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Caffeine consumption outcomes on Amyotrophic Lateral Sclerosis (ALS) including progression, survival and cognition remain poorly defined and may depend on its metabolization influenced by genetic variants. 378 ALS patients with a precise evaluation of their regular caffeine consumption were monitored as part of a prospective multicenter study. Demographic, clinical characteristics, functional disability as measured with revised ALS Functional Rating Scale (ALSFRS-R), cognitive deficits measured using Edinburgh Cognitive and Behavioural ALS Screen (ECAS), survival and riluzole treatment were recorded. 282 patients were genotyped for six single nucleotide polymorphisms tagging different genes involved in caffeine intake and/or metabolism: CYP1A1 (rs2472297), CYP1A2 (rs762551), AHR (rs4410790), POR (rs17685), XDH (rs206860) and ADORA2A (rs5751876) genes. Association between caffeine consumption and ALSFRS-R, ALSFRS-R rate, ECAS and survival were statistically analyzed to determine the outcome of regular caffeine consumption on ALS disease progression and cognition. No association was observed between caffeine consumption and survival (p = 0.25), functional disability (ALSFRS-R; p = 0.27) or progression of ALS (p = 0.076). However, a significant association was found with higher caffeine consumption and better cognitive performance on ECAS scores in patients carrying the C/T and T/T genotypes at rs2472297 (p-het = 0.004). Our results support the safety of regular caffeine consumption on ALS disease progression and survival and also show its beneficial impact on cognitive performance in patients carrying the minor allele T of rs2472297, considered as fast metabolizers, that would set the ground for a new pharmacogenetic therapeutic strategy., Competing Interests: Declaration of competing interest The authors have declared that no conflict of interest exists., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate muscle signal abnormalities on whole-body muscle MRI with T2 and diffusion-weighted imaging in early ALS stages., Methods: 101 muscles were analyzed in newly diagnosed ALS patients and healthy controls on a whole-body MRI protocol including four-point T2-Dixon imaging and diffusion-weighted imaging (b0 and b800). Sensitivity and inter-observer agreement were assessed., Results: 15 patients (mean age, 64 +/- 12 [SD], 9 men) who met the Awaji-Shima criteria for definite, probable or possible ALS and 9 healthy controls were assessed (mean age, 53 +/- 13 [SD], 2 men). 61 % of the muscles assessed in ALS patients (62/101) showed signal hyperintensities on T2-weighted imaging, mainly in the upper and lower extremities (legs, hands and feet). ALS patients had a significantly higher number of involved muscles compared to healthy controls (p = 0,006). Diffusion-weighted imaging allowed for the detection of additional involvement in 22 muscles, thus improving the sensitivity of whole-body MRI from 60 % (using T2-weighted imaging only) up to 80 % (with the combination of T2-weighted and diffusion-weighted imaging)., Conclusions: ALS patients exhibited significant muscle signal abnormalities on T2-weighted and diffusion-weighted imaging in early disease stages. Whole-body MRI could be used for pre-EMG mapping of muscle involvement in order to choose suitable targets, thus improving early diagnosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. 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.)

ANXA11 mutations have previously been discovered in amyotrophic lateral sclerosis (ALS) motor neuron disease. To confirm the contribution of ANXA11 mutations to ALS, a large exome data set obtained from 330 French patients, including 150 familial ALS index cases and 180 sporadic ALS cases, was analyzed, leading to the identification of 3 rare ANXA11 variants in 5 patients. The novel p.L254V variant was associated with early onset sporadic ALS. The novel p.D40Y mutation and the p.G38R variant concerned patients with predominant pyramidal tract involvement and cognitive decline. Neuropathologic findings in a p.G38R carrier associated the presence of ALS typical inclusions within the spinal cord, massive degeneration of the lateral tracts, and type A frontotemporal lobar degeneration. This mutant form of annexin A11 accumulated in various brain regions and in spinal cord motor neurons, although its stability was decreased in patients' lymphoblasts. Because most ANXA11 inclusions were not colocalized with transactive response DNA-binding protein 43 or p62 deposits, ANXA11 aggregation does not seem mandatory to trigger neurodegeneration with additional participants/partner proteins that could intervene., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Myasthenia gravis is an autoimmune disorder affecting neuromuscular junctions that has been associated with a small increased risk of amyotrophic lateral sclerosis (ALS). Here, we describe a retrospective series of seven cases with a concomitant diagnosis of ALS and myasthenia gravis, collected among the 18 French reference centers for ALS in a twelve year period. After careful review, only six patients strictly met the diagnostic criteria for both ALS and myasthenia gravis. In these patients, limb onset of ALS was reported in five (83%) cases. Localization of myasthenia gravis initial symptoms was ocular in three (50%) cases, generalized in two (33%) and bulbar in one (17%). Median delay between onset of the two conditions was 19 months (6-319 months). Anti-acetylcholine receptor antibodies testing was positive in all cases. All patients were treated with riluzole and one had an associated immune-mediated disease. In the one last ALS case, the final diagnosis was false-positivity for anti-acetylcholine receptor antibodies. The co-occurrence of ALS and myasthenia gravis is rare and requires strict diagnostic criteria. Its demonstration needs thoughtful interpretation of electrophysiological results and exclusion of false positivity for myasthenia gravis antibody testing in some ALS cases. This association may be triggered by a dysfunction of adaptive immunity., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background and Purpose: Our objective was to evaluate the extent to which the 2005 recommendations of the European Federation of Neurological Sciences (EFNS) on the multidisciplinary management of amyotrophic lateral sclerosis (ALS) are followed in clinical practice., Methods: This was a multicentre observational study involving six French ALS referral centres receiving prevalent and incident cases. Recommendations were translated into ad hoc questions referring to key aspects of management, and their application was evaluated by a clinical research assistant who independently examined the medical charts (MCs). When necessary, an independent board-certified neurologist answered the questions based on examination of the MC and interview of the caring neurologist. Questions regarding diagnosis and communication were put to patients in a self-administered questionnaire., Results: In all, 376 patients [176 incident, 200 prevalent cases; median age at diagnosis 62.8 years (interquartile range 55.7-72.3); sex ratio 1.37; 27.3% bulbar onset] were included. All the topics covered in the recommendations were evaluated: diagnostic delay (e.g. mean 13.6 months, associated with age and onset); breaking the news (e.g. criteria for communication quality were satisfactory in more than 90%); multidisciplinary and sustained support (e.g. clinic visits were scheduled every 2-3 months in 90%). Also considered were whether riluzole had been offered, symptom management, genetic testing, ventilation, communication defects, enteral nutrition, palliative and end-of-life care. Characteristics associated with poor compliance with some guidelines (schedule of visits, delayed riluzole initiation) were also identified., Conclusion: This is the first evaluation of the application of the EFNS recommendations for the management of ALS in a nationwide sample. The results allow us to highlight areas for improvement., (© 2016 EAN.)

This paper, written by French amyotrophic lateral sclerosis (ALS) center experts, presents an update of recent advances in fundamental, epidemiological and clinical research in ALS based on a review of the literature between September 2008 and November 2009. Among other pathophysiological mechanisms, the role of stress of the endoplasmic reticulum and the importance of energetic metabolic disturbances have been underscored. In the field of genetics, research has been advanced through the identification of mutations of the gene FUsed in Sarcoma/Translated in LipoSarcoma (FUS/TLS) in individuals with familial and sporadic ALS. This gene is involved in the regulation of transcription, splicing and RNA transport, and has functional homology to another ALS gene, TARDBP, which suggests that a common mechanism may underlie motor neuron degeneration. A report showed that mice expressing a mutant form of human TDP-43 develop a progressive and fatal neurodegenerative disease reminiscent of both ALS and frontotemporal lobar degeneration with ubiquitin aggregates (FTLD-U), providing a new animal model that may help to better understand the pathophysiology and test new therapeutics. Beside genetic studies, several epidemiologic studies have investigated the role of environmental factors. A recent study suggests that smoking is a risk factor for developing ALS and it is hypothesized that this could occur through lipid peroxidation via formaldehyde exposure. From a neuroprotective perspective, trials with IGF-1, sodium valproate, coenzyme Q or glatiramer acetate have failed to demonstrate any beneficial effect. A study published in 2008 argued that lithium may have a neuroprotective effect in ALS mice and also in patients. However, two preclinical studies failed to replicate the neuroprotective effect of lithium in ALS mice. Therapeutic trials have been performed or are currently ongoing in Europe and North America. Their results have not yet been published., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

This paper from a group of French experts in amyotrophic lateral sclerosis (ALS) presents an update of recent advances in fundamental, epidemiological and clinical research in ALS. Recent development in the pathogenesis of ALS suggests that motor neuron degeneration is a multifactorial and noncell autonomous process. Research has been advanced through the identification of the TAR-DNA-binding protein (TDP-43) as a common neuropathological marker of ALS and frontotemporal lobar degeneration with ubiquitin-positive inclusions. Recently, mutations in the TDP-43 gene have been described in individuals with familial and sporadic ALS. Fundamental research in ALS is expected to lead to the disclosure of new diagnostic markers and therapeutic targets. A small trial has suggested that lithium carbonate may slow ALS progression but larger trials will be needed to confirm these results.

Background and Purpose: To prospectively investigate causes of death and the circumstances surrounding death in 302 patients with amyotrophic lateral sclerosis (ALS). The functional status of patients immediately before death was also determined., Methods: Information was obtained from neurologists at ALS centres, patients' files, and, when deaths occurred outside a medical facility, attending physicians., Results: Most patients (63%) died in a medical facility. The most frequently reported cause of death was respiratory failure (77%), including terminal respiratory insufficiency (58%), pneumonia (14%), asphyxia due to a foreign body (3%) and pulmonary embolism (2%). Ten per cent of patients died from other causes: post-surgical or traumatic conditions (5%), cardiac causes (3.4%), suicide (1.3%) and sudden death of unknown origin (0.7%). The cause of death could not be determined in 13% of cases (6% inside a medical facility and 25% outside). At the time of death, only 55% of patients were receiving riluzole, 33% were undergoing non-invasive ventilation, 3% had a tracheotomy and 37% a gastrostomy., Conclusion: The information provided by this study helps to improve our understanding of the natural history of the disease and may help optimize the quality of care we can offer patients at the end of life.

Amyotrophic lateral sclerosis is a neurodegenerative disease that has no curative treatment. However, some symptoms of the disease can respond to specific treatments. The aim of these treatments is to enhance the patient's quality of life and in some instances survival. Besides physical therapy, and nutritional and respiratory supportive systems, several specific medications can be useful. However, despite the frequency of these symptoms, few studies have evaluated the benefit of these medications in ALS. Their use is most often based on clinical experience or on studies conducted in other neurological diseases. So, for most of these medications, available evidence does not permit a precise evaluation if their impact on quality of life and survival.

Electroneuromyography is essential for the diagnostic of amyotrophic lateral sclerosis. The aim of conventional needle examen is to detect peripheral motoneuron involvement by the identification of active and chronic diffuse neurogenic activities. This brings up the problem of the selection of the muscle to test to enhance the sensitivity of the exam. Recent techniques permit to study the reorganization of the motor units more precisely. Motoneuron loss is appraised by several methods for macro-EMG estimates of the number of motor units. The collateral reinnervation can be evaluated by single fibre EMG. The other main objective is to detect conduction abnormalities. These lead to differential diagnoses of pure motor neuropathy with conduction blocks. The different prognostic value of these different conditions required defining both sensitive and specific electrophysiological diagnostic criteria.

Progress in the last decades has greatly strengthened our understanding of the etiopathogenic mechanisms of amyotrophic lateral sclerosis. Such progress has lead to an evaluation of several compounds affecting excitotoxicity, oxidative stress, apoptosis, growth factors and inflammation. Riluzole has clearly proven efficiency on mortality with a 35 p.cent reduction of death or tracheotomy at 18 months. While the mechanism of action of this compound remains to be fully elucidated, there is evidence in favor of a neuroprotective effect. Other compounds have been tried in ALS. To date, results have been disappointing with worsening even being noted in some cases. These negative studies offer some insight into the pathophysiological mechanism regulating the disease, raising pertinent questions concerning the transposition of animals models to humans and about interractions between these different compounds and riluzole.