, we have defined the breakpoint junctions of these DPED alleles at the base pair resolution in 12 FSHD families and 4 control individuals facilitating a PCR-based diagnosis of these DPED alleles. Our resultsshow that half of the DPED alleles are derivates of an ancient founder allele. For some DPED alleles, we found that genetic elements are deleted such as DUX4c, FRG2, DBE-T and myogenic enhancers necessitating re-evaluation of their role in FSHD pathogenesis.
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http://dx.doi.org/10.1093/hmg/ddab250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8895739PMC
March 2022

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

Front Neurol 2021 28;12:683094. Epub 2021 Jul 28.

Department of Neurology, Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.

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. This study aims to explore the experiences, needs, and preferences of PD patients regarding the content and timing of ACP. 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. 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. 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.
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http://dx.doi.org/10.3389/fneur.2021.683094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8355553PMC
July 2021

New disease modifying therapies for two genetic childhood-onset neurometabolic disorders (metachromatic leucodystrophy and adrenoleucodystrophy).

Neurol Sci 2021 07 1;42(7):2603-2606. Epub 2021 Jul 1.

Department of Neurology, Amsterdam University Medical Centres, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1007/s10072-021-05412-xDOI Listing
July 2021

Efficacy and Safety of Bimagrumab in Sporadic Inclusion Body Myositis: Long-term Extension of RESILIENT.

Neurology 2021 03 17;96(12):e1595-e1607. Epub 2021 Feb 17.

From the Department of Neurology (A.A.A.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Medical Research Council Centre for Neuromuscular Diseases (M.G.H., P.M.M.) and Institute of Neurology, Department of Neuromuscular Diseases & Centre for Rheumatology (P.M.M.), University College London; Department of Rheumatology & Queen Square Centre for Neuromuscular Diseases (P.M.M.), University College London Hospitals NHS Foundation Trust; Department of Rheumatology (P.M.M.), Northwick Park Hospital, London North West University Healthcare NHS Trust, UK; Department of Neurology (U.A.B.), Leiden University Medical Center, Netherlands; National Institute for Health Research Manchester Biomedical Research Centre (H.C.), Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, The University of Manchester, UK; Department of Internal Medicine and Clinical Immunology (O.B.), Pitié-Salpêtrière Hospital, Sorbonne Université, Paris, France; Novartis Healthcare Pvt. Ltd. (K.A.K), Hyderabad, India; Novartis Pharmaceuticals (M.W., D.A.P.), East Hanover, NJ; Novartis Pharma AG (L.B.T., A.A.S-T.), Basel, Switzerland; Department of Neurology (T.E.L.), The Johns Hopkins University School of Medicine, Baltimore, MD; Institute for Immunology & Infectious Diseases (M.N.), Fiona Stanley Hospital, Murdoch University and Notre Dame University, Perth; Department of Neurology (C.L.), Royal North Shore Hospital, New South Wales; Calvary Health Care Bethlehem (K.A.R.), Caulfield South, Australia; Department of Neurology (M.d.V), Amsterdam University Medical Centre, the Netherlands; Department of Medicine (D.P.A.), University of Miami, FL; Department of Neurology (R.J.B., M.M.D.), University of Kansas Medical Center, Kansas City; Department of Neurology (J.A.L.M.), Newcastle upon Tyne Hospitals NHS Foundation Trust, UK; Department of Neurology (J.T.K.), The Ohio State University Wexner Medical Center, Columbus; Neuromuscular Research Center (B.O., N.C.J.), UC Davis School of Medicine, Sacramento, CA; Department of Neurology (P.V.d.B.), University Hospital Saint-Luc, University of Louvain, Brussels; Neuromuscular Reference Centre, Department of Neurology (J.B.), Antwerp University Hospital; Institute Born-Bunge (J.B.), University of Antwerp; Department of Neurology (J.L.d.B.), Ghent University Hospital, Belgium; Department of Neurology (C.K.), Oregon Health & Science University, Portland; Department of Neurology (W.S.D.), Massachusetts General Hospital, Neuromuscular Diagnostic Center and Electromyography Laboratory, Boston; Department of Neurology (M.M.), Fondazione Policlinico Universitario Agostino Gemelli IRCCS; Università Cattolica del Sacro Cuore (M.M.), Rome, Italy; Department of Neurology (S.P.N.), University of Texas Southwestern Medical Center, Dallas; Department of Neurology (H.H.J.), University Hospital and University of Zurich, Switzerland; Department of Neurosciences (E.P.), University of Padova School of Medicine; Fondazione IRCCS Istituto Neurologico Carlo Besta (L.M.), Milan; Unit of Neurology and Neuromuscular Disorders (C.R.), Azienda Ospedaliera Universitaria Policlinico G Martino, University of Messina; Center for Neuromuscular Diseases (M.F.), Unit of Neurology, ASST Spedali Civili and University of Brescia, Italy; Nerve and Muscle Center of Texas (A.I.S.), Houston; Neuromuscular Research Center (K.S.), Phoenix, AZ; Department of Neurology (N.A.G.), ALS & Neuromuscular Center, University of California Irvine, Orange; Department of Neurology (M.M.-Y.), National Center Hospital, National Center of Neurology and Psychiatry, Tokyo; Department of Neurology (S.Y.), Kumamoto University Hospital; Department of Neurology (N.S.), Tohoku University Hospital, Miyagi; Department of Neurology (M.A.), Tohoku University School of Medicine, Sendai; Department of Neurology (M.K.), Nagoya University Hospital, Aichi; Department of Neurology (H.M.), Osaka City General Hospital; Wakayama Medical University Hospital (K.M.); Tokushima University Hospital (H.N.); Department of Neuromuscular Research (I.N.), National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan; RTI Health Solutions (C.D.R., V.S.L.W.), Research Triangle Park, NC; Copenhagen Neuromuscular Center (J.V.), Rigshospitalet, University of Copenhagen, Denmark; and UCB (L.Z.A.), Bulle, Switzerland. H.N. is currently affiliated with the Department of Neurology, Kanazawa Medical University, Ishikawa, Japan. B.O. is currently affiliated with the Department of Neurology, Mayo Clinic, Jacksonville, FL.

Objective: To assess long-term (2 years) effects of bimagrumab in participants with sporadic inclusion body myositis (sIBM).

Methods: Participants (aged 36-85 years) who completed the core study (RESILIENT [Efficacy and Safety of Bimagrumab/BYM338 at 52 Weeks on Physical Function, Muscle Strength, Mobility in sIBM Patients]) were invited to join an extension study. Individuals continued on the same treatment as in the core study (10 mg/kg, 3 mg/kg, 1 mg/kg bimagrumab or matching placebo administered as IV infusions every 4 weeks). The co-primary outcome measures were 6-minute walk distance (6MWD) and safety.

Results: Between November 2015 and February 2017, 211 participants entered double-blind placebo-controlled period of the extension study. Mean change in 6MWD from baseline was highly variable across treatment groups, but indicated progressive deterioration from weeks 24-104 in all treatment groups. Overall, 91.0% (n = 142) of participants in the pooled bimagrumab group and 89.1% (n = 49) in the placebo group had ≥1 treatment-emergent adverse event (AE). Falls were slightly higher in the bimagrumab 3 mg/kg group vs 10 mg/kg, 1 mg/kg, and placebo groups (69.2% [n = 36 of 52] vs 56.6% [n = 30 of 53], 58.8% [n = 30 of 51], and 61.8% [n = 34 of 55], respectively). The most frequently reported AEs in the pooled bimagrumab group were diarrhea 14.7% (n = 23), involuntary muscle contractions 9.6% (n = 15), and rash 5.1% (n = 8). Incidence of serious AEs was comparable between the pooled bimagrumab and the placebo group (18.6% [n = 29] vs 14.5% [n = 8], respectively).

Conclusion: Extended treatment with bimagrumab up to 2 years produced a good safety profile and was well-tolerated, but did not provide clinical benefits in terms of improvement in mobility. The extension study was terminated early due to core study not meeting its primary endpoint.

Clinical Trial Registration: Clinicaltrials.gov identifier NCT02573467.

Classification Of Evidence: This study provides Class IV evidence that for patients with sIBM, long-term treatment with bimagrumab was safe, well-tolerated, and did not provide meaningful functional benefit. The study is rated Class IV because of the open-label design of extension treatment period 2.
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http://dx.doi.org/10.1212/WNL.0000000000011626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032371PMC
March 2021

Screening for cognition in amyotrophic lateral sclerosis: test characteristics of a new screen.

J Neurol 2021 Jul 6;268(7):2533-2540. Epub 2021 Feb 6.

Department of Neurology, Amsterdam UMC, Academic Medical Centre, University of Amsterdam, P.O. Box 22700, Amsterdam, The Netherlands.

Cognitive and behavioural impairment in amyotrophic lateral sclerosis (ALS) negatively influences the quality of life and survival, and, therefore, screening for these impairments is recommended. We developed a cognitive screening tool, the amyotrophic lateral sclerosis-frontotemporal dementia-cognitive screen (ALS-FTD-Cog) and aimed to validate it in patients with ALS. During the current study, the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was published and we, therefore, decided to compare these two cognitive screening methods. The ALS-FTD-Cog was administered to 72 patients with ALS, 21 patients with behavioural variant FTD (bvFTD) and 34 healthy controls. Twenty-nine patients with ALS underwent the ECAS. ROC curve analyses were performed and sensitivity and specificity of the ALS-FTD-Cog and ECAS were calculated, with a neuropsychological examination (NPE) as the gold standard. Cognitive impairment was present in 28% of patients with ALS. ROC curve analyses of the ALS-FTD-Cog and ECAS showed an area under the curve (AUC) of 0.72 (95% CI 0.58-0.86) and 0.95 (95% CI 0.86-1.03), respectively. Compared to a full NPE, sensitivity and specificity of the ALS-FTD-Cog were 65.0% and 63.5% and of the ECAS 83.3% and 91.3%, respectively. The sensitivity and specificity of the ALS-FTD-Cog in patients with bvFTD were 94.4% and 100%, respectively. Test characteristics of the ALS-FTD-Cog were moderate, suggesting restricted practical value, as compared to a comprehensive NPE. The ECAS had an excellent AUC and high sensitivity and specificity, indicating that it is a valid screening instrument for cognitive impairment in ALS.
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http://dx.doi.org/10.1007/s00415-021-10423-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217007PMC
July 2021

Late-onset myopathies: clinical features and diagnosis.

Acta Myol 2020 Dec 1;39(4):235-244. Epub 2020 Dec 1.

Department of Neurology, Amsterdam University Medical Centres, Amsterdam, The Netherlands.

Late-onset myopathies are not well-defined since there is no clear definition of 'late onset'. For practical reasons we decided to use the age of 40 years as a cut-off. There are diseases which only manifest as late onset myopathy (inclusion body myositis, oculopharyngeal muscular dystrophy and axial myopathy). In addition, there are diseases with a wide range of onset including 'late onset' muscle weakness. Well-known and rather frequently occurring examples are Becker muscular dystrophy, limb girdle muscular dystrophy, facioscapulohumeral dystrophy, Pompe disease, myotonic dystrophy type 2, and anoctamin-5-related distal myopathy. The above-mentioned diseases will be discussed in detail including clinical presentation - which can sometimes lead someone astray - and diagnostic tools based on real cases taken from the author's practice. Where appropriate a differential diagnosis is provided. Next generation sequencing (NGS) may speed up the diagnostic process in hereditary myopathies, but still there are diseases, e.g. with expansion repeats, deletions, etc, in which NGS is as yet not very helpful.
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http://dx.doi.org/10.36185/2532-1900-027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783434PMC
December 2020

Evaluation of the 2020 European Academy of Neurology virtual congress: transition from a face-to-face to a virtual meeting.

Eur J Neurol 2021 08 11;28(8):2523-2532. Epub 2021 Jun 11.

Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

Background And Purpose: Due to the COVID-19 pandemic, scientific congresses are increasingly being organized as virtual congresses (VCs). In May 2020, the European Academy of Neurology (EAN) held a VC, free of charge. In the absence of systematic studies on this topic, the aim of this study is to evaluate the attendance and perceived quality of the 2020 EAN VC compared to the 2019 EAN face-to-face congress (FFC).

Methods: An analysis of the demographic data of participants obtained from the online registration was done. A comparison of the two congresses based on a survey with questions on the perception of speakers' performance, quality of networking and other aspects was made.

Results: Of 43,596 registered participants, 20,694 active participants attended the VC. Compared to 2019, the number of participants tripled (6916 in 2019) and the cumulated number of participants attending the sessions was five times higher (169,334 in 2020 vs. 33,024 in 2019). Out of active participants 55% were from outside Europe, 42% were board-certified neurologists (FFC 80%) and 21% were students (FFC 0.6%). The content of the congress was evaluated as 'above expectation' by 56% of the attendees (FFC 41%). Of the respondents who had been exposed to earlier EAN congresses 73% preferred the FFC compared to the VC (17%).

Conclusion: The VC fulfilled the main mission of organizing high quality EAN congresses despite the restrictions of the impersonal format. The geographical distribution of the participants proves the expected higher inclusivity of a VC. The large participation of students and neurologists in training opens new educational potentials for the EAN.
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http://dx.doi.org/10.1111/ene.14702DOI Listing
August 2021

Dysphagia in adult myopathies.

Neuromuscul Disord 2021 01 13;31(1):5-20. Epub 2020 Nov 13.

Department of Neurology, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam Neuroscience, Amsterdam, the Netherlands. Electronic address:

Dysphagia (impaired swallowing) is not a rare problem in various neuromuscular disorders, both in the pediatric and the adult patient population. On many occasions such patients are first presented to other medical specialists or health professionals. Disorders of deglutition are probably underrecognized in patients with a neuromuscular disease as a result of patient's and doctor's delay. This review will focus on dysphagia in adults suffering from a myopathy. Dysphagia in myopathies usually affects the oropharyngeal phases which rely mostly on voluntary muscle activity of the mouth, pharynx and upper esophageal sphincter. Dysphagia is known to contribute to a reduction of quality of life and may also lead to increased morbidity and mortality. The review includes an overview on symptomatology and tools of assessments, and elaborates on dysphagia in specific hereditary and acquired myopathies.
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http://dx.doi.org/10.1016/j.nmd.2020.11.001DOI Listing
January 2021

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

Rheumatology (Oxford) 2021 04;60(4):1784-1792

Department of Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands.

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.
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http://dx.doi.org/10.1093/rheumatology/keaa459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023983PMC
April 2021

Oliver and de Visser's Response to Morrison: Advance Directives/Care Planning: Clear, Simple, and Wrong (DOI: 10.1089/jpm.2020.0272).

J Palliat Med 2021 02 20;24(2):174. Epub 2020 Oct 20.

Amsterdam University Medical Centres, Academic Medical Centre, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1089/jpm.2020.0605DOI Listing
February 2021

Assessing the content validity of patient-reported outcome measures in adult myositis: A report from the OMERACT myositis working group.

Semin Arthritis Rheum 2020 10 17;50(5):943-948. Epub 2020 Jun 17.

Division of Rheumatology, Department of Medicine, Johns Hopkins University, 5200 Eastern Ave, MFL Bldg, Center Tower, Suite 4100, Baltimore 21224, MD, USA. Electronic address:

Objective: To investigate the content validity of several patient-reported outcome measures (PROMs) in patients with idiopathic inflammatory myopathies (IIM).

Methods: Seven individual PROM instruments were selected by the Outcome Measures in Rheumatology (OMERACT) Myositis Working Group relating to the following domains: pain, fatigue, physical function and physical activity. Twenty patients from the Johns Hopkins Myositis Center were selected for one-on-one face-to-face or phone interviews for cognitive interviewing of individual PROMs to assess comprehension and content validity. Additionally, patients were asked if they thought muscle symptoms, an area originally identified in qualitative studies, were encapsulated by the other four domains.

Results: The majority of patients (>70%) felt that each of the instruments was clear, easy to read and understand, and could be used for assessment of its domain. Two-thirds (66%) of patients felt that 'muscle symptoms' were captured by the other domains.

Conclusions: We provided evidence to support adequate content validity for several PROMs. Further research is needed to determine whether 'muscle symptoms' warrant a separate domain.
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http://dx.doi.org/10.1016/j.semarthrit.2020.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646936PMC
October 2020

New genotype-phenotype correlations in a large European cohort of patients with sarcoglycanopathy.

Brain 2020 09;143(9):2696-2708

Center of Translational and Experimental Myology, IRCCS Istituto Giannina Gaslini, Genova, Italy.

Sarcoglycanopathies comprise four subtypes of autosomal recessive limb-girdle muscular dystrophies (LGMDR3, LGMDR4, LGMDR5 and LGMDR6) that are caused, respectively, by mutations in the SGCA, SGCB, SGCG and SGCD genes. In 2016, several clinicians involved in the diagnosis, management and care of patients with LGMDR3-6 created a European Sarcoglycanopathy Consortium. The aim of the present study was to determine the clinical and genetic spectrum of a large cohort of patients with sarcoglycanopathy in Europe. This was an observational retrospective study. A total of 33 neuromuscular centres from 13 different European countries collected data of the genetically confirmed patients with sarcoglycanopathy followed-up at their centres. Demographic, genetic and clinical data were collected for this study. Data from 439 patients from 13 different countries were collected. Forty-three patients were not included in the analysis because of insufficient clinical information available. A total of 159 patients had a confirmed diagnosis of LGMDR3, 73 of LGMDR4, 157 of LGMDR5 and seven of LGMDR6. Patients with LGMDR3 had a later onset and slower progression of the disease. Cardiac involvement was most frequent in LGMDR4. Sixty per cent of LGMDR3 patients carried one of the following mutations, either in a homozygous or heterozygous state: c.229C>T, c.739G>A or c.850C>T. Similarly, the most common mutations in LMGDR5 patients were c.525delT or c.848G>A. In LGMDR4 patients the most frequent mutation was c.341C>T. We identified onset of symptoms before 10 years of age and residual protein expression lower than 30% as independent risk factors for losing ambulation before 18 years of age, in LGMDR3, LGMDR4 and LGMDR5 patients. This study reports clinical, genetic and protein data of a large European cohort of patients with sarcoglycanopathy. Improving our knowledge about these extremely rare autosomal recessive forms of LGMD was helped by a collaborative effort of neuromuscular centres across Europe. Our study provides important data on the genotype-phenotype correlation that is relevant for the design of natural history studies and upcoming interventional trials in sarcoglycanopathies.
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http://dx.doi.org/10.1093/brain/awaa228DOI Listing
September 2020

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

Neurology 2020 09 13;95(11):e1512-e1527. Epub 2020 Aug 13.

From the Basic and Translational Myology Lab (R.N.V.-Q., V.G., A.F.), UMR8251, Université de Paris/CNRS; Centre de Référence des Maladies Neuromusculaires Nord/Est/Ile de France (R.N.V.-Q., B. Eymard, N.B.R., A.F.) and Neuromuscular Morphology Unit (N.B.R., M.F.), Institut de Myologie, Pitié-Salpêtrière Hospital, AP-HP, Paris, France; Department of Paediatric Neurology (M.v.d.H.), Medinzinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Germany; AP-HP (C.M., P.R.), Centre de Génétique Moléculaire et Chromosomique, UF Cardiogénétique et Myogénétique Moléculaire et Cellulaire, GH Pitié-Salpêtrière, Paris; Department of Neurology (V.G.), University Hospital of Montpellier, France; Neuromuscular and Neurogenetic Disorders of Childhood Section (S.D.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD; Unit of Neuromuscular and Neurodegenerative Disorders (E.B.), Bambino Gesu' Children's Research Hospital, Rome, Italy; Departamento de Neurología Pediátrica (C.C.), Clínica Las Condes, Santiago, Chile; Paediatrics Department (D.C.), Hôpital de Hautepierre, Strasbourg, France; Neuromuscular Unit (J.C.), Neuropaediatrics Department, Institut de Recerca Hospital Universitari Sant Joan de Deu, Barcelona; Center for the Biomedical Research on Rare Diseases (CIBERER) (J.C.), ISCIII; Department of Neurology (M.L.C.), Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos; Department of Medicine (M.L.C.), Universidad Complutense de Madrid, Spain; Department of Neurology (M.d.V.), Amsterdam University Medical Centre, Amsterdam Neuroscience, the Netherlands; Department of Pediatric Neurology (I.D.), Necker Enfants Malades Hospital, Paris Descartes University, France; Department of Child Neurology (N.G.), University Hospitals Leuven, Belgium; Department of Pediatric Neurology (A.K.), Center for Chronically Sick Children, Institute of Cell Biology and Neurobiology, Charité-Universitätsmedizin Berlin, Germany; Department of Neuropediatrics (E.L.), CHRU de Tours, Université François Rabelais de Tours, UMR INSERM U1253, Tours, France; Department of Neuropediatrics (J.L.), University Children's Hospital of Basel (UKBB), Switzerland; Centre de Référence des Maladies Neuromusculaires Nord/Est/Ile de France (E.M.), Neurology Department, Raymond-Poincaré Hospital, AP-HP, Garches; Centre de Référence des Maladies Neuromusculaires Nord/Est/Ile de France (M.M.), Service de Neuropédiatrie, Hôpital Trousseau, Paris, France; Department of Biomedical and Neuromotor Sciences (L.M.), University of Bologna, Italy; Réanimation Médicale, Physiologie-Explorations Fonctionnelles et Centre d'Investigation Clinique, UMR 1429 (D.O.), INSERM-UMR, 1179, UVSQ (D.O.), and Neuromuscular Unit, Department of Pediatric Neurology, Intensive Care and Rehabilitation, AP-HP, UVSQ Paris Saclay (B. Estournet, S.Q.-R.), Hôpital Raymond Poincaré, Garches, France; Department of Neurology (U.R.), Medizinische Fakultät Carl Gustav Carus Technische Universität Dresden, German; Division of Pediatric Neurology, Department of Pediatrics (M.A.S.), College of Medicine, King Saud University, Riyadh, Saudi Arabia; Friedrich-Baur-Institut (B.S.-W.), Department of Neurology, Ludwig-Maximilians-University of Munich; Department of Pediatric Neurology (M.S.), University of Tübingen, Germany; The John Walton Muscular Dystrophy Research Centre (V.S.), Institute of Genetic Medicine, Newcastle University, Newcastle Hospitals NHS Foundation Trust, UK; Department of Child Neurology (H.T.), Hacettepe University, School of Medicine, Ankara, Turkey; Centre de Compétence Neuromusculaire (J.A.U.), Hôpital Marin, Hendaye, France; Department of Neurology (A.v.d.K.), Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, the Netherlands; Pediatrics and Adolescent Medicine, Division of Pediatric Neurology (E.W.), University Medical Center Göttingen, Georg-August University Göttingen, Germany; Neuromuscular and Neurogenetic Disorders of Childhood Section (C.G.B.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD; and Department of Pediatric Neurology (U.S.), Developmental Neurology and Social Pediatrics, University of Essen, Germany.

Objective: To clarify the prevalence, long-term natural history, and severity determinants of -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 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 ( = 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, 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.
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http://dx.doi.org/10.1212/WNL.0000000000010327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713742PMC
September 2020

A call from the European Academy of Neurology on COVID-19.

Lancet Neurol 2020 06 26;19(6):482. Epub 2020 May 26.

Department of Neurology, University of Bern, Inselspital, Bern, Switzerland. Electronic address:

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http://dx.doi.org/10.1016/S1474-4422(20)30151-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250552PMC
June 2020

Editorial: Palliative Care in Neurology.

Front Neurol 2019 9;10:1370. Epub 2020 Jan 9.

Department of Palliative Medicine, Faculty of Medicine and University Hospital, University of Cologne, Köln, Germany.

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http://dx.doi.org/10.3389/fneur.2019.01370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970193PMC
January 2020
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