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Background: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disease of the peripheral nervous system that can lead to severe disability from muscle weakness and sensory disturbances. Around a third of patients do not respond to currently available treatments, and many patients with a partial response have residual neurological impairment, highlighting the need for effective alternatives. Efgartigimod alfa, a human IgG1 antibody Fc fragment, has demonstrated efficacy and safety in patients with generalised myasthenia gravis. We evaluated the safety, tolerability, and efficacy of subcutaneous efgartigimod PH20 in adults with CIDP., Methods: ADHERE, a multistage, double-blind, placebo-controlled trial, enrolled participants with CIDP from 146 clinical sites from Asia-Pacific, Europe, and North America. Participants with evidence of clinically meaningful deterioration entered an open-label phase of weekly 1000 mg subcutaneous efgartigimod PH20 for no longer than 12 weeks (stage A). Those with confirmed evidence of clinical improvement (ECI; treatment responders) entered a randomised-withdrawal phase of 1000 mg subcutaneous efgartigimod PH20 weekly treatment versus placebo for a maximum of 48 weeks (stage B). Participants were randomised (1:1) through interactive response technology and stratified by their adjusted Inflammatory Neuropathy Cause and Treatment (aINCAT) score change during stage A and their most recent CIDP medication within 6 months before screening. Investigators, the clinical research organisation, and participants were masked to the treatment. The primary endpoint in stage A, evaluated in the stage A safety population, was confirmed ECI (≥1 points aINCAT decrease, ≥4 points [centile metric] Inflammatory Rasch-built Overall Disability Scale increase, or ≥8 kPa grip strength increase after four injections and two consecutive visits). The primary endpoint in stage B, evaluated in the modified intention-to-treat population, was the risk of relapse (time to first aINCAT increase of ≥1 points). ADHERE is registered with ClinicalTrials.gov (NCT04281472) and EudraCT (2019-003076-39) and is completed., Findings: Between April 15, 2020, and May 11, 2023, 629 participants were screened; 322 (114 female, 208 male) entered stage A, of whom 214 (66%, 95% CI 61·0-71·6) had confirmed ECI. In stage B, 221 participants were randomised (79 female, 142 male; 111 to subcutaneous efgartigimod PH20, 110 to placebo). Subcutaneous efgartigimod PH20 significantly reduced the risk of relapse versus placebo (hazard ratio 0·39 [95% CI 0·25-0·61]; p<0·0001). 31 (27·9% [19·6-36·3]) participants given subcutaneous efgartigimod PH20 had a relapse versus 59 (53·6% [44·3-63·0]) given placebo. In stage A, treatment-emergent adverse events (TEAEs) occurred in 204 (63%) participants and serious TEAEs in 21 (7%). In stage B, TEAEs occurred in 71 (64%) participants on subcutaneous efgartigimod PH20 and 62 (56%) participants on placebo, and serious TEAEs in six (5%) on subcutaneous efgartigimod PH20 and six (5%) on placebo. Three deaths occurred: two in stage A (one non-related and one unlikely related to treatment) and one in stage B (placebo group)., Interpretation: ADHERE showed the efficacy of subcutaneous efgartigimod PH20 in reducing the risk of relapse versus placebo in people with CIDP who responded to treatment. Further studies are needed to provide data on the longer-term effects of efgartigimod alfa and how it compares with currently available treatment options., Funding: argenx., Competing Interests: Declaration of interests JAA reports consulting fees from Akcea Therapeutics, Alexion, Alnylam, Annexon Biosciences, argenx, CSL Behring, Grifols, Immunovant, ImmuPharma, Johnson & Johnson, and Takeda, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Alnylam, Annexon Biosciences, argenx, CSL Behring, and Takeda. TD reports participation on a data safety monitoring board or advisory board for Dianthus Therapeutics. CE reports grants or contracts from argenx; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from argenx; support for attending meetings and travel from argenx; and stock or stock options from argenx. AT was an employee of argenx, and reports stock or stock options at the time of the study completion. JTG is an employee of argenx; reports support for attending meetings and travel from argenx; and reports stock or stock options from argenx. BVH is an employee of argenx. PU is an employee of argenx; reports patents planned, issued, or pending from argenx; reports stock or stock options from argenx; and reports other financial or non-financial interests from argenx. EH is an employee of argenx; reports patents planned, issued, or pending from argenx; and reports stock or stock options from argenx. KGG reports consulting fees from Alexion, and UCB; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Alexion, argenx, and Xeris Pharmaceuticals; and leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid for Myasthenia Gravis Foundation of America. FL reports grants or contracts from German Ministry of Education and Research, German Research Society DFG, HORIZON MSCA 2022 Doctoral Network, and Stiftung Pathobiochemie of the German Society for Laboratory Medicine; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bayer, Biogen, Fresenius, Grifols, Novartis, Roche, and Teva Pharmaceuticals; support for attending meetings and travel from Bayer, Grifols, and Merck; and participation on a data safety monitoring board or advisory board for argenx, Alexion, Biogen, and Roche. MLi reports grants or contracts from Kedrion Biopharma; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from CSL Behring, Kedrion Biopharma, and Takeda; support for attending meetings and travel from CSL Behring, Kedrion Biopharma, and Takeda; and other financial or non-financial interests from argenx. MLo was an employee of argenx at the time of the study completion. LQ reports grants or contracts from argenx, CIBERER, Instituto de Salud Carlos III–Ministry of Economy and Innovation (Spain), and UCB; consulting fees from Annexon Biosciences, Alnylam, argenx, Avilar Therapeutics, CSL Behring, Dianthus Therapeutics, Janssen, LFB, Novartis, Nuvig Therapeutics, Roche, Sanofi, and Takeda; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Alnylam, argenx, CSL Behring, Novartis, Roche, and Sanofi; support for attending meetings and travel from Alnylam and Sanofi; participation on a data safety monitoring board or advisory board for argenx, CSL Behring, Sanofi, and UCB; and a leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, for Inflammatory Neuropathy Consortium and Peripheral Nerve Society. NS reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Alnylam, and participation on a data safety monitoring board or advisory board for Takeda. RY reports consulting fees from Japan Tobacco and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Alnylam Japan, CSL Behring, FP Pharm, Kyowa Kirin, Ono Pharmaceutical, and Takeda Pharmaceutical. RAL reports royalties or licenses from UpToDate; consulting fees from Annexon Biosciences, argenx, CSL Behring, Dianthus Therapeutics, Grifols, Immunovant, Janssen, Nuvig Therapeutics, Sanofi, and Takeda; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from argenx, CSL Behring, Medscape, and Sanofi; participation on a data safety monitoring board or advisory board for Boehringer Ingelheim and Novartis; and leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, for Peripheral Nerve Society and GBS-CIDP Foundation International. PAvD reports support for attending meetings and travel from argenx and participation on a data safety monitoring board or advisory board for argenx. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Motor neuron disorders comprise a clinically and pathologically heterogeneous group of neurologic diseases characterized by progressive degeneration of motor neurons (including both sporadic and hereditary diseases), affecting the upper motor neurons, lower motor neurons, or both. Hereditary motor neuron disorders themselves represent a vast and heterogeneous group, with numerous clinical and genetic overlaps that can be a source of error. This narrative review aims at providing an overview of the main types of inherited motor neuron disorders by recounting the stages in their historical descriptions. For practical purposes, this review of the literature sets out their various clinical characteristics and updates the list of all the genes involved in the various forms of inherited motor neuron disorders, including spinal muscular atrophy, familial amyotrophic lateral sclerosis, hereditary spastic paraplegia, distal hereditary motor neuropathies/neuronopathies, Kennedy's disease, riboflavin transporter deficiencies, VCPopathy and the neurogenic scapuloperoneal syndrome., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The tongue is an essential organ for the development of certain crucial functions such as swallowing and speech. The examination of the tongue can be very useful in neurology, as the various types of lingual alterations can lead to certain specific diagnoses, the tongue being a kind of 'mirror' of some neurological function., Review Summary: To discuss the elements of clinical examination of the tongue in relation to neurological disorders. After reviewing the different superficial lesions of the tongue, we deal with various movement disorders of the tongue (fasciculations/myokimia, orolingual tremor, choreic movements of the tongue, dystonia of the tongue, lingual myoclonus, and psychogenic movements), disorders of taste and lingual sensitivity and lingual pain., Conclusions: Examination of the tongue should not be limited to studying its motility and trophicity. It is equally important to check the sensory function and understand how to interpret abnormal movements involving the tongue. This study also aimed to demonstrate the importance of nonmotor tongue function in neurological practice., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The tongue is an essential organ for the development of certain crucial functions, such as swallowing and language. The examination of the tongue can be very useful in neurology, as the various types of lingual alterations can lead to certain specific diagnoses, the tongue being a kind of "mirror" of some neurological function., Review Summary: In this study, we reviewed the literature on anatomy, physiology, and the various aspects of the examination of the tongue., Conclusions: Examination of the tongue should be an integral part of the clinical examination of the cranial nerves. This study aimed to demonstrate the importance of tongue motor and non-motor functions in neurological practice., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Noninvasive ventilation (NIV) improves survival and quality of life in amyotrophic lateral sclerosis (ALS) patients. NIV initiation is mostly conducted at hospital, but a recurrent lack of hospital beds led to the necessity of exploring an at-home initiation process. Here, we report data from our NIV initiation cohort of ALS patients. Could our at-home NIV initiation process with telemonitoring in ALS patients be an efficient solution for adherence and nocturnal hypoxaemia correction?, Methods: We performed a retrospective analysis of data collected from 265 ALS patients treated at the Bordeaux ALS Centre for whom NIV initiation was carried out between September 2017 and June 2021, with two modalities: at-home initiation or in-hospital initiation. The primary outcome was adherence to NIV at 30 days. The secondary outcome was at-home NIV initiation process efficiency of nocturnal hypoxaemia correction., Results: At 30 days, NIV adherence (mean >4 h·day -1 ) was 66% of the total population, 70% of the at-home NIV initiation subgroup and 52% of the in-hospital NIV initiation subgroup. Nocturnal hypoxaemia correction was observed in 79% of adherent patients in the at-home NIV initiation subgroup. Mean delay of NIV prescription and at-home NIV initiation was 8.7 days (+/-6.5) versus 29.5 days in hospital., Conclusion: Our study shows that our at-home NIV initiation process in ALS patients is a good option to provide rapid access to NIV with good adherence and efficiency. Further literature on the benefits of at-home NIV initiation is welcomed, especially to evaluate long-term efficiency and global cost analysis., Competing Interests: Conflict of interest: T. Réginault reports support for the present manuscript from the Bordeaux University Foundation; and travel support from Vivisol and personal fees from Zéphyr Paramed, outside the submitted work. B. Bouteleux reports personal fees from Zéphyr Paramed outside the submitted work. P. Wibart reports support for the present manuscript from the Bordeaux University Foundation, and personal fees from Zéphyr Paramed outside the submitted work. L. Grassion received grants or contracts from AADAIRC, outside the submitted work; payment of honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from SOS Oxygene, ASTEN Santé, and ALMS, outside the submitted work; support for attending meetings and/or travel from SOS Oxygen, VIVISOL and ASTEN Santé, outside the submitted work; and participation on a data safety monitoring board or advisory board for VIVISOL, outside the submitted work. All other authors have nothing to disclose., (Copyright ©The authors 2023.)

Introduction: To describe the efficacy of subcutaneous immunoglobulin (SCIg) in patients with myasthenia gravis (MG)., Methods: This was a retrospective study conducted in the neuromuscular referral center of Bordeaux (between January 1, 2014 and March 31, 2021) with MG patients treated with SCIg. The main outcome was SCIg efficacy assessed by the before and after SCIg Myasthenia Gravis Foundation of America (MGFA) clinical classification, the duration of hospitalization and the number of days of orotracheal intubation (OTI)., Results: Sixteen patients were included in the study (11 females; 5 males). Nine patients were still treated with SCIg at the end of the study (March 31, 2021) and then underwent prospective follow-up. The average age of the patients was 56.1 (19-83) years. The median duration of MG at onset of SCIg was 37.4 months. Eight patients (50%) remained stable (4 in stage MGFA-IV and 4 in MGFA-III). Eight patients (50%) improved: 3 from MGFA-IV to MGFA-III, 1 from MGFA-IV to MGFA-II, 1 from MGFA-IV to MGFA-I, 2 from MGFA-III to MGFA-II and 1 from MGFA-III to MGFA-I (no patient worsened). The duration of disease progression did not appear to affect the response to SCIg therapy. The number of hospital days per month was significantly reduced after SCIg compared to before, and the number of days in intensive care unit and the number of days of OTI were also reduced. Only minor adverse effects were noted, and 80% of patients were in favor of continuing SCIg., Conclusions: SCIg is a well-tolerated and useful treatment in MG, offering interesting perspectives in the management of MG patients. However, further large-scale prospective studies are needed to confirm these results., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Animal envenomation in humans is usually accidental or for defensive purposes. Depending on the venom composition and administration, different reactions can be observed. After reporting the first case of acute polyradiculitis in a 57-year-old healthy male after red lionfish envenomation, we propose to analyze rare similar cases of acute neuritis after animal envenomation published in the medical literature. Including our case, we found 54 patients who developed acute peripheral neuropathy after having been stung or bitten by various animals, mainly hymenoptera (in half of the cases) but also jellyfishes, snakes, corals or nonhooked arthropods. We observed two distinct patterns of peripheral neuropathy: more than half of them were polyneuropathy while the others were focal neuropathy. The prognosis was favorable in most cases. The pathophysiological mechanism associated with these rare complications remain unknown, although some hypotheses may be proposed. A direct action of certain components of the venom, such as phospholipase-A2, could explain the focal forms of peripheral neuropathy trough toxic reactions and/or vasculitis processes. The more diffuse clinical situations could be due to an allergy-triggered immune-mediated reaction (possibly linked to a molecular mimicry mechanism between venom proteins and some myelin proteins of the peripheral nervous system), or to the action of some venom components on membrane ionic channels particularly at the node of Ranvier. Even if acute peripheral neuropathies are rare after envenomation, they may occur after envenomation from various animals, and their usually favorable prognoses should be known by neurologists., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: Lambert-Eaton myasthenic syndrome (LEMS) is characterized by autoantibodies against voltage-gated calcium channels (VGCC) at the neuromuscular junction causing proximal muscle weakness, decreased tendon reflexes, and autonomic changes. The European LEMS registry aimed to collate observational safety data for 3,4-diaminopyridine phosphate (3,4-DAPP) and examine long-term outcomes for patients with LEMS., Methods: Thirty centers across four countries participated in the non-interventional European LEMS registry. Any patients diagnosed with LEMS by means of clinical assessment and abnormal neurophysiological testing, or clinical assessment and positive for VGCC antibodies were eligible to participate. Patients were monitored using standard assessments for LEMS-related clinical manifestations., Results: Among 96 evaluable participants, 50 (52.1%) were being treated with 3,4-DAPP, 21 (21.9%) with 3,4-diaminopyridine (3,4-DAP), and 25 (26.0%) with other treatments (e.g., pyridostigmine, corticosteroids, immunoglobulins, and azathioprine); 74 participants (77.1%) were exposed to 3,4-DAPP at any time. Quantitative myasthenia gravis scores were similar across treatment groups. Muscle strength was generally good and maintained during follow-up. Cerebellar ataxia, defined as a negative Romberg's test and at least one other positive ataxia test, was observed in 30 (56.6%) patients. Most participants had reduced reflex tone and limited functioning. Sustained or improved functioning was observed in participants administered 3,4-DAPP. Inconsistent and sporadic functional improvement and regression was observed with 3,4-DAP and other treatments. Fifty-five treatment-related adverse events (AEs) were reported by 32 (33.3%) participants. Eight (8.3%) participants reported nine treatment-related serious AEs. No new safety signals were identified., Conclusion: No new safety signals were observed following long-term management of LEMS with 3,4-DAPP., (© 2022. The Author(s).)

Background: Livedoid vasculopathy (LV) is a chronic dermatosis associated with micro-thrombosis of the vessels of the dermis, leading to ischemic lesions and painful skin ulcerations of the lower limbs. This thrombosing occlusive vasculopathy, clearly distinct from 'classical vasculitis' (not related to alteration of vessel walls), may lead to peripheral neuropathy., Objective: To clarify the main clinical, electrophysiological and pathological characteristics of peripheral neuropathy linked to LV., Method: We presented a series of personal cases of peripheral neuropathy due to LV. We also conducted a review of the literature (since the first description of LV in 1974) using multiple combinations of keywords from 'PubMed', 'Google Scholar' and 'ScienceDirect' databases according to the 'Preferred Reporting Items for Systematic reviews and Meta-Analyses' guidelines., Results: We identified 16 patients (6 personal cases and 10 cases from the medical literature). Our personal cases were five females and one male, with a median age (at the onset of cutaneous signs of LV) of 38 (range 25-62). Several types of skin lesions of the lower limbs were observed. Median age at the onset of peripheral neuropathy symptoms was 48 years (range 29-66), with a main clinical and electrophysiological pattern of mononeuropathy multiplex., Discussion: We observed a typical pattern of peripheral neuropathy, mostly mononeuropathy multiplex, whose pathophysiology might be related to occlusions of the small vessels of the nerves, as seen in the dermis. Moreover, LV may also be associated with other types of peripheral neuropathies (sometimes of autoimmune etiology) not directly related to the skin lesions., Conclusion: The 'ischemic form' of peripheral neuropathy linked to LV is mainly responsible for sensory disturbances (with multifocal distribution), sometimes for motor disturbances. This type of peripheral neuropathy has to be distinguished from 'classical vasculitic neuropathies' which are usually treated with antithrombotic therapies., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Giant cell arteritis, the most frequent form of vasculitis in persons over 50 years of age, is a granulomatous chronic vasculitis involving large and medium-sized vessels, most commonly the temporal and other cranial arteries. This common, treatable condition is associated with various clinical symptoms, including neurological ones, affecting both the central and peripheral nervous systems. In this review, we discuss the cranial and extra cranial neurological complications of giant cell arteritis, to help avoid the many pitfalls in the diagnosis of giant cell arteritis., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Introduction: Myasthenia gravis (MG) Lambert-Eaton (LE) overlap syndrome is a rare condition. Here, we describe the first case of MG-LE overlap syndrome revealed by the anti-programmed cell death 1 inhibitor, nivolumab, in a patient treated for metastatic melanoma., Case: Three months after receiving nivolumab and 1 month after brain metastasis radiotherapy, our patient developed generalized fatigue with intermittent ptosis and swallowing difficulty suggesting a myasthenic syndrome. Electromyogram findings, anti-acetylcholine receptor, and anti-calcium channel antibodies levels were consistent with an immune-related myasthenic syndrome with specific features for both MG and LE syndromes. Immunotherapy with nivolumab was stopped. Patient was treated with systemic immunosuppressive and anti-cholinesterase drugs, with remarkable improvement of his neurological symptoms. Prolonged partial remission was obtained for his metastatic melanoma without need for a third-line treatment. Two years later, a relapse of hismyasthenic symptoms was observed along with new neurological symptoms related to brain radiation necrosis., Conclusion: We describe the first case of MG-LE overlap syndrome diagnosed after anti-PD1 immunotherapy for metastatic melanoma, which appeared after radiation therapy and then relapsed after brain radiation necrosis. We hypothesized a role for brain inflammation as a trigger for MG-LE onset. Neuro-muscular junctions disease induced or revealed by checkpoint inhibitors can be challenging and requires long-term follow-up., (© 2021. Fondazione Società Italiana di Neurologia.)

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)., (© 2020. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Purpose: Charcot-Marie-Tooth (CMT) disease, an untreatable hereditary polyneuropathy, may mimic chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), a treatable neuropathy., Methods: In this retrospective study, we analyzed the characteristics of CMT patients misdiagnosed as CIDP at 16 university hospitals in three countries, compared these patients with a reference group of CIDP patients, and estimated the cost of misdiagnosis., Results: Among 1104 CIDP cases, we identified 35 CMT patients misdiagnosed as CIDP (3.2%). All were initially diagnosed with definite or probable CIDP (European Federation of Neurological Societies/Peripheral Nerve Society criteria), and mutations in PMP22, MPZ, and 10 other CMT genes were found in 34%, 31%, and 35% of cases, respectively. In comparison with a reference group of 35 CIDP patients, CMT patients were younger (median age at disease onset = 39 vs. 56 years) and more frequently had motor weakness at disease onset (80% vs. 29%), hearing loss (14% vs. 0%), normal brachial plexus imaging (70% vs. 40%), lower cerebrospinal fluid protein content (median = 0.5 vs. 0.8 g/L), and lower treatment response (20% vs. 69%). Treatment cost in these 35 misdiagnosed patients was estimated at 4.6 million euros (M€), whereas the cost of CMT genetic analysis in 1104 patients was estimated at 2.7 M€., Conclusions: In this study, 35 of 1104 (3.2%) patients initially diagnosed with CIDP had CMT. Importantly, the cost of treating these 35 misdiagnosed patients was significantly higher than the cost of performing CMT genetic analysis in 1104 patients (4.6 M€ vs. 2.7 M€), suggesting that CMT genetic investigations should be more widely used before diagnosing CIDP., (© 2021 European Academy of Neurology.)

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., (Published by Elsevier B.V.)

Objectives: To determine whether the familial clustering of amyotrophic lateral sclerosis (ALS) cases and the phenotype of the disease may help identify the pathogenic genes involved., Methods: We conducted a targeted next-generation sequencing analysis on 235 French familial ALS (FALS), unrelated probands to identify mutations in 30 genes linked to the disease. The genealogy, that is, number of cases and generations with ALS, gender, age, site of onset and the duration of the disease were analysed., Results: Regarding the number of generations, 49 pedigrees had only one affected generation, 152 had two affected generations and 34 had at least three affected generations. Among the 149 pedigrees (63.4%) for which a deleterious variant was found, an abnormal G4C2 expansion in C9orf72 was found in 98 cases as well as SOD1 , TARBP or FUS mutations in 30, 9 and 7 cases, respectively. Considering pedigrees from the number of generations, abnormal G4C2 expansion in C9orf72 was more frequent in pedigrees with pairs of affected ALS cases, which represented 65.2% of our cohort. SOD1 mutation involved all types of pedigrees. No TARDBP nor FUS mutation was present in monogenerational pedigrees. TARDBP mutation predominated in bigenerational pedigrees with at least three cases and FUS mutation in multigenerational pedigrees with more than seven cases, on average, and with an age of onset younger than 45 years., Conclusion: Our results suggest that familial clustering, phenotypes and genotypes are interconnected in FALS, and thus it might be possible to target the genetic screening from the familial architecture and the phenotype of ALS cases., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To 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., Methods: The 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., Results: Among 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., Conclusions: This 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., (© 2021 American Academy of Neurology.)

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.

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.

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., (© 2020 American Academy of Neurology.)

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., (© 2020 American Academy of Neurology.)

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")., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Martin Matharan et al.)

Background: 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., Method: 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., Results: 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., Conclusion: 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.

Background: In 90% of Amyotrophic Lateral Sclerosis (ALS) cases, the disease is sporadic, the remaining 10% being familial. Many genes have been associated with the disease. The use of next generation sequencing has allowed increasing the number of genes analysed in routine diagnostics. However, this increase raises the issue of genetic variants interpretation within a growing number of ALS-associated-genes. Variant classification is based on a combinatory analysis of multiple factors. Among them, functional analyses provide strong arguments on pathogenicity interpretation. Objectives: We developed a simple animal model, the Zebrafish, for the functional analysis of candidate variants pathogenicity identified by routine genetic testing. Methods: Transient overexpression of different ALS associated genetic variants has been performed by mRNA injection in 1-cell stage zebrafish eggs. Validation of protein overexpression has been done by western blot. Embryos mortality, developmental delay and morphological abnormalities have been assessed within the first two days of development. Cellular phenotype has been investigated by the analysis of axonal length of 2-days old larvae with confocal microscopy. Motor phenotype of 5-days old larvae has been explored by touched-evoked response assay. Results: The model has been validated by the analysis of well-described ALS mutations, SOD1-Gly93Ala and OPTN Glu478Gly. Overexpression of this mutated protein was shown to provoke a shortening of axons and a premature axonal branching, as well as an impairment of motor performances as expected. We did not observe these aberrations in SOD1-WT injected fishes. Two candidate variants observed in ALS-patients have been explored with our model: SOD1 NM&#95;000454.4:c.400&#95;402del, p.Glu134del and OPTN NM&#95;021980.4:c.1475T > G, p. Leu492Arg. Overexpression of both variants induced morphological abnormalities and motor impairment, suggesting a pathogenic involvement of these variants in ALS-patients. Discussion and conclusions: We developed for the first time a simple animal model, the Zebrafish, useful for the functional analysis of variant pathogenicity in order to assist ALS molecular diagnosis. Our model has been used to assess the pathogenicity of SOD1 and OPTN candidate variants, allowing to improve genetic testing interpretation.

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.

Nodoparanodopathy is a recent concept in the field of peripheral neuropathy, corresponding to peripheral nerve disorders stemming from an autoimmune attack directed and limited to the nodal region. This concept was identified using modern techniques of electrophysiology, immunology, and pathology (including electron microscopy). We present here what we believe to be the earlier well-documented case of nodoparanodopathy in the medical literature, based on an article written by Samuel Gilbert Webber (1838-1926) in 1884., (© 2019 American Academy of Neurology.)

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.

Introduction: 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.

The efficacy of intravenous immunoglobulins (IVIg) in patients with autoimmune diseases (AID) has been known for several decades. Majority of these patients received IVIg in hospital. A retrospective study was conducted in 22 centers in France to evaluate the feasibility of the administration of Tegeline, an IVIg from LFB Biomedicaments, and assess its safety at home, compared to in hospital, in patients with AID. The included patients were at least 18 years old, suffering from AID, and treated with at least 1 cycle of Tegeline at home after receiving 3 consecutive cycles of hospital-based treatment with Tegeline at a dose between 1 and 2 g/kg/cycle. Forty-six patients with AID, in most cases immune-mediated neuropathies, received a total of 138 cycles of Tegeline in hospital and then 323 at home. Forty-five drug-related adverse events occurred in 17 patients who received their cycles at home compared to 24 adverse events in hospital in 15 patients. Serious adverse events occurred in 3 patients during home treatment, but they were not life-threatening and did not lead to discontinuation of Tegeline. Forty-five patients continued their treatment with Tegeline at home or in hospital; 39 (84.8%) were still receiving home treatment at the end of the study. In conclusion, the study demonstrates the good safety profile of Tegeline administered at home at high doses in patients with AID who are eligible for home administration of Tegeline.

Objective: The 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., Methods: We 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)., Results: Of 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., Conclusions: Based on recent proposals in the medical literature, these results highlight that most specialists think that changes are needed to the classification of CMT., (© 2018 American Academy of Neurology.)

Background: Prior clinical trials have suggested that home-based Ig treatment in multifocal motor neuropathy (MMN) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and its variant Lewis-Sumner syndrome (LSS) is safe and effective and is less costly than hospital-administered intravenous immunoglobulin (IVIg)., Methods: A French prospective, dual-center, cost minimization analysis was carried out to evaluate IVIg administration (5% concentrated) at home versus in hospital with regard to costs, patients' autonomy, and patients' quality of life. The primary endpoint was the overall cost of treatment, and we adopted the perspective of the payer (French Social Health Insurance)., Results: Twenty-four patients aged 52.3 (12.2) years were analyzed: nine patients with MMN, eight with CIDP, and seven with LSS. IVIg (g/kg) dosage was 1.51 ± 0.43 in hospital and 1.52 ± 0.4 at home. Nine-month total costs per patient extrapolated to 1 year of treatment were €48,189 ± 26,105 versus €91,798 ± 51,125 in the home and hospital groups, respectively ( p  <   .0001). The most frequently reported factors for choosing home treatment were the good tolerance and absence of side effects of IVIg administration, as well as a good understanding of the advantages and drawbacks of home treatment (75% of respondents). The mRankin scores before and after switch to home treatment were 1.61 ± 0.72 and 1.36 ± 0.76, respectively ( p  =   .027)., Discussion: The switch from hospital-based to home-based IVIg treatment for patients with immune neuropathy represents potentially significant savings in the management of the disease.

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., Competing Interests: The authors declare no conflict of interest.

The wide spectrum of hereditary muscular disorders leads to unavoidable difficulties in their classification, even for specialists. For this reason, new proposals are required that would ultimately replace our current rather complex classifications by a simpler structure. Our proposal will be limited to dystrophic and non-dystrophic myopathies (excluding metabolic disorders, mitochondriopathies, and channelopathies) for which similar proposals would also be relevant. Various genes (encoding structural proteins associated with the sarcolemma, nuclear membrane proteins, and proteins involved in myofiber metabolism have now been sequenced and mutations ascribed to specific forms of inherited muscular disorders. Based on our observations and our recent proposals in other neurogenetic conditions and informal discussions with specialists of neuromuscular disorders, the prerequisite for a simple and sound classification for inherited muscular disorders should encompass the clinical and pathological phenotypes (described in a simple and clear manner), the mode of inheritance, and the mutated gene. We think that the denomination of the different subtypes could be simplified considerably, although any new proposal of classification of muscular disorders will need to be discussed in the neurological and genetic communities., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: Giant cell arteritis (GCA), a vasculitis involving large-sized and medium-sized vessels (which most commonly involves temporal arteries), is easily recognized in older patients presenting with headache, scalp tenderness, and raised inflammatory markers. Neurological complications (either central or peripheral) are classically described in GCA., Case Report: We report the case of an 85-year-old woman with bilateral acute brachial radiculoplexopathy, a rare neurological complication of GCA. She also presented right oculomotor palsy (with ptosis) and raised inflammatory markers, but she did not complain of the other classic cranial symptoms of the disease. We compare this case with 16 similar cases reported in the medical literature., Conclusions: In assessing a patient over 50 years of age with unexplained (unilateral or bilateral) brachial radiculoplexopathy (especially if C5-C6 nerve roots are affected) and elevated inflammatory markers, we would recommend specific enquiries with regard to the manifestations of GCA. The purpose is to reduce the risk of missing the wider spectrum of this condition and minimize the subsequent risk for disability of this treatable disease.

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., (© 2017 American Academy of Neurology.)

Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disorder affecting both upper and lower motor neurons. Despite much research and effort, no clear insights into a unifying hypothesis for the pathogenesis has so far emerged for this disease. Areas covered: We review the main pathophysiological hypotheses and the potential therapeutic targets in ALS, as well as the management of these patients (in order to improve their survival and quality of life). Expert commentary: ALS is a complex neurodegenerative disease, these days considered as a multisystem disorder with predominant motor symptoms (and various clinical forms). Further comprehension of the pathophysiology of this disease is required, although pathophysiological mechanisms (such as TDP-43) show promise in the search for new therapies. There is still no curative treatment for ALS, but the emergence of multidisciplinary specialized ALS clinics has increased both the quality of life and the survival of these patients.

Amyotrophic lateral sclerosis (ALS), identified as a distinct clinical entity by Charcot since the end of the nineteenth century, is a devastating and fatal neurodegenerative disorder that affects motor neurons in the brain, brainstem and spinal cord. Survival of patients with ALS is associated with several factors such as clinical phenotype, age at onset, gender, early presence of respiratory failure, weight loss and treatment with Riluzole (the only disease-modifying drug approved for this disease). Nowadays, there is still no curative treatment for ALS: palliative care and symptomatic treatment are therefore essential components in the management of these patients. Nevertheless, the scientific knowledge in the field of ALS motor neuron degeneration is growing, with the prospect of new treatments. Based on this physiopathological knowledge, several new therapeutic targets are being studied, involving various mechanisms such as excitotoxicity, neuroinflammation, mitochondrial dysfunction, oxidative stress, RNA metabolism and other attractive concepts. Moreover, it is also important to identify reliable biomarkers that will be essential components for future therapeutic development and study design in ALS. In this review, we present the main recent advances and promising therapeutics and biomarkers in the field of ALS., Competing Interests: Conflicts of interest: None declared.

Introduction: IgM monoclonal gammopathy with anti-MAG (myelin associated glycoprotein) antibodies is associated with demyelinating polyneuropathy. MAG mediates adhesion between the Schwann cell membrane (non-compact myelin) and axons. Various drugs have been tried in this form of neuropathy, with varying responses, but to date there is no consensus on the treatment of this disease., Areas Covered: Based on the medical literature and the experience of our group of clinicians, we offer some proposals for the management of anti-MAG neuropathy. Expert commentary: It is not certain that anti-MAG antibodies are the only factor responsible for symptoms of this clinically heterogeneous neuropathy. Some patients with mild non-evolving symptoms do not require treatment; for more severe cases, treatment should be prompt: intravenous immunoglobulins (or sometimes therapeutic plasma exchange) as first line treatment, then immunosuppressant in refractory forms (such as rituximab).

Introduction: Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder affecting the neuromuscular junction, clinically characterized by proximal muscle weakness and autonomic changes. LEMS is often associated with an underlying tumor (paraneoplastic form) but also occurs in the absence of cancer (idiopathic form). Treatment consists of immunomodulation (immunosuppression), anticancer treatment when carcinoma is present, and symptomatic treatment [acetylcholinesterase inhibitors and potassium channel blockers, e.g., amifampridine (3,4-diaminopyridine, i.e., 3,4-DAP), to improve neurotransmission]. Although there has long been information from case reports, several randomized controlled trials, and treatment guidelines, population data are still scarce., Methods: The LEMS patient registry was launched in the European community in mid-2010 as a voluntary, multinational, observational, non-interventional program to collect structured empirical data on clinical course, treatment utilization, and safety and efficacy from the use of LEMS-specific treatments., Results: Sixty-nine patients have been enrolled [36 males, 32 females, 1 gender not reported; mean age 61.5 (27-84) years]. Eighteen patients (26%) were diagnosed with an associated carcinoma. At the time of enrollment, the majority of patients (65%) were receiving amifampridine [either compounded 3,4-DAP (22%) or 3,4-DAP phosphate, Firdapse(®) (43%)]. At enrollment, most patients demonstrate a profile of mild-to-moderate deficits in daily functioning but generally have good muscle strength, albeit with reduced deep tendon reflexes, frequent ataxia during walking, and signs of autonomic dysfunction including dry mouth, bladder dysfunction, and constipation., Conclusion: The LEMS European Union registry will continue to enroll patients and periodically report the accrued longitudinal data obtained on clinical assessments and laboratory findings, treatment practices, the safety and efficacy of treatment approaches, and long-term clinical outcomes., Funding: BioMarin Pharmaceutical Inc., Novato, CA, USA.

To explore the link between bioenergetics and motor neuron degeneration, we used a computational model in which detailed morphology and ion conductance are paired with intracellular ATP production and consumption. We found that reduced ATP availability increases the metabolic cost of a single action potential and disrupts K+/Na+ homeostasis, resulting in a chronic depolarization. The magnitude of the ATP shortage at which this ionic instability occurs depends on the morphology and intrinsic conductance characteristic of the neuron. If ATP shortage is confined to the distal part of the axon, the ensuing local ionic instability eventually spreads to the whole neuron and involves fasciculation-like spiking events. A shortage of ATP also causes a rise in intracellular calcium. Our modeling work supports the notion that mitochondrial dysfunction can account for salient features of the paralytic disorder amyotrophic lateral sclerosis, including motor neuron hyperexcitability, fasciculation, and differential vulnerability of motor neuron subpopulations., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The pituitary gland releases hormones in a pulsatile fashion guaranteeing signalling efficiency. The determinants of pulsatility are poorly circumscribed. Here we show in magnocellular hypothalamo-neurohypophyseal oxytocin (OT) neurons that the bursting activity underlying the neurohormonal pulses necessary for parturition and the milk-ejection reflex is entirely driven by a female-specific central pattern generator (CPG). Surprisingly, this CPG is active in both male and female neonates, but is inactivated in males after the first week of life. CPG activity can be restored in males by orchidectomy or silenced in females by exogenous testosterone. This steroid effect is aromatase and caspase dependent, and is mediated via oestrogen receptor-α. This indicates the apoptosis of the CPG network during hypothalamic sexual differentiation, explaining why OT neurons do not burst in adult males. This supports the view that stereotypic neuroendocrine pulsatility is governed by CPGs, some of which are subjected to gender-specific perinatal programming.

The endocannabinoid (eCB) system and the cannabinoid CB1 receptor (CB1R) play key roles in the modulation of brain functions. Although actions of eCBs and CB1Rs are well described at the synaptic level, little is known of their modulation of neural activity at the network level. Using microelectrode arrays, we have examined the role of CB1R activation in the modulation of the electrical activity of rat and mice cortical neural networks in vitro. We find that exogenous activation of CB1Rs expressed on glutamatergic neurons decreases the spontaneous activity of cortical neural networks. Moreover, we observe that the net effect of the CB1R antagonist AM251 inversely correlates with the initial level of activity in the network: blocking CB1Rs increases network activity when basal network activity is low, whereas it depresses spontaneous activity when its initial level is high. Our results reveal a complex role of CB1Rs in shaping spontaneous network activity, and suggest that the outcome of endogenous neuromodulation on network function might be state dependent.

Following infection of the central nervous system (CNS), the immune system is faced with the challenge of eliminating the pathogen without causing significant damage to neurons, which have limited capacities of renewal. In particular, it was thought that neurons were protected from direct attack by cytotoxic T lymphocytes (CTL) because they do not express major histocompatibility class I (MHC I) molecules, at least at steady state. To date, most of our current knowledge on the specifics of neuron-CTL interaction is based on studies artificially inducing MHC I expression on neurons, loading them with exogenous peptide and applying CTL clones or lines often differentiated in culture. Thus, much remains to be uncovered regarding the modalities of the interaction between infected neurons and antiviral CD8 T cells in the course of a natural disease. Here, we used the model of neuroinflammation caused by neurotropic Borna disease virus (BDV), in which virus-specific CTL have been demonstrated as the main immune effectors triggering disease. We tested the pathogenic properties of brain-isolated CD8 T cells against pure neuronal cultures infected with BDV. We observed that BDV infection of cortical neurons triggered a significant up regulation of MHC I molecules, rendering them susceptible to recognition by antiviral CTL, freshly isolated from the brains of acutely infected rats. Using real-time imaging, we analyzed the spatio-temporal relationships between neurons and CTL. Brain-isolated CTL exhibited a reduced mobility and established stable contacts with BDV-infected neurons, in an antigen- and MHC-dependent manner. This interaction induced rapid morphological changes of the neurons, without immediate killing or impairment of electrical activity. Early signs of neuronal apoptosis were detected only hours after this initial contact. Thus, our results show that infected neurons can be recognized efficiently by brain-isolated antiviral CD8 T cells and uncover the unusual modalities of CTL-induced neuronal damage.

Deep dorsal horn relay neurons (dDHNs) of the spinal cord are known to exhibit multiple firing patterns under the control of local metabotropic neuromodulation: tonic firing, plateau potential, and spontaneous oscillations. This work investigates the role of interactions between voltage-gated channels and the occurrence of different firing patterns and then correlates these two phenomena with their functional role in sensory information processing. We designed a conductance-based model using the NEURON software package, which successfully reproduced the classical features of plateau in dDHNs, including a wind-up of the neuronal response after repetitive stimulation. This modeling approach allowed us to systematically test the impact of conductance interactions on the firing patterns. We found that the expression of multiple firing patterns can be reproduced by changes in the balance between two currents (L-type calcium and potassium inward rectifier conductances). By investigating a possible generalization of the firing state switch, we found that the switch can also occur by varying the balance of any hyperpolarizing and depolarizing conductances. This result extends the control of the firing switch to neuromodulators or to network effects such as synaptic inhibition. We observed that the switch between the different firing patterns occurs as a continuous function in the model, revealing a particular intermediate state called the accelerating mode. To characterize the functional effect of a firing switch on information transfer, we used correlation analysis between a model of peripheral nociceptive afference and the dDHN model. The simulation results indicate that the accelerating mode was the optimal firing state for information transfer.