Epidemiology of myasthenia gravis in France: A retrospective claims database study (STAMINA).

BACKGROUND: The objectives of this observational study were to report the incidence and prevalence of myasthenia gravis (MG) in France, describe patients' characteristics and treatment patterns, and estimate mortality. METHODS: A historical cohort analysis was performed using the French National Health Data System (SNDS) database between 2008 and 2020. Patients with MG were identified based on ICD-10 codes during hospitalization and/or long-term disease (ALD) status, which leads to a 100% reimbursement for healthcare expenses related to MG. The study population was matched to a control group based on age, sex and region of residence. RESULTS: The overall incidence of MG was estimated at 2.5/100,000 in 2019 and the overall prevalence at 34.2/100,000. The mean age was 58.3 years for incident patients and 58.6 for prevalent patients. Among patients with MG, 57.1% were women. In the first year after identification of MG, acetylcholinesterase inhibitors were the most commonly used treatments (87.0%). Corticosteroids were delivered to 58.3% of patients, intravenous immunoglobulin to 34.4%, and azathioprine to 29.9%. Additionally, 8% of patients underwent thymectomy. The proportions of patients with exacerbations and crises were 59.7% and 13.5% respectively in the first year after MG identification. All-cause mortality was significantly higher in patients with MG compared to matched controls (HR=1.82 (95% CI [1.74;1.90], P<0.0001)). CONCLUSION: In this study, the incidence and prevalence of MG estimated in France were found to be higher than previously reported. Most exacerbations and crises occurred within the first year after MG identification. MG was associated with increased mortality compared to a control population matched on age, gender, and geographical region.

Should we prevent thrombosis related to intravenous immunoglobulin infusions with systematic anticoagulant prophylaxis?

Intravenous immunoglobulins (IVIg) are commonly used for treatment of dysimmune diseases, but they are known to promote thrombotic events. The medical records of patients who received IVIg infusions to treat neuromuscular disorders were retrospectively studied during two periods: the on-demand period (May 2013-January 2015), when patients received anticoagulant prophylaxis based on personal thrombotic risk factors, and the systematic period (May 2015-January 2017), when patients received systematic anticoagulant prophylaxis. Of the 334 total patients included, 19/153 received anticoagulant prophylaxis in the on-demand period, and 181 were treated in the systematic period. In the on-demand period, thrombosis occurred in three patients (1.96%) as one central retinal artery occlusion, one pulmonary embolism, and one brachiocephalic vein thrombosis. In the systematic period, thrombosis occurred in two patients (1.1%), both as pulmonary embolisms. There was no statistical difference in thrombosis incidence between the periods (P=0.66). The only factor associated with thrombosis was splenectomy (20% versus 0.3% in patients without thrombosis, P=0.03). There were no adverse events due to thromboprophylaxis by low-molecular-weight heparin in either period. Systematic thromboprophylaxis did not significantly reduce the incidence of thrombosis versus thromboprophylaxis based on personal thrombotic risk.

Clinical features of spinal muscular atrophy (SMA) type 3 (Kugelberg-Welander disease).

Spinal muscular atrophy type 3 (SMA3), also called Kugelberg-Welander SMA, typically presents with muscle fatigue, slowly progressive weakness and atrophy of lower limbs once they have already acquired independent ambulation. Visceral involvement frequent in type 1 and 2 subtypes is rare in SMA3. Hypotonia, hyperlaxity and absent osteo-tendinous reflexes are typical features. By definition, standing or walking without support is achieved but the vast majority of SMA3 patients lose ambulation with time. Lifespan is normal. In some classifications, an additional subtype is included in the mild end of the spectrum, namely spinal muscular atrophy type 4 (SMA4). In this rare subtype, symptoms begin in adulthood; patients remain ambulatory at least until the fifth decade and have a normal respiratory function. Molecular genetic testing is the gold standard tool for diagnosis of SMA. However, diagnosis in a child affected with SMA3 is often challenging because clinical presentation mimics a muscular dystrophy. Electrodiagnostic studies and muscle biopsy are useful tools for demonstrating the presence of denervation but sometimes may not show meaningful differences to help distinguish between SMA and myopathy. Recent specific therapies show promising results before severe neuronal degeneration and motor dysfunction is installed. Therefore, high suspicion should be maintained and genetic analysis performed early in the diagnostic process when facing patients with symmetric and prominent proximal weakness, especially if they present progressive motor impairment. © 2020 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.

Guidance for the care of neuromuscular patients during the COVID-19 pandemic outbreak from the French Rare Health Care for Neuromuscular Diseases Network.

In France, the epidemic phase of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began in February 2020 and resulted in the implementation of emergency measures and a degradation in the organization of neuromuscular reference centers. In this special context, the French Rare Health Care for Neuromuscular Diseases Network (FILNEMUS) has established guidance in an attempt to homogenize the management of neuromuscular (NM) patients within the French territory. Hospitalization should be reserved for emergencies, the conduct of treatments that cannot be postponed, check-ups for which the diagnostic delay may result in a loss of survival chance, and cardiorespiratory assessments for which the delay could be detrimental to the patient. A national strategy was adopted during a period of 1 to 2months concerning treatments usually administered in hospitalization. NM patients treated with steroid/immunosuppressants for a dysimmune pathology should continue all of their treatments in the absence of any manifestations suggestive of COVID-19. A frequently asked questions (FAQ) sheet has been compiled and updated on the FILNEMUS website. Various support systems for self-rehabilitation and guided exercises have been also provided on the website. In the context of NM diseases, particular attention must be paid to two experimental COVID-19 treatments, hydroxycholoroquine and azithromycin: risk of exacerbation of myasthenia gravis and QT prolongation in patients with pre-existing cardiac involvement. The unfavorable emergency context related to COVID-19 may specially affect the potential for intensive care admission (ICU) for people with NMD. In order to preserve the fairest medical decision, a multidisciplinary working group has listed the neuromuscular diseases with a good prognosis, usually eligible for resuscitation admission in ICU and, for other NM conditions, the positive criteria suggesting a good prognosis. Adaptation of the use of noninvasive ventilation (NIV) make it possible to limit nebulization and continue using NIV in ventilator-dependent patients.

Guillain-Barré syndrome subtypes: A clinical electrophysiological study of 100 patients.

INTRODUCTION: A retrospective analysis was performed to document the clinical and electrophysiological features of Guillain-Barré syndrome (GBS) subtypes using different diagnostic criteria. METHODS: One hundred GBS patients were included. Clinical and laboratory features were analyzed, and patients were classified according to four sets of diagnostic criteria. Electrodiagnostic criteria were also analyzed. RESULTS: A total of 69 patients met Asbury and Cornblath's criteria, 96 met Van der Meché's criteria, 99 met Wakerley's diagnostic classification and 86 met level 1 or 2 of the Brighton criteria. Rates of GBS subtypes were: 69% classic GBS; 8% Miller-Fisher syndrome; 12% paraparetic GBS; 2% pharyngeal-cervical-brachial GBS; and 9% unclassified. Those for electrodiagnostic subtypes were 52% demyelinating and 9% axonal according to Hadden's criteria vs 41% demyelinating and 41% axonal as per Rajabally's criteria. CONCLUSION: In this study of case distribution within the GBS spectrum of a retrospective cohort of French patients, the application of new diagnostic criteria enabled accurate diagnoses and classifications of the different subtypes, and also increased the recognition of axonal GBS.

Muscle MRI of facioscapulohumeral dystrophy (FSHD): A growing demand and a promising approach.

Facioscapulohumeral muscular dystrophy (FSHD), an inherited and progressive muscle disorder, is among the most common hereditary muscle disorders. From a clinical vantage point, FSHD is characterized by weakness of the facial, shoulder (often with scapular winging), arm (including biceps and triceps) and abdominal muscles. Forearm muscles are usually spared and weakness is usually asymmetrical. Over the past few decades, muscle magnetic resonance imaging (MRI) has become established as a reliable and accurate noninvasive tool for the diagnosis and assessment of progression in neuromuscular diseases, showing specific patterns of muscle involvement for a number of myopathies. More recently, MRI has been used to noninvasively identify quantitative biomarkers, allowing evaluation of the natural progression of disease and assessment of therapeutic interventions. In the present review, the intention was to present the most significant MRI developments related to diagnosis and pattern recognition in FSHD and to discuss its capacity to provide outcome measures.

Myofibrillar myopathies: State of the art, present and future challenges.

Myofibrillar myopathies (MFM) have been described in the mid-1990s as a group of diseases sharing common histological features, including an abnormal accumulation of intrasarcoplasmic proteins, the presence of vacuoles and a disorganization of the intermyofibrillar network beginning at the Z-disk. The boundaries of this concept are still uncertain, and whereas six genes (DES, CRYAB, LDB3/ZASP, MYOT, FLNC and BAG3) are now classically considered as responsible for MFM, other entities such as FHL1 myopathy or Hereditary Myopathy with Early Respiratory Failure linked to mutations of titin can now as well be included in this group. The diagnosis of MFM is not always easy; as histological lesions can be focal, and muscle biopsy may be disappointing; this has led to a growing importance of muscle imaging, and the selectivity of muscle involvement has now been described in several disorders. Due to the rarity of these myopathies, if some clinical patterns (such as distal myopathy associated with cardiomyopathy due to desmin mutations) are now well known, surprises remain possible and should lead to systematic testing of the known genes in case of a typical histological presentation. In this paper, we aim at reviewing the data acquired on the six main genes listed above as well as presenting the experience from two French reference centres, Paris and Marseilles.

[Necrotizing myopathies: From genetic to acquired forms]. / Myopathies nécrosantes : des formes héréditaires aux formes acquises.

Necrotizing myopathies (NM) are defined by histological features. Muscle biopsy demonstrates marked muscle necrosis with regeneration, with little or an absence of inflammatory infiltrate. Histological pattern of NM is unspecific and can be encountered in diverse conditions as acquired myopathies and muscular dystrophies. Among acquired forms of NM, necrotizing autoimmune myopathy (NAM) is a recently recognized sub-group of the idiopathic inflammatory myopathies. Classically, patients present with a subacute severe proximal myopathy, associated with a markedly elevated creatine kinase level, usually greater than 10 times the upper limit of normal. Nevertheless, the clinical presentation can be misleading, with chronic course mimicking muscular dystrophy. Different forms of NAM can be distinguished with various underlying inciting conditions, including autoantibodies to the SRP, autoantibodies to the HMG-CoA reductase, association to connective tissue disease or underlying malignancy. Other associated conditions need yet to be identified. To confirm a diagnosis of NAM, other causes of NM should be excluded as toxic myopathies, muscular dystrophies and other inflammatory myopathies with a misleading histological pattern. NAM is a rare condition but is probably underdiagnosed. Both clinicoserologic and pathologic data must be taken into account to improve this diagnosis. We propose guidelines for diagnosis of NAM according to clinical course, to be used in clinical practice.

The French Pompe registry. Baseline characteristics of a cohort of 126 patients with adult Pompe disease.

Pompe disease is a rare autosomal recessive muscle lysosomal glycogenosis, characterised by limb-girdle muscle weakness and frequent respiratory involvement. The French Pompe registry was created in 2004 with the initial aim of studying the natural history of French patients with adult Pompe disease. Since the marketing in 2006 of enzyme replacement therapy (alglucosidase alfa, Myozyme(®)), the French Pompe registry has also been used to prospectively gather the biological and clinical follow-up data of all adult patients currently treated in France. This report describes the main clinical and molecular features, at the time of inclusion in the French registry, of 126 patients followed up in 21 hospital-based neuromuscular or metabolic centres. Sixty-five men and 61 women have been included in the registry. Median age at inclusion was 49 years, and the median age at onset of progressive limb weakness was 35 years. Fifty-five percent of the patients were walking without assistance, 24% were using a stick or a walking frame, and 21% were using a wheelchair. Forty-six percent of the patients needed ventilatory assistance, which was non-invasive in 35% of the cases. When performed, muscle biopsies showed specific features of Pompe disease in less than two-thirds of the cases, confirming the importance of acid alpha-glucosidase enzymatic assessment to establish the diagnosis. Molecular analysis detected the common c.-32-13T>G mutation, in at least one allele, in 90% of patients. The French Pompe registry is so far the largest country-based prospective study of patients with Pompe disease, and further analysis will be performed to study the impact of enzyme replacement therapy on the progression of the disease.

[Clinical and molecular diagnosis of facioscapulohumeral dystrophy type 1 (FSHD1) in 2012]. / Diagnostic clinique et moléculaire de la myopathie facioscapulo-humérale de type 1 (FSHD1) en 2012.

INTRODUCTION: Diagnosis of facioscapulohumeral dystrophy type 1 (FSHD1) is supported by a suggestive clinical presentation and associated with a heterozygous contraction of the D4Z4 repeat array on chromosome 4q35. STATE OF THE ART: The FSHD1 phenotype has a widely variable course with great inter- and intrafamilial heterogeneity. Three clinical forms can be distinguished: the classical phenotype associated with four to seven repeat units (RU) and a variable course, a severe infantile form with one to three RU, and a mild phenotype associated with borderline UR (8 to 10 RU). At the molecular level, for D4Z4 contraction to be pathogenic, it needs to occur on a specific chromosomal background, namely on the 4qA allelic variant of chromosome 4. In most cases, once FSHD is clinically suspected, the diagnosis can be genetically confirmed with a DNA test using Southern Blotting and hybridization to a set of probes. However, diagnosis of FSHD1 remains challenging. Firstly, some patients may present with an atypical phenotype with highly focal or unusual symptoms. Secondly, there are potential pitfalls in the genetic diagnosis of FSHD resulting in false positive or false negative results. In the absence of genetic confirmation, other investigations, mainly EMG and muscle biopsy, are needed to rule out another diagnosis. In cases with no clear diagnosis and a permissive chromosome without contraction, FSHD2 may be suspected. PERSPECTIVES: Molecular combing is a new technique which permits visualization and sizing of the D4Z4 repeat array on its genetic background on stretched single DNA fibers by fluorescence microscopy. This tool will improve genetic diagnosis in FSHD patients. CONCLUSION: Diagnosis of FSHD1 is mainly supported by clinical features. Clinicians need to be aware of unusual presentations of this disease. The wide spectrum of intrafamilial variability and the lack of good correlation between genotype and phenotype present challenges for genetic counseling and prognostication. More studies are needed concerning penetrance and genotype-phenotype correlation.

Recommendations for the management of facioscapulohumeral muscular dystrophy in 2011.

Facioscapulohumeral muscular dystrophy (FSHD) is a neuromuscular disease, characterized by an autosomal dominant mode of inheritance, facial involvement, and selectivity and asymmetry of muscle involvement. In general, FSHD typically presents before age 20 years. Usually, FSHD muscle involvement starts in the face and then progresses to the shoulder girdle, the humeral muscles and the abdominal muscles, and then the anterolateral compartment of the leg. Disease severity is highly variable and progression is very slow. About 20% of FSHD patients become wheelchair-bound. Lifespan is not shortened. The diagnosis of FSHD is based on a genetic test by which a deletion of 3.3kb DNA repeats (named D4Z4 and mapping to the subtelomeric region of chromosome 4q35) is identified. The progressive pattern of FSHD requires that the severity of symptoms as well as their physical, social and psychological impact be evaluated on a regular basis. A yearly assessment is recommended. Multidisciplinary management of FSHD--consisting of a combination of genetic counselling, functional assessment, an assessment by a physical therapist, prescription of symptomatic therapies and prevention of known complications of this disease--is required. Prescription of physical therapy sessions and orthopedic appliances are to be adapted to the patient's deficiencies and contractures.

Immunolabelling and flow cytometry as new tools to explore dysferlinopathies.

Dysferlinopathies are autosomal recessive muscular dystrophies caused by DYSF mutations, which lead to a reduced amount or a complete lack of dysferlin. One step in dysferlinopathies diagnosis consists in Western blot analysis of proteins extracted from muscle biopsy, or blood monocytes. We have taken advantage of dysferlin expression in monocytes to develop a whole blood flow cytometry (WBFC), using antibodies directed against dysferlin. Six patients were submitted to WBFC analysis and immunofluorescence analysis on monocytes. Results obtained are correlated to Western blot from monocytes and muscle biopsies. The possible usefulness of this flow cytometry analysis in routine diagnosis is presented.

[Seronegative myasthenia and myasthenia gravis with anti-MuSK antibody: a retrospective study of 20 cases]. / Myasthénie séronégative et myasthénie avec anticorps anti-MuSK : une série rétrospective de 20 cas.

INTRODUCTION: Despite the fact that anti-muscle specific tyrosine kinase (MuSK) antibodies have been discovered for seven years, only a few studies have, until now, focused on myasthenia without acetylcholine-receptors antibodies (ab) (formerly known as "seronegative myasthenia"), and among them, anti-MuSK-antibody-positive and -negative patients. METHOD: We retrospectively studied 20 patients with "seronegative" myasthenia gravis, eight of them being anti-MuSK-ab positive, the remaining twelve being negative. We searched for clinical, neurophysiological, and therapeutic differences between the two groups (anti-MuSK-ab positive: anti-MuSK+ versus anti-MuSK-ab negative: anti-MuSK-). RESULTS: Anti-MuSK+ patients had more predominantly bulbar involvement and had more severe disease (these patients required referral to intensive care more frequently). There was no difference between the two groups concerning treatment efficiency and tolerance. Most of our patients were treated with acetylcholinesterase-inhibitors, and immunomodulatory or immunosuppressive drugs that could indirectly reflect greater severity. However, there was no difference in treatments for anti-MuSK+ versus anti-MuSK- patients. CONCLUSION: These results both confirm and complete the preexisting data on RACh-negative myasthenia, and especially on myasthenia associated with MuSK antibodies.

Should SDMT substitute for PASAT in MSFC? A 5-year longitudinal study.

BACKGROUND: The multiple sclerosis functional composite (MSFC) includes the Paced Auditory Serial Addition test (PASAT) as a measure of cognition. OBJECTIVES AND METHODS: We compared the MSFC incorporating the Symbol Digit Modalities test (SDMT) (MSFC [sdmt]) to the usually applied MSFC (MSFC [pasat]) in a sample of 46 ptients with relapsing-remitting MS who were followed over a five-year period. Magnetic resonance imaging was performed at baseline. RESULTS: The Expanded Disability Status scale (EDSS) deteriorated significantly over 5 years (P < 0.01), but MSFC scores remained stable. MSFC [sdmt] correlated with EDSS at all time points of evaluation, but MSFC [pasat] correlated with EDSS only at baseline, 1, and 5 years. The 5-year EDSS correlated significantly with baseline MSFC [sdmt] and MSFC [pasat] but did not correlate after adjustment for baseline EDSS. No significant correlation was found at baseline between MSFC and imaging parameters (lesion load, brain parenchymal fraction [BPF], ventricular fraction, mean magnetization transfer ratio of lesions and normal-appearing brain tissue), but baseline BPF correlated significantly with changes of SDMT z score (P = 0.0003), MSFC [pasat] (P = 0.006), and MSFC [sdmt] (P = 0.0002) over 5 years. CONCLUSION: We propose not to substitute PASAT by SDMT in the MSFC but to consider SDMT as a complementary useful approach to evaluate overall MS disease.

[Cognitive disorders in multiple sclerosis]. / Les troubles cognitifs au cours de la sclérose en plaques.

Forty to sixty percent of patients with multiple sclerosis (MS) have cognitive dysfunction. The frequency of cognitive disturbances according to the clinical form is not completely understood and the natural history of these disorders has not been extensively studied. Cognitive deficits can be detected in early stages of the disease. Their frequency increases from clinically isolated syndromes, to relapsing-remitting and secondary progressive MS. Cognitive abnormalities are frequently observed also in primary progressive MS. The most frequently impaired functions are information processing speed, attention and memory. Dementia is uncommon but may disclose the disease. Diffuse cerebral injury, assessed by magnetic resonance imaging, contributes to cognitive dysfunction in MS, probably by interrupting connecting fibers between neuronal networks involved in these cognitive functions. Compensatory mechanisms may occur at early stages but they are limited by extension of brain injury.