Management of amyotrophic lateral sclerosis in clinical practice: Results of the expert consensus using the Delphi methodology.

Amyotrophic lateral sclerosis (ALS) is a rare disease characterized by a progressive and irreversible degeneration of upper and lower motor neurons leading to death. In France, limited data exist describing the criteria used in clinical practice for diagnosis and follow-up, and how novel therapies may fit in. The objective of this Delphi panel was to obtain an overview of current French practices in ALS diagnosis, management, and follow-up by determining the scales and criteria used in clinical practice outside of clinical trials, as well as the place of a future treatment like AMX0035, acting on endoplasmic reticulum (ER) stress and mitochondrial dysfunction, in the current therapeutic strategies. A questionnaire was administered to 24 ALS healthcare providers practicing in ALS centers in France. Two rounds of remote voting were organized, before proposition of final consensus statements. Consensus was considered reached when at least 66% of the voters agreed. Consensus were obtained to define the new Gold Coast criteria as the ones used in clinical practice to establish the diagnosis of ALS, thus replacing the revised El Escorial criteria, considered too complex and now mainly used to characterize the patient populations to be included in clinical trials. The clinical factors considered to establish ALS diagnosis are mainly the demonstration of progression of the motor deficit and elimination of differential diagnoses. The ALSFRS-R scale is used in daily clinical practice to assess patient's functional impairment in terms of number of points lost, with the bulbar, respiratory, and fine motor subscores being the most important to evaluate independently. A critical medical need was identified regarding the provision of new therapeutic alternatives in ALS. The panel members would support the earliest management of patients. In this landscape, based on data from a very encouraging phase II (Centaur trial), AMX0035 represents a new tool of choice in current treatment strategies for all patients for whom experts are confident in the diagnosis of ALS, in combination with riluzole. These results will need to be confirmed by the ongoing phase III trial (Phoenix trial).

French National Protocol for genetic of amyotrophic lateral sclerosis.

Relationships between genes and amyotrophic lateral sclerosis (ALS) have been widely accepted since the first studies highlighting pathogenic mutations in the SOD1 gene 30years ago. Over the last three decades, scientific literature has clearly highlighted the central role played by genetic factors in the disease, in both clinics and pathophysiology, as well as in therapeutics. This implies that health professionals who care for patients with ALS are increasingly faced with patients and relatives eager to have answers to questions related to the role of genetic factors in the occurrence of the disease and the risk for their relatives to develop ALS. In order to address these public health issues, the French ALS network FILSLAN proposed to the Haute Autorité de santé (HAS) the drafting of a French National Protocol (PNDS) on ALS genetics. This PNDS was developed according to the "method for developing a national diagnosis and care protocol for rare diseases" published by the HAS in 2012 (methodological guide for PNDS available on the HAS website: http://www.has-sante.fr/). This document aims to provide the most recent data on the role of genes in ALS and to detail the implications for diagnosis and care.

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

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

Retinal vessels as a window on amyotrophic lateral sclerosis pathophysiology: A systematic review.

Amyotrophic lateral sclerosis (ALS) is a rare fatal motor neuron disease. Although many potential mechanisms have been proposed, the pathophysiology of the disease remains unknown. Currently available treatments can only delay the progression of the disease and prolong life expectancy by a few months. There is still no definitive cure for ALS, and the development of new treatments is limited by a lack of understanding of the underlying biological processes that trigger and promote neurodegeneration. Several scientific results suggest a neurovascular impairment in ALS providing perspectives for the development of new biomarkers and treatments. In this article, we performed a systematic review using PRISMA guidelines including PubMed, EmBase, GoogleScholar, and Web of Science Core Collection to analyze the scientific literature published between 2000 and 2021 discussing the neurocardiovascular involvement and ophthalmologic abnormalities in ALS. In total, 122 articles were included to establish this systematic review. Indeed, microvascular pathology seems to be involved in ALS, affecting all the neurovascular unit components. Retinal changes have also been recently highlighted without significant alteration of the visual pathways. Despite the peripheral location of the retina, it is considered as an extension of the central nervous system (CNS) as it displays similarities to the brain, the inner blood-retinal barrier, and the blood-brain barrier. This suggests that the eye could be considered as a 'window' into the brain in many CNS disorders. Thus, studying ocular manifestations of brain pathologies seems very promising in understanding neurodegenerative disorders, mainly ALS. Optical coherence tomography angiography (OCT-A) could therefore be a powerful approach for exploration of retinal microvascularization allowing to obtain new diagnostic and prognostic biomarkers of ALS.

STochastic Optical Reconstruction Microscopy (STORM) reveals the nanoscale organization of pathological aggregates in human brain.

AIMS: Histological analysis of brain tissue samples provides valuable information about the pathological processes leading to common neurodegenerative disorders. In this context, the development of novel high-resolution imaging approaches is a current challenge in neuroscience. METHODS: To this end, we used a recent super-resolution imaging technique called STochastic Optical Reconstruction Microscopy (STORM) to analyse human brain sections. We combined STORM cell imaging protocols with neuropathological techniques to image cryopreserved brain samples from control subjects and patients with neurodegenerative diseases. RESULTS: This approach allowed us to perform 2D-, 3D- and two-colour-STORM in neocortex, white matter and brainstem samples. STORM proved to be particularly effective at visualizing the organization of dense protein inclusions and we imaged with a <50 nm resolution pathological aggregates within the central nervous system of patients with Alzheimer's disease, Parkinson's disease, Lewy body dementia and fronto-temporal lobar degeneration. Aggregated Aß branches appeared reticulated and cross-linked in the extracellular matrix, with widths from 60 to 240 nm. Intraneuronal Tau and TDP-43 inclusions were denser, with a honeycomb pattern in the soma and a filamentous organization in the axons. Finally, STORM imaging of α-synuclein pathology revealed the internal organization of Lewy bodies that could not be observed by conventional fluorescence microscopy. CONCLUSIONS: STORM imaging of human brain samples opens further gates to a more comprehensive understanding of common neurological disorders. The convenience of this technique should open a straightforward extension of its application for super-resolution imaging of the human brain, with promising avenues to current challenges in neuroscience.

Efficacy and safety of rituximab in myasthenia gravis: a French multicentre real-life study.

BACKGROUND AND PURPOSE: Fifteen percent of patients with myasthenia gravis (MG) are refractory to conventional treatment. Case reports and a few studies show probable benefit of rituximab in these cases. Our objective was to assess the efficacy and the safety of rituximab in patients with MG, in a multicentric real-life study. METHOD: Inclusion criteria were: age > 18 years; MG with anti-acetylcholine receptor (AChR) antibodies, anti-muscle-specific kinase (MuSk) antibodies or significant decrement after repetitive nerve stimulation; Myasthenia Gravis Foundation of America (MGFA) class >II; refractory or steroid-dependent MG; and treatment with rituximab. Efficacy was assessed at 6 months using the MGFA-post-intervention status (PIS) score, the myasthenic muscle score (MMS) and the number of patients receiving steroids <10 mg/day. Data on adverse events were collected. RESULTS: Twenty-nine patients were included: 20 with anti-AChR MG, five with anti-MuSK MG and four with seronegative MG. MGFA-PIS score was improved or better (improved, minimal manifestations or remission) in 86.2% of patients after 6 months of treatment (P < 0.0001). The mean MMS increased from 68.8 to 83.1 (P < 0.0001). A decrease in steroid dosage (<10 mg/day) was effective in 57.9% of treated patients. In all, 42.8% of patients experienced adverse events: infections (21.4% of patients); infusion reaction (7%); bradycardia (3.7%); and cytopenia (7%). CONCLUSION: The present study demonstrates the efficacy and safety of rituximab in patients with MG. Additional studies remain necessary to determine the role of rituximab in the pharmacopeia of MG treatment and to establish precise recommendations for the infusion protocol.

Prevalence, correlates and impact of pain and cramps in anti-MAG neuropathy: a multicentre European study.

BACKGROUND AND PURPOSE: The frequency of pain and cramps is uncertain in anti-myelin associated glycoprotein antibody (anti-MAG) neuropathy. Whether these symptoms may affect function/quality of life is unknown. METHODS: A cross-sectional study of the prevalence, correlates and impact of pain, pain subtypes and cramps, their severity, frequency and anatomical distribution was performed for 55 clinically stable patients with anti-MAG neuropathy. RESULTS: Pain of any type was reported by 80% of subjects. The most common subtype was paraesthesiae and dysaesthesiae (70%). Cramps were reported by >60% of patients, with lower limb cramps in all and upper limb cramps in about 20%. Cramps affected daily activities in >30% of these subjects, sleep in 60%, ability to exercise in >30%. Total pain score correlated with several Short Form 36 health-related quality of life (SF-36 HR-QoL) measures (P < 0.05), with Inflammatory Rasch-built Overall Disability Scale (I-RODS) (P = 0.006) and 10-m timed walk (P = 0.019). An independent association was ascertained with I-RODS (P = 0.002). Different pain subtypes showed multiple associations with SF-36 HR-QoL measures and/or functional scales. Upper limb cramps had multiple SF-36 HR-QoL functional correlates, with an independent association with the Overall Neuropathy Limitation Score (ONLS) (P = 0.004). Cramp severity correlated with ONLS (P = 0.04) and I-RODS (P = 0.028) and inversely with level of physiotherapy input (P = 0.009). Cramp frequency was associated with tremor score (P = 0.004) and multiple SF-36 HR-QoL subsections. CONCLUSIONS: Neuropathic pain and cramps may affect function and quality of life in anti-MAG neuropathy. Optimizing treatments of these symptoms, including by adequate levels of physiotherapy, may be beneficial in affected patients and requires further research.

Disease status in chronic inflammatory demyelinating polyneuropathy: inter-centre comparative analysis and correlates.

BACKGROUND AND PURPOSE: Chronic inflammatory demyelinating polyneuropathy (CIDP) may have variable evolution profiles, which have not been compared between cohorts. The relationship of disease status with motor strength, function and electrophysiology is uncertain. METHODS: Disease status was studied with a simplified proposed scale in two patient cohorts totalling 72 subjects from Leicester, U.K., and Angers, France. Clinical and electrophysiological records were analysed. RESULTS: Independent ascertainment of disease status in each cohort revealed similar rates of remission (P = 0.23), stable/improving disease (P = 0.34) and unstable/active disease (P = 1). No correlation was ascertained with strength or function. Median nerve compound muscle action potential was the only independent electrophysiological predictor of disease status ascertained (P = 0.046). CONCLUSIONS: Disease status distribution may represent an important comparative indicator for management of CIDP cohorts and could be useful for benchmarking service and treatment provision. Degree of upper limb motor axonal loss may represent a useful electrophysiological marker of disease status in CIDP.

Somatosensory evoked potentials in the assessment of peripheral neuropathies: Commented results of a survey among French-speaking practitioners and recommendations for practice.

BACKGROUND: Somatosensory evoked potentials (SSEPs) are increasingly performed for the assessment of peripheral neuropathies, but no practical guidelines have yet been established in this specific application. STUDY AIM: To determine the relevant indication criteria and optimal technical parameters for SSEP recording in peripheral neuropathy investigation. METHODS: A survey was conducted among the French-speaking practitioners with experience of SSEP recording in the context of peripheral neuropathies. The results of the survey were analyzed and discussed to provide recommendations for practice. RESULTS: SSEPs appear to be a second-line test when electroneuromyographic investigation is not sufficiently conclusive, providing complementary and valuable information on central and proximal peripheral conduction in the somatosensory pathways. CONCLUSIONS: Guidelines for a standardized recording protocol, including the various parameters to be measured, are proposed. CLINICAL RELEVANCE: We hope that these proposals will help to recognize the value of this technique in peripheral neuropathy assessment in clinical practice.

Inherited peripheral neuropathies due to mitochondrial disorders.

Mitochondrial disorders (MIDs) are frequently responsible for neuropathies with variable severity. Mitochondrial diseases causing peripheral neuropathies (PNP) may be due to mutations of mitochondrial DNA (mtDNA), as is the case in MERRF and MELAS syndromes, or to mutations of nuclear genes. Secondary abnormalities of mtDNA (such as multiple deletions of muscle mtDNA) may result from mitochondrial disorders due to mutations in nuclear genes involved in mtDNA maintenance. This is the case in several syndromes caused by impaired mtDNA maintenance, such as Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoplegia (SANDO) due to recessive mutations in the POLG gene, which encodes the catalytic subunit of mtDNA polymerase (DNA polymerase gamma), or Mitochondrial Neuro-Gastro-Intestinal Encephalomyopathy (MNGIE), due to recessive mutations in the TYMP gene, which encodes thymidine phosphorylase. The last years have seen a growing list of evidence demonstrating that mitochondrial bioenergetics and dynamics might be dysfunctional in axonal Charcot-Marie-Tooth disease (CMT2), and these mechanisms might present a common link between dissimilar CMT2-causing genes.

Axonal regeneration is compromised in NFH-LacZ transgenic mice but not in NFH-GFP mice.

To investigate neurofilament (NF) dynamics during the cytoskeleton reorganization in regenerating axons, and their electrophysiological and histological consequences, we used two transgenic lines of mice: neurofilament high (NFH)-LacZ and NFH-green fluorescent protein (GFP). In NFH-LacZ mice, NFs are retained in cell bodies and deficient in axons (Eyer and Peterson, 1994), while in NFH-GFP mice the fluorescent fusion protein is normally transported along axons (Letournel et al., 2006). Following a crush of the sciatic nerve, conduction recovery in NFH-GFP mice is similar to wild-type (wt) mice, but it is reduced in NFH-LacZ mice. Moreover, changes of axonal calibres following regeneration are similar between NFH-GFP and wt mice, but they are systematically reduced in NFH-LacZ mice. Finally, the axonal transport of NFH-GFP fusion protein and NFs is re-initiated after the crush as evidenced by the fluorescent and immunolabelling of axons distal from the crushed point, but NFs and the fusion protein are not transported along axons during regeneration in NFH-LacZ mice. Together, these results argue that the absence of axonal NFs in NFH-LacZ mice compromises the axonal regeneration, and that the NFH-GFP reporter fusion protein represents an efficient model to evaluate the NF dynamics during axonal regeneration.

A European multicentre reappraisal of distal compound muscle action potential duration in chronic inflammatory demyelinating polyneuropathy.

BACKGROUND: The electrodiagnostic value of distal compound muscle action potential duration (DCMAPD) has been studied rarely in chronic inflammatory demyelinating polyneuropathy (CIDP). Cut-offs proposed have not been widely evaluated. The influence of low-cut EMG filter settings ≤ 10 Hz as used in Europe is uncertain. METHODS: We retrospectively reviewed records of 110 patients with typical, treatment-responsive CIDP, from Leicester, U.K., Paris and Angers, France. All fulfilled revised European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) clinical and electrodiagnostic criteria for typical CIDP (2010), before consideration of DCMAPD prolongation. Results were compared with those of 110 controls with chronic sensory/sensory-motor axonal neuropathy. We constructed receiver operating characteristic (ROC) curves for each nerve and derived cut-offs for DCMAPD prolongation, offering specificity of ≥ 98% vs. controls. RESULTS: DCMAPD was significantly greater in all nerves for CIDP patients, compared with controls (P < 0.001). ROC curves allowed derivation of cut-offs of sensitivities ranging from 27.1% (ulnar nerve) to 60% (tibial nerve). Using these cut-offs to define DCMAPD prolongation in any studied motor nerve offered a sensitivity of 69.1% for CIDP and specificity of 97.3% vs. controls. CONCLUSION: Cut-offs for DCMAPD are dependent on EMG filter settings. DCMAPD prolongation in any motor nerve, using our derived cut-offs, represents a sensitive and specific marker of CIDP in patients studied with EMG equipment with low-cut filter settings ≤ 10 Hz. Appropriate use of this parameter appears an essential criterion to consider in assessing suspected CIDP, which may be helpful in limiting extensiveness and duration of electrophysiological testing, thereby reducing patient discomfort.

Chronic inflammatory demyelinating polyneuropathy in Waldenström's macroglobulinemia.

INTRODUCTION: Waldenström's disease (WD) is frequently associated with a predominantly sensory neuropathy with a progressive course due to the monoclonal IgM activity against Myelin Associated Glycoprotein (MAG). However, neurolymphomatosis or chronic demyelinating inflammatory polyneuropathy (CDIP) may occur in some patients with WD. CASE REPORT: We report a case of Waldenström's macroglobulinemia in an adult male presenting with cranial nerve palsy and rapidly progressive asymmetric polyneuropathy. Intravenous IgM treatment that provided transient amelioration was followed by a relapse involving tetraparesis. Cerebrospinal fluid analysis, medullar magnetic resonance imaging, and electrophysiological studies led to equivocal findings suggesting the presence of either neurolymphomatosis or CIDP. Finally, sural nerve biopsy results supported the diagnosis of CIDP, which then received appropriate treatment. CONCLUSION: In patients with WD, the possible occurrence of CIDP should be investigated with a neuromuscular biopsy when other investigations are equivocal since the disease calls for a specific treatment.

Phenotypic spectrum of MFN2 mutations in the Spanish population.

INTRODUCTION: The most common form of axonal Charcot-Marie-Tooth (CMT) disease is type 2A, caused by mutations in the mitochondrial GTPase mitofusin 2 (MFN2). OBJECTIVE: The objective of our study is to establish the incidence of MFN2 mutations in a cohort of Spanish patients with axonal CMT neuropathy. MATERIAL AND METHODS: Eighty-five families with suspected axonal CMT were studied. All MFN2 exons were studied through direct sequencing. A bioenergetics study in fibroblasts was conducted using a skin biopsy taken from a patient with an Arg468His mutation. RESULTS: Twenty-four patients from 14 different families were identified with nine different MFN2 mutations (Arg94Trp, Arg94Gln, Ile203Met, Asn252Lys, Gln276His, Gly296Arg, Met376Val, Arg364Gln and Arg468His). All mutations were found in the heterozygous state and four of these mutations had not been described previously. MFN2 mutations were responsible for CMT2 in 16% +/- 7% of the families studied and in 30.8 +/- 14.2% (12/39) of families with known dominant inheritance. The bioenergetic studies in fibroblasts show typical results of MFN2 patients with a mitochondrial coupling defect (ATP/O) and an increase of the respiration rate linked to complex II. CONCLUSION: It is concluded that mutations in MFN2 are the most frequent cause of CMT2 in this region. The Arg468His mutation was the most prevalent (6/14 families), and our study confirms that it is pathological, presenting as a neuropathy in a mild to moderate degree. This study also demonstrates the value of MFN2 studies in cases of congenital axonal neuropathy, especially in cases of dominant inheritance, severe clinical symptoms or additional symptoms such as optic atrophy.

An intraventricular clear cell meningioma revealed by an inflammatory syndrome in a male adult: a case report.

Intraventricular meningiomas are infrequent intracranial tumors. Clinical symptoms are mainly due to an increased intracranial pressure or a direct pressure on the surrounding brain structures. Inflammatory syndrome was described in some patients with chordoid meningiomas. Here we report a case of right intraventricular clear cell meningioma in a 50-year-old man who presented with fever, headache, and inflammatory syndrome. Clinical and biological normalization was rapidly obtained after tumor removal. Immunohistochemical examination showed tumor cells and lymphocytes positivity for the pyrogenic cytokine interleukin-6, with a same intensity. To our knowledge, this is the first case described in the literature concerning an adult man with an intraventricular clear cell meningioma associated with a systemic inflammatory syndrome.

An autopsy case of acute multiple sclerosis (Marburg's type) during pregnancy.

We report a case of a 9-month pregnant woman who presented acute psychiatric and neurological symptoms with extensive involvement of the white matter on MRI and no oligoclonal bands on CSF examination. Despite high doses of intravenous steroids, plasmapheresis and immunosuppressive drugs, a fatal outcome (coma) was noted 8 months later. Neuropathological examination confirmed the diagnosis of Marburg's type of multiple sclerosis showing sharp-edged lesions of demyelination, giant astrocytes, numerous macrophages and little perivascular inflammation. We discuss the definition and limits of the Marburg entity with reference to acute disseminated encephalomyelitis, impact of pregnancy, unusual MRI features, neuropathology and treatment.