Transthyretin amyloid polyneuropathy in France: A cross-sectional study with 413 patients and real-world tafamidis meglumine use (2009-2019).

OBJECTIVE: We aimed to describe characteristics of patients with ATTR variant polyneuropathy (ATTRv-PN) and ATTRv-mixed and assess the real-world use and safety profile of tafamidis meglumine 20mg. METHODS: Thirty-eight French hospitals were invited. Patient files were reviewed to identify clinical manifestations, diagnostic methods, and treatment compliance. RESULTS: Four hundred and thirteen patients (296 ATTRv-PN, 117 ATTRv-mixed) were analyzed. Patients were predominantly male (68.0%) with a mean age of 57.2±17.2 years. Interval between first symptom(s) and diagnosis was 3.4±4.3 years. First symptoms included sensory complaints (85.9%), dysautonomia (38.5%), motor deficits (26.4%), carpal tunnel syndrome (31.5%), shortness of breath (13.3%), and unexplained weight loss (16.0%). Mini-invasive accessory salivary gland or punch skin and nerve biopsies were most common, with a performance of 78.8-100%. TTR genetic sequencing, performed in all patients, revealed 31 TTR variants. Tafamidis meglumine was initiated in 156/214 (72.9%) ATTRv-PN patients at an early disease stage. Median treatment duration was 6.00 years in ATTRv-PN and 3.42 years in ATTRv-mixed patients. Tafamidis was well tolerated, with 20 adverse events likely related to study drug among the 336 patients. CONCLUSION: In France, ATTRv patients are usually identified early thanks to the national network and the help of diagnosis combining genetic testing and mini-invasive biopsies.

French protocol for the diagnosis and management of hematopoietic stem cell transplantation in autoimmune diseases.

Hematopoietic stem cell transplantation (HSCT) for severe ADs was developed over the past 25years and is now validated by national and international medical societies for severe early systemic sclerosis (SSc) and relapsing-remitting multiple sclerosis (MS) and available as part of routine care in accredited center. HSCT is also recommended, with varying levels of evidence, as an alternative treatment for several ADs, when refractory to conventional therapy, including specific cases of connective tissue diseases or vasculitis, inflammatory neurological diseases, and more rarely severe refractory Crohn's disease. The aim of this document was to provide guidelines for the current indications, procedures and follow-up of HSCT in ADs. Patient safety considerations are central to guidance on patient selection and conditioning, always validated at the national MATHEC multidisciplinary team meeting (MDTM) based on recent (less than 3months) thorough patient evaluation. HSCT procedural aspects and follow-up are then carried out within appropriately experienced and Joint Accreditation Committee of International Society for Cellular Therapy and SFGM-TC accredited centres in close collaboration with the ADs specialist. These French recommendations were performed according to HAS/FAI2R standard operating procedures and coordinated by the Île-de-France MATHEC Reference Centre for Rare Systemic Autoimmune Diseases (CRMR MATHEC) within the Filière FAI2R and in association with the Filière MaRIH. The task force consisted of 3 patients and 64 clinical experts from various specialties and French centres. These data-derived and consensus-derived recommendations will help clinicians to propose HSCT for their severe ADs patients in an evidence-based way. These recommendations also give directions for future clinical research in this area. These recommendations will be updated according to newly emerging data. Of note, other cell therapies that have not yet been approved for clinical practice or are the subject of ongoing clinical research will not be addressed in this document.

Current clinical management of CIDP with immunoglobulins in France: An expert opinion.

Treatment strategies in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) must be adapted on a case-to-case basis. Validated and reproducible tools for monitoring treatment response are required at diagnosis, when initiating treatment and throughout follow-up. A task force of French neurologists, experts in neuromuscular disease reference centers, was assembled to provide expert advice on the management of typical CIDP with intravenous immunoglobulins (Ig), and to harmonize treatment practices in public and private hospitals. The task force also referred to the practical experience of treating CIDP with Ig at the diagnostic, induction and follow-up stages, including the assessment and management of Ig dependence, and following the recommendations of the French health agency.

A new score combining compound muscle action potential (CMAP) amplitudes and motor score is predictive of motor outcome after AVXS-101 (Onasemnogene Abeparvovec) SMA therapy.

Spinal muscular atrophy 1 (SMA1) is a severe early genetic disease with degeneration of motor neurons. Motor development is still suboptimal after gene replacement therapy in symptomatic patients. In this study, compound muscle action potential (CMAP) amplitudes were explored as predictors of motor recovery after gene therapy. Thirteen symptomatic SMA1 patients were prospectively included at the Necker Enfants Malades Hospital, Paris, France (Cohort 1) and 12 at the other pediatric neuromuscular reference centers of the French Filnemus network (Cohort 2). In Cohort 1, median CMAP amplitudes showed the best improvement between baseline and the 12 months visit compared to the other tested nerves (ulnar, fibular and tibial). High median CMAP amplitudes at baseline was associated with unaided sitting achievement at M6 (AUC 90%). None of the patients with CHOPINTEND at M0 < 30/64 and median CMAP < 0.5 mV achieved unaided sitting at M6 and this result was confirmed on Cohort 2 used as an independent validation data. Thus, median CMAP amplitude is a valid biomarker for routine practice to predict sitting at M6. A median CMAP amplitude over 0.5 mV at baseline may predict better motor recovery.

Current treatments of spinal muscular atrophy in adults.

Spinal muscular atrophy (SMA) is a rare autosomal recessive neuromuscular disorder related to motor neuron degeneration. SMA patients present generally severe muscular weakness and atrophy, which can reduce life expectancy and lead to severe functional disability. In recent years, the management of this condition has been revolutionized by the development of innovative therapies that target alternative splicing of pre-messenger SMN2 RNA by antisense oligonucleotides or small molecules and by the approval of the first vector-based SMN1 gene therapy. The high significance of the trials in children led to fast-tracking of these therapies to all SMA patients despite the absence of data in adults. Real-life data are progressively providing a better understanding of the expected benefits and tolerability. They also highlight the difficulties of evaluating these patients and the need to take into account the patients' reported expectations and outcome. A review of the main data in adult patients is presented. The mechanisms of action of these innovative therapies are discussed as well as the limits of evaluations of these therapies in adults with longstanding severe amyotrophy.

[Parsonage-Turner syndrome following severe SARS-CoV-2 infection]. / Syndrome de Parsonage-Turner compliquant une infection sévère à SARS-CoV-2.

INTRODUCTION: Complications following COVID-19 are starting to emerge; neurological disorders are already described in the literature. CASE REPORT: This case is about a 20-year old male with a severe COVID-19, hospitalized in a Reanimation and Intensive Care Unit with an Acute Respiratory Distress Syndrome, thromboembolic complication and secondary bacterial infection. This patient had a non-specific neurological disorder with a pseudobulbar palsy, (MRI, ENMG and lumbar puncture were normal), associated 4 months later with persistent left shoulder motor deficit and respiratory failure. Respiratory and neurological check-up led to a diagnosis of the Parsonage-Turner syndrome or neuralgic amyotrophy affecting C5-C6 nerve roots, the lateral pectoral and phrenic nerves at the origin of the scapular belt, amyotrophy and left diaphragm paralysis. CONCLUSIONS: This case shows that persistant dyspnoea after COVID 19 infection should lead to a search for a diaphragmatic cause which is not always the result of Reanimation Neuropathy but may also indicate a neuralgic amyotrophy. It is the fourth case of neuralgic amyotrophy following COVID-19. This brings the medical community to consider the risk of diaphragm paralysis apart from critical illness polyneuropathy. Respiratory muscle evaluation and diaphragmatic ultrasound should be considered in case of persistent dyspnoea.

[Autologous hematopoietic stem cell transplantation for chronic inflammatory demyelinating polyneuropathy]. / Carrefour des spécialités : autogreffe de cellules souches hématopoïétiques périphériques pour la prise en charge thérapeutique des polyradiculonévrites inflammatoires démyélinisantes chroniques.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a dysimmune neuropathy with sensory and/or motor symptoms due to destruction of the myelin sheat secondary to an auto-immune attack. A quarter to a third of patients do not respond to immunomodulatory first line recommended therapies. No second line treatment has shown its effectiveness with a sufficient level of evidence. Autologous hematopoietic stem cell transplantation (AHSCT) is a promising therapy for autoimmune disease, especially for CIDP in recent works. We present in this article an update on the diagnosis of CIDP, its conventional treatments as well as the results of AHSCT in this indication, which was the subject of French recommendations under the aegis of the SFGMTC and neuromuscular disease french faculty (FILNEMUS) as a third line therapy after failure of two first-line and one second-line treatments.

Clinical Phenotype in an Early-Onset French Pediatric Population: Charcot-Marie-Tooth's Disease Type 2A.

Charcot-Marie-Tooth's disease type 2A (MCT2A), induced by mutation of the mitofusin 2 (MFN2) gene represents the main cause of MCT2. The aim of this study is to provide details of the clinical and electromyographic phenotype of MCT2A in a pediatric population. We conducted a French multicenter retrospective study, including all children with a genetic diagnosis of MCT2A. Thirteen MCT2A children were included with a beginning of symptoms before the age of 10 years ("early-onset group"). We report two new mutations: c.1070 A → T (p.Lys357.Met) and c.280 C → G (p.Arg94Gly). The evolution of the disease is marked by a fast worsening for three patients with loss of motor autonomy, while the evolution is relatively stable for eight patients. The group of early-onset MCT2A seems more heterogeneous than previously described, with a nonconstant severe phenotype.

Ultrasonographic anatomy of the long thoracic nerve: A reappraisal using high frequency (24-MHz) probe.

PURPOSE: The purpose of this study was to analyze the potential of ultrasound with a high frequency probe (24-MHz) in the assessment of the long thoracic nerve (LTN) and describe ultrasonographic landmarks that can be used for standardization. MATERIAL AND METHODS: Ultrasonography analysis of the LTN was done on 2 LTNs in a cadaver specimen and then on 30 LTNs in 15 healthy volunteers (12 men, 3 women; mean age, 28.8±3.8 [SD] years; age range: 24-39 years) by two independent radiologists (R1 and R2) using a 24-MHz probe. Interrater agreement was assessed using Kappa test (K) and intraclass correlation coefficient (ICC). RESULTS: In the cadaver, dissection confirmed that the India ink was injected near the LTN in the middle scalene muscle. In volunteers, visibility of the LTN above the clavicle was highly reproducible for the branches arising from C5 (R1: 87% [26/30]; R2: 90% [27/30]; K=0.83) and from C6 (R1: 100% [30/30]; R2: 97% [29/30]; K=0.94). Where the nerve emerged from the middle scalene muscle, the mean diameter was 0.85±0.24 (SD) mm (range: 0.4-1.6mm) for R1 and 0.9±0.23 (SD) mm (range: 0.4-1.7mm) for R2 (ICC: 0.96; 95% CI: 0.92-0.98%). Along the thoracic wall, where LTN run along the lateral thoracic artery, the mean diameter was 0.83±0.19 (SD) mm (range: 0.5-1.27mm) for R1 and 0.89±0.21 (SD) mm (range: 0.6-1.2mm) for R2 (ICC: 0.86; 95% CI: 0.72-0.93%). CONCLUSION: The LTN can be analyzed with ultrasound using high-frequency probe by using the C5 and C6 roots, the middle scalene muscle above the clavicle and the lateral thoracic artery on the chest wall as landmarks.

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.

Novel CAPN3 variant associated with an autosomal dominant calpainopathy.

AIMS: The most common autosomal recessive limb girdle muscular dystrophy is associated with the CAPN3 gene. The exclusively recessive inheritance of this disorder has been recently challenged by the description of the recurrent variants, c.643_663del21 [p.(Ser215_Gly221del)] and c.598_612del15 [p.(Phe200_Leu204del)], associated with autosomal dominant inheritance. Our objective was to confirm the existence of autosomal dominant calpainopathies. METHODS: Through our activity as one of the reference centres for genetic diagnosis of calpainopathies in France and the resulting collaborations through the French National Network for Rare Neuromuscular Diseases (FILNEMUS), we identified four families harbouring the same CAPN3 heterozygous variant with supposedly autosomal dominant inheritance. RESULTS: We identified a novel dominantly inherited CAPN3 variant, c.1333G>A [p.(Gly445Arg)] in 14 affected patients from four unrelated families. The complementary phenotypic, functional and genetic findings correlate with an autosomal dominant inheritance in these families, emphasizing the existence of this novel transmission mode for calpainopathies. The mild phenotype associated with these autosomal dominant cases widens the phenotypic spectrum of calpainopathies and should therefore be considered in clinical practice. CONCLUSIONS: We confirm the existence of autosomal dominant calpainopathies as an entity beyond the cases related to the in-frame deletions c.643_663del21 and c.598_612del15, with the identification of a novel dominantly inherited and well-documented CAPN3 missense variant, c.1333G>A [p.(Gly445Arg)]. In addition to the consequences for genetic counselling, the confirmation of an autosomal dominant transmission mode for calpainopathies underlines the importance of re-assessing other myopathies for which the inheritance is considered as strictly autosomal recessive.

Implication of the SH3TC2 gene in Charcot-Marie-Tooth disease associated with deafness and/or scoliosis: Illustration with four new pathogenic variants.

The autosomal recessive demyelinating form of Charcot-Marie-Tooth can be due to SH3TC2 gene pathogenic variants (CMT4C, AR-CMTde-SH3TC2). We report on a series of 13 patients with AR-CMTde-SH3TC2 among a French cohort of 350 patients suffering from all type of inheritance peripheral neuropathy. The SH3TC2 gene appeared to be the most frequently mutated gene for demyelinating neuropathy in this series by NGS. Four new pathogenic variants have been identified: two nonsense variants (p.(Tyr970*), p.(Trp1199*)) and two missense variants (p.(Leu1126Pro), p.(Ala1206Asp)). The recurrent variant p.Arg954* was present in 62%, and seems to be a founder mutation. The phenotype is fairly homogeneous, as all these patients, except the youngest ones, presented scoliosis and/or hearing loss.

A Case Report of Myotonic Disease and Gastric Bypass and a Literature Review.

We report the case of a woman with myotonic dystrophy type 1, followed for 8 years after a Roux-en-Y gastric bypass. Weigh loss was substantial (53% of initial body weight) with functional improvement in spite of the natural course of the pathology. Five other cases have been published and have reported a relatively positive benefit/risk ratio. Precautions are to be taken at the time of anesthesia and follow-up in order to detect possible degradation of muscle function.

Cervical laminectomy and micro resection of the posterior venous plexus in Hirayama disease.

INTRODUCTION: Hirayama disease is a rare cervical myelopathy predominantly affecting young adults and mainly found in Asia. It results in a pure motor distal lesion of the upper limbs with slow progression. Dynamic magnetic resonance imaging (MRI), which allows the diagnosis to be made, shows a typical appearance of anterior compression of the cervical spinal cord associated with enlargement of the posterior epidural spaces due to a dilated venous plexus. Surgery is considered when conservative treatment has failed. However, the type of surgery is not well standardized in this compressive myelopathy. METHODS: We report on three patients with Hirayama disease operated using an original method: cervical decompressive laminectomy and coagulation of the posterior epidural plexus without fixation. The clinical, radiological and surgical data of these three patients were analyzed. Each patient underwent postoperative MR imaging. RESULTS: The mean age at diagnosis was 18.6 years (16-20 years) with a history of progressive symptoms lasting 1 to 4 years before treatment. Follow-up was 21 to 66 months after surgery. Neurological and electrophysiological improvement was noted in two patients; the third had stabilized. Postoperative MRI confirmed normalization of flexion imaging on MRI. None of the three patients complained of disabling neck pain. CONCLUSION: Posterior cervical decompression with coagulation of epidural venous plexus is a technique that seems effective in Hirayama disease in young subjects. It effectively treats patients by avoiding permanent cervical fixation.

Benign focal amyotrophy.

Within lower motor neuron diseases, benign focal amyotrophy is a rare syndrome characterized by insidious neurogenic asymmetric atrophy restricted to upper or lower limbs with a good prognosis over time. Described under several terms, the nosology is probably heterogeneous. In juvenile distal upper-limbs forms, specific MRI signs with in particular a compression of the spinal cord by forward displacement of dura, lead to evoke a mechanical process. In other forms, occurring later in the life, affecting proximal part of upper limbs or lower limbs, the physiopathology is still unknown and a focal spinal muscular atrophy is suspected. In this review, we will discuss the clinical, electrophysiological and radiological features of each presentation.

Evaluation of the application of the European guidelines for the diagnosis and clinical care of amyotrophic lateral sclerosis (ALS) patients in six French ALS centres.

BACKGROUND AND PURPOSE: Our objective was to evaluate the extent to which the 2005 recommendations of the European Federation of Neurological Sciences (EFNS) on the multidisciplinary management of amyotrophic lateral sclerosis (ALS) are followed in clinical practice. METHODS: This was a multicentre observational study involving six French ALS referral centres receiving prevalent and incident cases. Recommendations were translated into ad hoc questions referring to key aspects of management, and their application was evaluated by a clinical research assistant who independently examined the medical charts (MCs). When necessary, an independent board-certified neurologist answered the questions based on examination of the MC and interview of the caring neurologist. Questions regarding diagnosis and communication were put to patients in a self-administered questionnaire. RESULTS: In all, 376 patients [176 incident, 200 prevalent cases; median age at diagnosis 62.8 years (interquartile range 55.7-72.3); sex ratio 1.37; 27.3% bulbar onset] were included. All the topics covered in the recommendations were evaluated: diagnostic delay (e.g. mean 13.6 months, associated with age and onset); breaking the news (e.g. criteria for communication quality were satisfactory in more than 90%); multidisciplinary and sustained support (e.g. clinic visits were scheduled every 2-3 months in 90%). Also considered were whether riluzole had been offered, symptom management, genetic testing, ventilation, communication defects, enteral nutrition, palliative and end-of-life care. Characteristics associated with poor compliance with some guidelines (schedule of visits, delayed riluzole initiation) were also identified. CONCLUSION: This is the first evaluation of the application of the EFNS recommendations for the management of ALS in a nationwide sample. The results allow us to highlight areas for improvement.

Neurologic Disorders in Immunocompetent Patients with Autochthonous Acute Hepatitis E.

Neurologic disorders, mainly Guillain-Barré syndrome and Parsonage­Turner syndrome (PTS), have been described in patients with hepatitis E virus (HEV) infection in industrialized and developing countries. We report a wider range of neurologic disorders in nonimmunocompromised patients with acute HEV infection. Data from 15 French immunocompetent patients with acute HEV infection and neurologic disorders were retrospectively recorded from January 2006 through June 2013. The disorders could be divided into 4 main entities: mononeuritis multiplex, PTS, meningoradiculitis, and acute demyelinating neuropathy. HEV infection was treated with ribavirin in 3 patients (for PTS or mononeuritis multiplex). One patient was treated with corticosteroids (for mononeuropathy multiplex), and 5 others received intravenous immunoglobulin (for PTS, meningoradiculitis, Guillain-Barré syndrome, or Miller Fisher syndrome). We conclude that pleiotropic neurologic disorders are seen in HEV-infected immunocompetent patients. Patients with acute neurologic manifestations and aminotransferase abnormalities should be screened for HEV infection.

Motor neuronopathy in Chediak-Higashi syndrome.

Chediak-Higashi syndrome is a rare autosomal recessive disease characterized by partial oculocutaneous albinism, recurrent pyogenic infections and the presence of giant granules in many cells such as leucocytes (hallmark of the disease). Neurological symptoms are rare. We describe two sisters who presented the same phenotype of slowly progressive motor neuronopathy (with Babinski sign in one patient); biopsy of the sural nerve showed an abnormal endoneurial accumulation of lipofuscin granules. We discuss these two observations and compare them with the few case reports of neuropathy in Chediak-Higashi syndrome.

[The role of dynamic electromyography in the follow-up of chronic immune polyneuropathies]. / Intérêt de l'EMG dynamique dans le suivi des polyneuropathies dysimmunes chroniques.

Nerve conduction studies providing insight into demyelinating process are essential for the diagnostic of chronic inflammatory demyelinating polyradiculoneuropathy. For the diagnostic, several sets of electrophysiologic criteria have been established. To assess the response to treatment, nerve conduction studies are often used in trials and in clinical practice. Nevertheless, the useful of these classical electrophysiologic techniques is debated because of their lack of sensibility and specificity. In the last 20 years, several works have showed that dysfunction of channels and pump of the axonal membrane at the site and around the site of the conduction block can precipitate conduction failure and produce weakness. These important features explaining clinical status are not correctly assessed by conventional nerve conduction studies. New nerve conduction examinations in dynamic conditions can explore these hyperexcitability modifications.

[Research in amyotrophic lateral sclerosis: what is new in 2009?]. / La recherche sur la SLA en 2009 : compte rendu du groupe bibliographique de la coordination des centres SLA.

This paper, written by French amyotrophic lateral sclerosis (ALS) center experts, presents an update of recent advances in fundamental, epidemiological and clinical research in ALS based on a review of the literature between September 2008 and November 2009. Among other pathophysiological mechanisms, the role of stress of the endoplasmic reticulum and the importance of energetic metabolic disturbances have been underscored. In the field of genetics, research has been advanced through the identification of mutations of the gene FUsed in Sarcoma/Translated in LipoSarcoma (FUS/TLS) in individuals with familial and sporadic ALS. This gene is involved in the regulation of transcription, splicing and RNA transport, and has functional homology to another ALS gene, TARDBP, which suggests that a common mechanism may underlie motor neuron degeneration. A report showed that mice expressing a mutant form of human TDP-43 develop a progressive and fatal neurodegenerative disease reminiscent of both ALS and frontotemporal lobar degeneration with ubiquitin aggregates (FTLD-U), providing a new animal model that may help to better understand the pathophysiology and test new therapeutics. Beside genetic studies, several epidemiologic studies have investigated the role of environmental factors. A recent study suggests that smoking is a risk factor for developing ALS and it is hypothesized that this could occur through lipid peroxidation via formaldehyde exposure. From a neuroprotective perspective, trials with IGF-1, sodium valproate, coenzyme Q or glatiramer acetate have failed to demonstrate any beneficial effect. A study published in 2008 argued that lithium may have a neuroprotective effect in ALS mice and also in patients. However, two preclinical studies failed to replicate the neuroprotective effect of lithium in ALS mice. Therapeutic trials have been performed or are currently ongoing in Europe and North America. Their results have not yet been published.