Search

Autoimmune neuropathies are named by eponyms, by descriptive terminology or because of the presence of specific antibodies and are traditionally classified, on the basis of pathology and electrophysiology, as primary demyelinating or axonal. However, autoimmune disorders targeting specific molecules of the nodal region, although not showing pathological evidence of demyelination, can exhibit all the electrophysiological changes considered characteristic of a demyelinating neuropathy and acute neuropathies with antiganglioside antibodies, classified as axonal and due to nodal dysfunction, can present with reversible conduction failure and prompt recovery that appear contradictory with the common view of an axonal neuropathy. These observations bring into question the concepts of demyelinating and axonal nerve conduction changes and the groundwork of the classical dichotomous classification.We propose a classification of autoimmune neuropathies based on the involved domains of the myelinated fibre and, when known, on the antigen. This classification, in our opinion, helps to better systematise autoimmune neuropathies because points to the site and molecular target of the autoimmune attack, reconciles some contrasting pathological and electrophysiological findings, circumvents the apparent paradox that neuropathies labelled as axonal may be promptly reversible and finally avoids taxonomic confusion and possible misdiagnosis.

ObjectiveTo describe the clinical characteristics and outcomes of coronavirus disease 2019 (COVID-19) among patients with myasthenia gravis (MG) and identify factors associated with COVID-19 severity in patients with MG.MethodsThe CO-MY-COVID registry was a multicenter, retrospective, observational cohort study conducted in neuromuscular referral centers and general hospitals of the FILNEMUS (Filière Neuromusculaire) network (between March 1, 2020, and June 8, 2020), including patients with MG with a confirmed or highly suspected diagnosis of COVID-19. COVID-19 was diagnosed based on a PCR test from a nasopharyngeal swab or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serology, thoracic CT scan, or typical symptoms. The main outcome was COVID-19 severity based on location of treatment/management (home, hospitalized in a medical unit, or in an intensive care unit). We collected information on demographic variables, general history, and risk factors for severe COVID-19. Multivariate ordinal regression models were used to identify factors associated with severe COVID-19 outcomes.ResultsAmong 3,558 patients with MG registered in the French database for rare disorders, 34 (0.96%) had COVID-19. The mean age at COVID-19 onset was 55.0 ± 19.9 years (mean MG duration: 8.5 ± 8.5 years). By the end of the study period, 28 patients recovered from COVID-19, 1 remained affected, and 5 died. Only high Myasthenia Gravis Foundation of America (MGFA) class (≥IV) before COVID-19 was associated with severe COVID-19 (p = 0.004); factors that were not associated included sex, MG duration, and medium MGFA classes (≤IIIb). The type of MG treatment had no independent effect on COVID-19 severity.ConclusionsThis registry-based cohort study shows that COVID-19 had a limited effect on most patients, and immunosuppressive medications and corticosteroids used for MG management are not risk factors for poorer outcomes. However, the risk of severe COVID-19 is elevated in patients with high MGFA classes (odds ratio, 102.6 [4.4–2,371.9]). These results are important for establishing evidence-based guidelines for the management of patients with MG during the COVID-19 pandemic.

Monoclonal gammopathy is encountered quite frequently in the general population. This type of hematologic abnormality may be mild, referred to as monoclonal gammopathy of undetermined significance or related to different types of hematologic malignancies. The association of a peripheral neuropathy with monoclonal gammopathy is also fairly common, and hemopathy may be discovered in an investigation of peripheral neuropathy. In such a situation, it is essential to determine the exact nature of the hematologic process in order not to miss a malignant disease and thus initiate the appropriate treatment (in conjunction with hematologists and oncologists). In this respect, nerve biopsy (discussed on a case-by-case basis) is of great value in the management of such patients. We therefore propose to present the objectives and main interests of nerve biopsy in this situation.

International audience; The history of mankind is marked by numerous epidemics, some of which involved diseases of the peripheral nervous system, either infectious or otherwise. We describe here the three main infectious causes of epidemics that affect the peripheral nervous system: leprosy, poliomyelitis and diphtheria. We then discuss the main epidemics of immune-mediated origin.

International audience; Peripheral neuropathies have various causes, both infectious and non-infectious. When we think of “epidemics”, we often refer to an infectious or even post-infectious origin. Nevertheless, the history of mankind is marked by episodes of epidemics of peripheral neuropathies of non-infectious nature, either of nutritional or toxic origin: we present here the main causes of such epidemics.

Introduction. Amyotrophic lateral sclerosis (ALS), usually fatal in a few years, is a neurodegenerative disorder where the diagnostic delay, although variable according to the studies, remains too long. The main objective of this study was to determine the average time to diagnose ALS and the role of each physician, general practitioner (GP), or specialist (neurologist or not) involved in the management of these patients. The secondary objective was to propose some simple schemes to quickly identify an ALS suspicion with the aim to reduce this delay. Patients and Methods. This retrospective study evaluated the diagnostic delay (and other intermediate delays) of 90 ALS patients registered in the ALS Center of Bordeaux (France) in 2013. The main clinical signs encountered (and their order of appearance) were studied. Results. The average diagnostic delay was 17 months, with a median diagnostic delay of 12 months. The average diagnostic delay was 2.7 months between the first symptoms and the first complaint to GP, followed by an additional 6.5 month delay before the patient’s first visit to a neurologist. This period could be shortened, especially if GP performed additional tests quickly (p=0.01), as the time spent consulting various specialists often extends this crucial step. Overall, diagnostic delay accounted for 40% of the total duration of the disease progression. Conclusion. In relation to total survival time, the diagnostic delay of ALS appears to be proportionately very long, sometimes longer than that observed in previous studies (because it also included the total delay to diagnostic or treatment initiation). The rapid execution of useful additional tests by the first medical doctor, often GP (with the help of a neurologist), considerably reduces the diagnostic delay. The central role of GP seems to be crucial in the management of patients with ALS. The main objective is, of course, to initiate appropriate treatment and care as soon as possible. Finally, based on our results, we also provide a short practical diagram to help nonneurologist practitioners to quickly discuss the diagnosis of ALS in case of some specific symptoms (“red flags”).

Guillain-Barré syndrome (GBS) is an acute inflammatory polyradiculoneuropathy described in 1916 by Guillain, Barré, and Strohl. However, many similar cases had been reported earlier under various terms, with less detail and with various explanations about its pathophysiologic origin. Based on the analysis of old articles, we propose an overview of the history of acute inflammatory polyradiculoneuropathy before the official description of GBS.

Although Guillain-Barre syndrome was officially described in 1916, other cases had been reported earlier, such as some cases of Landry's paralysis. This year is the 250th anniversary of the birth of Georges Cuvier (1769–1832), one of the fathers of comparative anatomy and palaeontology: he died at age 63 from an unknown disease. By reading medical reports about his last days and hours, we conclude Cuvier died from a severe form of Guillain-Barre syndrome. Moreover, we think this observation could be the first complete report of acute polyradiculoneuropathy with pharyngeal-cervical-brachial onset.

Olfaction, one of our five main qualitative sensory abilities, is the action of smelling or the capacity to smell. Olfactory impairment can be a sign of a medical problem, from a benign nasal/sinus problem up to a potentially serious brain injury. However, although clinicians (neurologists or not) usually test the olfactory nerves in specific clinical situations (for example, when a neurodegenerative disorder is suspected), they may omit such tests in many other situations. With the recent COVID-19 pandemic, the resurgence of anosmia has reminded us of the importance of testing this sensorineural function. We retrace here the main historical steps and discoveries concerning olfaction and anosmia.

Anti-MAG polyneuropathy (anti-MAG PN) is an immune-mediated peripheral sensorimotor neuropathy characterized by distal demyelination and ataxia. However, this disorder, unlike other immune-mediated neuropathies, is difficult to treat in most cases. We retrospectively collected all anti-MAG PN patients followed in two hospitals for a period of 12 years to determine prognostic factors, especially those that indicated a good response to the various therapeutic strategies used. Forty-seven patients were included in the study; of these, 61% had a classical ‘distal demyelinating pattern’, 34.2% had a ‘CIDP-like pattern’, and the others had an ‘axonal pattern’. The most commonly used treatments were intravenous immunoglobulin (IVIg) as the first-line treatment and rituximab as the second- or third-line treatment. No prognostic factor was identified for IVIg, but electrophysiological parameters at onset were better in patients with a good response to rituximab than in non-responder patients, even though mild or high disability was observed in nearly half the patients at last examination. Even though disability seems to progress in most cases despite the treatments used, our results suggest that an early electrophysiological reduction in sensory nerves could be considered a ‘red flag’ for the prompt initiation of rituximab to try to delay long-term disability.

Scleromyxedema is a chronic, idiopathic disorder associated with monoclonal gammopathy, and characterized by dermal mucin deposition. However, systemic manifestations are frequent, including neuromuscular symptoms. We herein present a 71-year-old man who developed a vacuolar myopathy in a context of a known scleromyxedema, and we compare our observation with the nineteen other cases found in the medical literature. Such an association (especially with suggestive skin abnormalities) has to be known for two reasons. First, this diagnosis might be quite challenging because the myopathy may precede the typical skin changes. Secondly, conversely to other forms of vacuolar myopathy, some of the symptoms may respond (even partially) to immunomodulatory and/or immunosuppressant therapeutics.

Vitamin B12 (B12) has a fundamental role in both central and peripheral nervous system function at all ages. Neurologic manifestations may be the earliest and often the only manifestation of B12 deficiency. Mostly because of the poor sensitivity of methods of determination for B12 levels, peripheral neuropathy remains a classical but underdiagnosed complication of B12 deficiency. So the clinical and electrophysiological characteristics of B12-responsive neuropathy are not well known.A retrospective study of patients with B12-responsive neuropathy was conducted at our hospital on a 3-year period. The criteria for inclusion were: (a) neuropathy confirmed by the electrophysiological study (nerve conduction study); and (b) improvement of at least 1 point of the total Overall Neuropathy Limitations Scale score after vitamin B12 treatment.Nine patients were identified. Serum B12 level was low in only four. Four patients had sensorimotor (predominantly sensory) axonal polyneuropathy while five had only sensory neuronopathy. Six improved in less than 1 month after B12 supplementation.B12-responsive neuropathy is a more heterogeneous group of neuropathy than previously described. B12 deficiency is a cause of peripheral neuropathy and should systematically be ruled out in the clinical setting of idiopathic neuropathy or sensory neuronopathy because of potential reversibility.B12: vitamin B12; CMAP: compound muscle action potentials; DRG: dorsal root ganglia; ENMG: electroneuromyography; MCCT: motor central conduction time; MEP: motor evoked potentials; MMA: methylmalonic acid; MMCoAM: L-methylmalonyl-CoenzymeA mutase; ONLS: overall neuropathy limitations scale; SCV: sensory conduction velocities; SNAP: sensory nerve action potentials; SNN: sensory neuronopathy; SSS: SNAP sum score.

International audience; Background: Charcot-Marie-Tooth diseases (CMT) are due to abnormalities of many genes, the most frequent being linked to PMP22 (Peripheral Myelin Protein 22). In the past, only spontaneous genetic anomalies occurring in mouse mutants such as Trembler (Tr) mice were available; more recently, several rodent models have been generated for exploration of the pathophysiological mechanisms underlying these neuropathies.Methods: Based on the personal experience of our team, we describe here the pathological hallmarks of most of these animal models and compare them to the pathological features observed in some CMT patient nerves (CMT types 1A and E; hereditary neuropathy with liability to pressure palsies, HNPP).Results: We describe clinical data and detailed pathological analysis mainly by electron microscopy of the sciatic nerves of these animal models conducted in our laboratory; lesions of PMP22 deficient animals (KO and mutated PMP22) and PMP22 overexpressed models are described and compared to ultrastructural anomalies of nerve biopsies from CMT patients due to PMP22 gene anomalies. It is of note that while there are some similarities, there are also significant differences between the lesions in animal models and human cases. Such observations highlight the complex roles played by PMP22 in nerve development.Conclusion: It should be borne in mind that we require additional correlations between animal models of hereditary neuropathies and CMT patients to rationalize the development of efficient drugs.

The history of mankind is marked by numerous epidemics, some of which involved diseases of the peripheral nervous system, either infectious or otherwise. We describe here the three main infectious causes of epidemics that affect the peripheral nervous system: leprosy, poliomyelitis and diphtheria. We then discuss the main epidemics of immune-mediated origin.

Ataxia is a frequent symptom in neurological cases with many causes. Sensory ataxia (due to involvement of the proprioceptive pathways) is observed in conditions affecting the central nervous system (spinal cord disorder) and the peripheral nervous system (peripheral neuropathy). The latter correspond to what we refer to as 'ataxic neuropathies'. Ataxic neuropathies represent a wide and heterogeneous spectrum of disorders that may affect dorsal root nerves, dorsal root ganglia, nerve trunks, distal nerve endings or all of them together. The identification of a predominant sensory ataxia in a case of peripheral neuropathy should raise the possibility of some specific etiologies. We propose here to present the main causes of ataxic neuropathies, which are identified with diagnostic workflows that are dictated by the topography of the likely sites of lesions in the proprioceptive pathway together with the timing of their occurrence (acute, subacute, or chronic).

International audience; Background and purpose Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a heterogeneous autoimmune disorder critically lacking diagnostic biomarkers. Autoantibodies to nodal and paranodal components have recently been described in a small subset of patients. Here, the diagnostic value of immune reactivity toward the myelin compartment was investigated. Methods Ninety-four French CIDP patients were retrospectively studied. The reactivity toward the peripheral nerve was investigated. Sural nerve biopsies were examined by electron microscopy and immunofluorescence. Results Twenty-one patients (22%) and three patients (3%) presented with a strong immunoglobulin G or immunoglobulin M reactivity respectively against the myelin compartment. The clinical, electrophysiological and morphological features were examined in nine of these patients for whom sural nerve biopsies were available. Seven patients were electrodiagnosed with definite CIDP, one with possible CIDP and one was unclassifiable but sural nerve biopsy argued for CIDP diagnosis. Electron microscopy of sural nerve biopsies demonstrated the presence of macrophage-mediated demyelination restricted to the internode in all nine patients. Immunolabelling for voltage-gated sodium channels, myelin and axonal markers confirmed the presence of segmental demyelination and of remyelination. The nodal and paranodal regions, however, were unaffected in these patients. Nerve conduction studies corroborated the multifocal and segmental profile, and seven patients showed increased duration of proximal (1.5-5.1 times) and/or distal (1.2-3.4 times) compound muscle action potential in at least two nerves. Conclusion Antibody- and macrophage-mediated demyelination appears responsible for conduction alterations in CIDP patients and nerve immunostaining assays may serve as a supportive diagnostic biomarker.

Vasculitis is characterized by blood vessel inflammation, which may lead to tissue injury. It may be idiopathic (primary vasculitis) or attributable to definable causes (secondary vasculitis). Vasculitic neuropathy is defined as a peripheral neuropathy due to necrotizing vasculitis of the vasa nervorum, leading to various clinical phenotypes, with painful multiple mononeuropathy being the most classical. Although the electrophysiological, clinical, biological, or radiological signs may be indicative, the diagnosis of vasculitic neuropathy needs to be confirmed by nerve biopsy, showing a combination of vascular and inflammatory features. The treatment is based on the guidelines of the underlying disease, but corticosteroids and immunosuppressants are the treatments of choice, except in virus-associated vasculitis.

First reported by Guillain, Barré, and Strohl during the Great War, the concept of “Guillain-Barré syndrome” (GBS) progressively emerged as a clinical entity in its own right. Despite many debates about its clinical and pathophysiologic characteristics, GBS is now recognized as a disease throughout the world. We describe here the main steps of the rich history of GBS, from 1916 to the present.

ObjectiveThe continual discovery of disease-causing gene mutations has led to difficulties in the complex classification of Charcot-Marie-Tooth diseases (CMT) that needs to be revised.MethodsWe recently published a proposal to update the classification of inherited neuropathies. The reactions from colleagues prompted us to diffuse the proposal and ask people if they would be ready for such a change. We therefore performed an internet survey (from October 1, 2016, to December 1, 2016) that included more than 300 CMT worldwide specialists (practitioners and scientists) from various countries. A questionnaire (with proposals to update and simplify the way in which CMT is classified) was sent by e-mail to all participants in the last International Charcot-Marie-Tooth and Related Neuropathy Consortium meeting held in Venice, September 8–10, 2016 (as identified through an e-mail list).ResultsOf the 107 CMT specialists who answered the survey, 65% considered that changes are needed and that our proposals constituted an improvement over the historical classification of CMT.ConclusionsBased on recent proposals in the medical literature, these results highlight that most specialists think that changes are needed to the classification of CMT.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated and treatable disease that may be associated with various systemic conditions. Our objective is to describe the clinical, electrophysiological and pathological data of a series of patients with both CIDP and hemopathy. In this retrospective study, we analyzed 21 patients with CIDP and various hemopathies (malignant or not), consecutively observed for almost five years. In this particular context (with a risk of neurological complications of the hemopathy), a nerve biopsy was taken from each patient (after written consent). All the patients fulfilled the EAN/PNS electrodiagnostic criteria (2021) of CIDP: 16 with ‘CIDP’ and 2 with ‘possible CIDP’ (no data for 3 patients). For each patient, pathological analysis of nerve biopsy was compatible with the diagnosis of CIDP, and there was no evidence for hematological complication of the peripheral nervous system. In cases of peripheral neuropathy and malignant hemopathy, the possibility that the peripheral neuropathy is CIDP should not be overlooked because CIDP is clearly accessible to appropriate therapies, with high potential for a positive clinical response. If the diagnosis of CIDP is usually suspected clinically and electrophysiologically, it should be confirmed by pathological study (nerve biopsy) in certain cases. The management of such patients benefits from the collaboration of neurologists, hematologists and oncologists.

Guillain-Barré syndrome (GBS) is a heterogeneous group of acute immune-mediated neuropathies, including acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). AMAN is an axonal subtype of GBS that has been known since the 1990s; this term was first used to describe a summer epidemic of acute ascending paralysis observed in children in northern China (and Mexico). It is pathologically characterized by noninflammatory axonal degeneration of the motor nerves (with little or no demyelination). The French neurologist Jules Dejerine (1849–1917) conducted a clinical and pathologic description of AMAN in the late 19th century. We describe his observations, which provide us with valuable information on the course of pathologic lesions in this disease.

Introduction Papilledema is a common sign in ophthalmology and is typically associated with increased intracranial pressure (ICP) in neurological diseases. Since the beginning of the 20th century, some cases of papilledema have been reported in association with acute or chronic inflammatory neuropathies. Case report We describe a 42-year-old man with acute-onset inflammatory polyradiculoneuropathy and bilateral papilledema. Conclusions Based on a personal case report and from an extensive review of the medical literature, we identify 2 distinct patterns. First, radiculoneuropathy may be a consequence of intracranial pressure (peripheral nerve involvement corresponding to a "false localizing sign"). Second, papilledema may occur after the onset of inflammatory neuropathy. For such cases, the pathophysiological mechanism remains unknown (eg, reactional inflammatory processes or actions of unknown autoantibodies) and requires further elucidation.

Whatever the cause of myelin damage of the peripheral nervous system, the initial attack on myelin by a dysimmune process may begin either at the internodal area or in the paranodal and nodal regions. The term “nodo-paranodopathy” was first applied to some “axonal Guillain-Barré syndrome” subtypes, then extended to cases classified as chronic inflammatory demyelinating polyradiculoneuropathy bearing IgG4 antibodies against paranodal axoglial proteins. In these cases, paranodal dissection develops in the absence of macrophage-induced demyelination. In contrast, the mechanisms of demyelination of other dysimmune neuropathies induced by macrophages are unexplained, as no antibodies have been identified in such cases. Electron microscopy of longitudinal sections of nerve biopsies is useful to visualize and authenticate the characteristic lesions of paranodes/nodes. However, it should be borne in mind that identical ultrastructural aspects are seen in other types of polyneuropathies: Genetic, experimental, and in a few polyneuropathies for which there is no obvious etiology. Ultrastructural nerve studies confirm the initial involvement of nodes/paranodes in various types of acquired and genetic neuropathies. For some of them, the antibodies or the proteins involved by mutations are clearly identified such as Caspr-1, Contactin-1, NFasc155, and NFasc186; other unidentified proteins are likely to be involved as well.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of the motor pathways, invariably leading to death within a few years of onset. Most cases of ALS are sporadic, but familial forms of the disease (FALS) constitute 10% of the cases. Since the first identification of a causative gene in the 1990s and with recent advances in genetics, more than twenty genes have now been linked to FALS. This increased number of genes led to a tremendous amount of research, clearly contributed to a better understanding of the pathophysiology of this disorder, and paved the way for the development of new therapeutics and new hope for this fatal disease.

With the discovery of TRAPPIST-1 and its seven planets residing within 0.06 au, it is becoming increasingly necessary to carry out correct treatments of tidal interactions. The eccentricity, rotation, and obliquity of the planets of TRAPPIST-1 do indeed result from the tidal evolution over the lifetime of the system. Tidal interactions can also lead to tidal heating in the interior of the planets (as for Io), which may then be responsible for volcanism or surface deformation. In the majority of studies aimed at estimating the rotation of close-in planets or their tidal heating, the planets are considered as homogeneous bodies and their rheology is often taken to be a Maxwell rheology. Here, we investigate the impact of taking into account a multi-layer structure and an Andrade rheology in the way planets dissipate tidal energy as a function of the excitation frequency. We use an internal structure model, which provides the radial profile of structural and rheological quantities (such as density, shear modulus, and viscosity) to compute the tidal response of multi-layered bodies. We then compare the outcome to the dissipation of a homogeneous planet (which only take a uniform value for shear modulus and viscosity). We find that for purely rocky bodies, it is possible to approximate the response of a multi-layer planet by that of a homogeneous planet. However, using average profiles of shear modulus and viscosity to compute the homogeneous planet response leads to an overestimation of the averaged dissipation. We provide fitted values of shear modulus and viscosity that are capable of reproducing the response of various types of rocky planets. However, we find that if the planet has an icy layer, its tidal response can no longer be approximated by a homogeneous body because of the very different properties of the icy layers (in particular, their viscosity), which leads to a second dissipation peak at higher frequencies. We also compute the tidal heating profiles for the outer TRAPPIST-1 planets (e to h).

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a chronic immune-mediated neuropathy: it is clinically heterogeneous (relapsing-remitting form, chronic progressive form, monophasic form or CIDP having a Guillain–Barré syndrome-like onset), but potentially treatable. Although its pathophysiology remains largely unknown, CIDP is considered an immune-mediated neuropathy. Therefore, many immunotherapies have been proposed in this peripheral nervous system disorder, the most known efficient treatments being intravenous immunoglobulin, corticosteroids and plasma exchange. However, these therapies remain unsatisfactory for many patients, so numerous other immunotherapeutic strategies have been evaluated, based on their immunosuppressant or immunomodulatory potency. We have performed a large review of the literature about treatment in CIDP, with a special emphasis on novel and alternative immunotherapeutic strategies.

Peripheral polyneuropathies are common and their diagnosis may be challenging. We compared the results from sural-nerve and skin biopsies in 33 patients with a polyneuropathy and neuropathic pain examined in our hospital over a 6-year period. The biopsies were all from the same lower limb of each patient. Intraepidermal nerve fiber (IENF) densities in the skin were determined by fluorescence microscopy; unmyelinated fiber densities in sural-nerve biopsies (UFNB) were determined by electron microscopy. There was no correlation with age or gender in either biopsy type; there was a weak trend to correlation between UFNB density and IENF density, possibly because of the small sample size. The sensitivity of detection of quantitative abnormalities of unmyelinated fibers was better in the skin than in the nerves. Proximal and distal IENF densities were strongly correlated; and counts of UFNB were highly reproducible. Thus, quantification of unmyelinated fibers in sural-nerve and skin biopsies seem to be complementary. Sural-nerve biopsy may be required to confirm a specific diagnosis, to identify lesion mechanisms, and to devise therapeutic strategies, whereas skin biopsy seems to be more efficient in the follow-up of length-dependent polyneuropathies and in the diagnosis of neuropathic pain.

International audience; Peripheral neuropathy is a common symptom throughout the population, with numerous possible etiologies. The diagnosis of peripheral neuropathies (and their causes) is mainly based on clinical, electrophysiological, biological, and imaging features. Areas covered: This paper reviews the main causes of neuropathy and discusses the usefulness of nerve biopsy (NB) in such cases. Expert commentary: In most cases, NB is not mandatory in the diagnostic work-up of a peripheral neuropathy. However, NB is clearly an indication in cases of vasculitis. It is also valuable in peripheral neuropathies with severe and rapid worsening (without clear cause) in order to uncover a pathological hallmark (amyloid deposits). Although NB is considered an invasive method, it may be useful in the management of peripheral neuropathy, especially to guide treatment in certain cases. In summary, although NB is not a systematic procedure, it is a useful tool that should be discussed on a case-by-case basis within the clinical context.

International audience; Dear Editor, In a recent publication in the Journal of the Neurological Sciences, we highlighted the current difficulties in classifying the various forms of inherited myopathies [1]. These suggestions were based on our initial proposals for Charcot-Marie-Tooth disease (CMT) and other neurogenetic disorders) [2]. Recently, we conducted an internet survey to evaluate the interest of the scientific community: 65% of the people consulted considered that changes are needed and that our proposals constitute an improvement over the historical classification of CMT [3, 4]. There have also been recent attempts to solve such problems in other neurogenetic disorders such as hereditary ataxias [5]. We are aware that any new classification of neuromuscular disorders will need to be discussed in the neurological and genetic communities, but we have proposed simplifying the classification of inherited muscular disorders by using the same three successive steps: clinical phenotype, mode of inheritance, then the name of the causative gene (Fig. 1A) [1]....

Amyotrophic lateral sclerosis (ALS) is a fatal motor disease in adults. Its pathophysiology remains mysterious, but tremendous advances have been made with the discovery of the most frequent mutations of its more common familial form linked to the C9ORF72 gene. Although most cases are still considered sporadic, these genetic mutations have revealed the role of RNA production, processing and transport in ALS, and may be important players in all ALS forms. There are no disease-modifying treatments for adult human neurodegenerative diseases, including ALS. As in spinal muscular atrophy, RNA-targeted therapies have been proposed as potential strategies for treating this neurodegenerative disorder. Successes achieved in various animal models of ALS have proven that RNA therapies are both safe and effective. With careful consideration of the applicability of such therapies in humans, it is possible to anticipate ongoing in vivo research and clinical trial development of RNA therapies for treating ALS.

Peripheral nervous system disorders are common in older people. Most peripheral neuropathies are secondary to metabolic (diabetes) or toxic causes (medications, alcohol), but several other aetiologies are possible, requiring clinical, electrophysiological, biological, and sometimes pathological (nerve biopsy) examinations to make the right diagnosis and instigate effective treatments. However, despite using this strategy, no cause is found in some axonal polyneuropathies, leading to the concept of chronic idiopathic axonal polyneuropathy (CIAP). Amyotrophic lateral sclerosis (ALS) affects the peripheral nervous system, but is also characterized by central nervous system involvement: it is a strictly motor disorder affecting both the first and second motor neurons, usually presenting during the sixth or seventh decade. This rapidly progressive, still incurable neurodegenerative disease leads to death in all cases.

International audience; Background: Charcot-Marie-Tooth (CMT) disease, the most frequent form of inherited neuropathy, is a genetically heterogeneous group of disorders of the peripheral nervous system, but with a quite homogeneous clinical phenotype (progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss and usually decreased tendon reflexes). Our aim was to review the various CMT subtypes identified at the present time.Methods: We have analysed the medical literature and performed a historical retrospective of the main steps from the individualisation of the disease (at the end of the nineteenth century) to the recent knowledge about CMT.Results: To date, >60 genes (expressed in Schwann cells and neurons) have been implicated in CMT and related syndromes. The recent advances in molecular genetic techniques (such as next-generation sequencing) are promising in CMT, but it is still useful to recognise some specific clinical or pathological signs that enable us to validate genetic results. In this review, we discuss the diagnostic approaches and the underlying molecular pathogenesis.Conclusions: We suggest a modification of the current classification and explain why such a change is needed.

A B S T R A C T Purpose: Neuropathies are common in the elderly. The main aim of the study was to determine the most frequent causes of neuropathy in individuals more than 65-years-old, but also to determine their principle electrophysiological characteristics and the potential differences in the etiologies of the neuropathies as a function of age. Methods: We conducted a retrospective study of 785 patients (500 men and 285 women) over 65 years of age (examined in the Department of Clinical Neurophysiology of the CHU Pitie ´ -Salpetriere of Paris for suspicion of neuropathy) over a period of eight years. Results: We observed 27 patients (3.4%) with a hereditary neuropathy; the 758 other patients had an acquired neuropathy of which 278 were idiopathic (35.4%). We found that 93.7% of patients presented axonal neuropathies, against only 6.2% of demyelinating neuropathy, with no significant statistical difference related to age. The first disease causing neuropathy in the elderly was diabetes (18.8%). Other causes were immune disorders (7.9%), toxic causes (7.4%), and inflammatory neuropathies (6%); other causes were < 3.5%. Conclusion: In our large group of patients, idiopathic neuropathies were the most common main cause of neuropathy in the elderly, the second being diabetes. However, idiopathic neuropathies seem to be particularly high in comparison with that observed in younger people. This observation could in part be explained by the aging of the peripheral nervous system (but also probably by a selection bias due to the

Background: Several treatments are available to treat the immune-mediated chronic inflammatory demyelinating polyneuropathy (CIDP). Among these treatments, intravenous immunoglobulins, corticosteroids and plasma exchanges are validated and widely used. A few immunosuppressive drugs have been tried, but they had little efficiency. Methods: We describe three CIDP patients treated by Natalizumab (acting against cellular adhesion and T-cell migration) after a failure of the validated treatments. Results: We observed a long-term improvement in one patient, a dramatic improvement over a significant duration in another patient and stabilization in the last one. Conclusion: This open label study provides evidence for the value of Natalizumab as second-line treatment for individual patients with a high dependency on waning efficacy of first-line therapies. CIDP is characterized by heterogeneity of clinical phenotypes, electrophysiological and pathological features, and various variable courses types of evolution. The different responses to drugs of our patients are consistent with some reported cases and may reflect the spectrum of lesional mechanisms and the molecular dysfunctions in CIDP.

Polyneuropathy associated with IgM monoclonal gammopathy and anti-myelin associated glycoprotein (MAG) antibodies is an immune-mediated demyelinating neuropathy. The pathophysiology of this condition is likely to involve anti-MAG antibody deposition on myelin sheaths of the peripheral nerves and it is supposed to be distinct from chronic inflammatory demyelinating neuropathy (CIDP), another immune-mediated demyelinating peripheral neuropathy. In this series, we have retrospectively reviewed clinical and laboratory findings from 60 patients with polyneuropathy, IgM gammopathy, and anti-MAG antibodies. We found that the clinical picture in these patients is highly variable suggesting a direct link between the monoclonal gammopathy and the neuropathy. Conversely, one-third of patients had a CIDP-like phenotype on electrodiagnostic testing and this was correlated with a low titer of anti-MAG antibodies and the absence of widening of myelin lamellae. Our data suggest that polyneuropathy associated with anti-MAG antibodies is less homogeneous than previously said and that the pathophysiology of the condition is likely to be heterogeneous as well with the self-antigen being MAG in most of the patients but possibly being another component of myelin in the others.

Vitamin B12 (B12) deficiency is known to be associated with various neurological manifestations. Although central manifestations such as dementia or subacute combined degeneration are the most classic, neurological manifestations also include sensory neuropathies. However, B12 deficiency is still rarely integrated as a potential cause of sensory neuronopathy. Moreover, as many medical conditions can falsely normalize serum B12 levels even in the context of a real B12 deficiency, some cases may easily remain underdiagnosed. We report the illustrating case of an anorexic patient with sensory neuronopathy and consistently normal serum B12 levels. After all classical causes of sensory neuronopathy were ruled out, her clinical and electrophysiological conditions first worsened after folate administration, but finally improved dramatically after B12 administration. B12 deficiency should be systematically part of the etiologic workup of sensory neuronopathy, especially in a high risk context such as anorexia nervosa.

Jules Dejerine (1849–1917) was a French neurologist who contributed to the description of numerous neurologic conditions ranging from neurovascular pathology to neuromuscular disorders. A considerable body of his research was devoted to the peripheral nervous system. In this area, the eponymous Dejerine-Sottas syndrome refers to a form of infantile hereditary neuropathy. Dejerine also contributed to the description of many other disorders of the peripheral nervous system and was even a precursor in the study of acquired neuropathies (as well as acute inflammatory neuropathies, before the first description of the Guillain-Barré syndrome) and in the field of radicular pathology. In this centennial year of his death, we emphasize the variety and originality of Dejerine’s opus on diseases of the peripheral nervous system.

There are no validated criteria for the diagnosis of sensory neuronopathy (SNN) yet. In a preliminary monocenter study a set of criteria relying on clinical and electrophysiological data showed good sensitivity and specificity for a diagnosis of probable SNN. The aim of this study was to test these criteria on a French multicenter study. 210 patients with sensory neuropathies from 15 francophone reference centers for neuromuscular diseases were included in the study with an expert diagnosis of non-SNN, SNN or suspected SNN according to the investigations performed in these centers. Diagnosis was obtained independently from the set of criteria to be tested. The expert diagnosis was taken as the reference against which the proposed SNN criteria were tested. The set relied on clinical and electrophysiological data easily obtainable with routine investigations. 9/61 (16.4 %) of non-SNN patients, 23/36 (63.9 %) of suspected SNN, and 102/113 (90.3 %) of SNN patients according to the expert diagnosis were classified as SNN by the criteria. The SNN criteria tested against the expert diagnosis in the SNN and non-SNN groups had 90.3 % (102/113) sensitivity, 85.2 % (52/61) specificity, 91.9 % (102/111) positive predictive value, and 82.5 % (52/63) negative predictive value. Discordance between the expert diagnosis and the SNN criteria occurred in 20 cases. After analysis of these cases, 11 could be reallocated to a correct diagnosis in accordance with the SNN criteria. The proposed criteria may be useful for the diagnosis of probable SNN in patients with sensory neuropathy. They can be reached with simple clinical and paraclinical investigations.

The Sun, the closest and most well studied of stars, is generally used as a standard that other stars are compared to. Models of the Sun are constantly tested with helioseismic data. These data allow us to probe the internal structure and dynamics of the Sun. Among the main sources of the data is the SOHO spacecraft that has been continuously observing the Sun for more than a solar cycle. Current solar models, although good, do not include all the physical processes that are present in the Sun. In this chapter we focus on specific inputs to solar models and discuss generally neglected dynamical physical processes whose inclusion could result in models that are much better representatives of the Sun.

Immune-mediated neuromuscular disorders include pathologies of the peripheral nervous system, neuromuscular junction, and muscles. If overlap syndromes (or the association of almost two autoimmune disorders) are recognized, the simultaneous occurrence of several autoimmune neuromuscular disorders is rare. We describe two patients presenting the simultaneous occurrence of inflammatory neuropathy, myositis, and myasthenia gravis (with positive acetylcholine receptor antibodies). For each patient, we carried out a pathological analysis (nerve and muscle) and an electrophysiological study (and follow-up). To our knowledge, this is the first description of such a triple immune-mediated neuromuscular syndrome. We compared our observations with a few other cases of simultaneous diagnosis of two inflammatory neuromuscular disorders.

This review focuses on recent advances in the diagnostic approaches and the underlying pathophysiological mechanisms of Charcot-Marie-Tooth (CMT) disease. We also discuss the emerging therapies for this hereditary neuropathy.To date, numerous genes are implicated in CMT, and new genes have recently been found to be associated with this neuropathy (INF2, FBLN5, etc.). Some specific or evocative clinical signs of CMT subtypes (proteinuria with INF2 mutations, etc.) have been identified. Characteristic pathological findings, which may suggest gene mutations, are also recognized by nerve biopsy (mainly ultrastructural lesions).CMT disease is the most common inherited neuromuscular disorder, with a fairly homogeneous clinical phenotype (progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, and depressed tendon reflexes). With more than 40 genes implicated, an update of the present and rather confusing classification of CMT is needed. Over the last few years, new mutated genes have been discovered. Although nerve biopsy is not routinely carried out in CMT neuropathies, it may show characteristic features, which can orientate the search for the mutated gene. There are currently no effective medications for CMT, but clinical trials are ongoing or planned.

International audience; Antibodies to Contactin-1 and Neurofascin 155 (Nfasc155) have recently been associated with subsets of patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Contactin-1 and Nfasc155 are cell adhesion molecules that constitute the septate-like junctions observed by electron microscopy in the paranodes of myelinated axons. Antibodies to Contactin-1 have been shown to affect the localization of paranodal proteins both in patient nerve biopsies and in animal models after passive transfer. However, it is unclear whether these antibodies alter the paranodal ultrastructure. We examined by electron microscopy sural nerve biopsies from two patients presenting with anti-Nfasc155 antibodies, and also four patients lacking antibodies, three normal controls, and five patients with other neuropathies. We found that patients with anti-Nfasc155 antibodies presented a selective loss of the septate-like junctions at all paranodes examined. Further, cellular processes penetrated into the expanded spaces between the paranodal myelin loops and the axolemma in these patients. These patients presented with important nerve conduction slowing and demyelination. Also, the reactivity of anti-Nfasc155 antibodies from these patients was abolished in neurofascin-deficient mice, confirming that the antibodies specifically target paranodal proteins. Our data indicate that anti-Nfasc155 destabilizes the paranodal axo-glial junctions and may participate in conduction deterioration.

Background: Monoclonal gammopathy of undeterminated significance is the most common form of plasma cell dyscrasia, usually considered as benign. In rare cases it may have a malignant course, sometimes limited to an organ such as peripheral nerves. Methods: We describe clinical, electrophysiological and pathological findings in a patient presenting a immunoglobulin G (IgG) paraproteinemic polyneuropathy clinically mimicking a chronic inflammatory demyelinating polyneuropathy. Results: Immuno-electron microscopy (immune-EM) demonstrated that the widenings of the myelin lamellae resulted from the infiltration of IgG between a significant number of myelin lamellae (with absence of inflammatory cells in the epineurium, endoneurium, and perineurium, and the lack signs of vasculitis). This patient was finally treated successfully with lenalidomide then mycophenolate mofetil. Conclusions: In polyneuropathies associated to a monoclonal gammopathy, a nerve biopsy may clinch the diagnosis. Immuno-EM may be required to determine the role of the pathological immunoglobulin in the destruction of the peripheral nerve parenchyma. Diagnosis of such a direct involvement of peripheral nerve can endorse more aggressive treatment of real efficiency.