Characteristics and Prognosis of Oldest Old Subjects with Amyotrophic Lateral Sclerosis.

BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is an age-related neurodegenerative disease with unclear characteristics and prognosis in the oldest old (80 years and over). The aim of this study was to compare the oldest old and younger ALS patients in terms of clinical and socio-demographic characteristics, and prognosis. METHODS: ALS incident cases from the register of ALS in Limousin (FRALim), diagnosed between January 2000 and July 2013, were included. Descriptive and comparative analyses by age group were carried out. For time to event univariate analysis, Kaplan-Meier estimator and log rank test were used. Univariate and multivariate survival analyses were carried out with Cox's proportional hazard model. RESULTS: Out of 322 patients, 50 (15.5%) were aged 80 or over ("oldest old" ALS) at the time of diagnosis. Among them, the male:female gender-ratio was 1.27, and 32.6% had a bulbar onset (not different from subjects aged less than 80 years). With increasing age, there was a worsening of the clinical state of the patients at time of diagnosis in terms of weight loss, forced vital capacity, ALSFRS-R and manual muscular testing. Access to ALS referral centres decreased with age, and the use of riluzole tended to be lower in the oldest old group. The median survival of oldest old patients appeared to be 10 months shorter than that of subjects aged less than 80 years (7.4 vs. 17.4 months). CONCLUSION: The survival of oldest old ALS patients is particularly short. It relates to prognostic features at baseline and to an independent effect of advanced age.

Population-Based Evidence that Survival in Amyotrophic Lateral Sclerosis is Related to Weight Loss at Diagnosis.

BACKGROUND/AIMS: In a population-based setting, we aimed to (i) describe weight loss (WL) of amyotrophic lateral sclerosis (ALS) patients at the time of diagnosis and (ii) evaluate the association between WL and survival. METHODS: All patients recruited in the FRALim register (2000-2013) were considered to be included in this study. Time-to-death analyses were performed using a multivariable Cox model. Model discrimination and calibration were assessed. RESULTS: Among 322 patients in the register, 261 (81%) were included. At the time of diagnosis, 50.6% of patients reported a WL of more than 5%: 14.6% with WL between 5 and 10% and 36.0% with a WL of more than 10%. WL was independently associated with survival (p = 0.002). Patients with a WL of 10% or more experienced a 45% increase in the risk of death (95% CI 6-99) with respect to patients with a WL lower than 5% or no WL. The introduction of WL significantly improved the model's discrimination achieving a survival C statistic of 79.5% (95% CI 75.6-83.5, p = 0.006) at 12 months. CONCLUSION: More than 50% of ALS patients experience a WL of more than 5% at the time of diagnosis. This finding highlights the need for randomized trials to evaluate the effect of nutritional interventions to improve ALS survival.

Epidemiological evidence that physical activity is not a risk factor for ALS.

To elucidate whether physical activity (PA) and sport increase the risk of developing amyotrophic lateral sclerosis (ALS), a literature review of epidemiological studies was conducted according to the Meta-analysis of Observational Studies in Epidemiology guidelines. Six databases (Pubmed, Scopus, ScienceDirect, IngentaConnect, Refdoc and the Cochrane database) were searched to April 2014. Experts were asked to identify studies in press. Studies of interest were examined for their level of evidence and synthetized using Armon's classification for exogenous risk factors for ALS. Of 37 epidemiological works included in the review, two (5.5%) provided class I evidence, and five (13.5%) class II. Others offered evidence of class III (n = 8, 21.6%), IV (n = 16, 43.2%) and V (n = 6, 16.2%). Results were stratified according to type of exposure: (1) PA related to sport and work (n = 14), (2) soccer and American football (n = 9), (3) occupation (n = 12), (4) proxies of PA (n = 2). Among articles which considered "PA related to sport and work", two class I studies and one class II study concluded that PA is not a risk factor for ALS. This evidence establishes (level A) that PA is not a risk factor for ALS. As regards "occupational related activity" a level of evidence of U was obtained (it is unknown whether the professional category "physical worker" is a risk factor for ALS). Football/soccer may be considered as a possible risk factor for ALS (level C) and there is a need for further research taking into account the numerous confounding factors that may arise in this field.

First assessment at home of amyotrophic lateral sclerosis (ALS) patients by a nutrition network in the French region of Limousin.

Malnutrition is associated with poor survival among patients with amyotrophic lateral sclerosis (ALS). This study aimed to evaluate nutritional assessment by a network during first consultations in patients' homes. Patients identified by the regional ALS centre gave their informed consent. Assessment included functional, nutritional issues, evaluation of the need for help, whether personal or the use of aids, and noted any dietary supplementation and modification of the texture of food. Forty patients were seen a mean of 7.4 months after diagnosis; 52.5% had bulbar disease, 7.5% were malnourished; 29.4 ± 10.1 kcal/kg/day were consumed and protein intake was 1.3 ± 0.5 g/kg/day. Thirty-five percent of patients were anorexic, 43.8% reported taste disorders, and 70% had dysphagia, significantly associated with salivary stasis. Only 30% of dysphagic patients ate texture-modified food, and 90% of patients with problems drinking liquids did not use a thickener. In conclusion, assessment at home by a nutritional network can be conducted promptly. Malnutrition is rare in early disease, despite the fact that patients' diets are often low in energy and dysphagia is common. Unexpected taste disorders are detected. Dysphagia is very common but inadequately addressed. Consequently, home assessment by the network led several beneficial interventions.

Increased resting energy expenditure compared with predictive theoretical equations in amyotrophic lateral sclerosis.

OBJECTIVES: Approximately 50% to 60% of amyotrophic lateral sclerosis (ALS) is characterized by an increase in metabolic rate. The Harris and Benedict (HB) 1919 formula is the equation mainly used to calculate resting energy expenditure (cREE) compared with measured REE (mREE) by indirect calorimetry (IC), but other formulas are also applied in current practice. The present study aimed to assess mREE in patients with ALS compared with 12 cREE formulas and study the relevant threshold of REE variation to screen patients with a higher evolving risk. METHODS: Nutritional assessments and body composition (by bioimpedance analysis) were performed in patients with ALS. mREE was measured by IC, and cREE was calculated using the HB 1919, HB 1984, World Schofield, De Lorenzo, Johnstone, Mifflin, World Health Organization/Food and Agriculture Organization, Owen, Fleisch, Wang, Rosenbaum, and Nelson formulas. Functional and respiratory evolution and survival by log-rank test according to two thresholds of REE variation (10% and 20%) were studied. RESULTS: A total of 315 patients with ALS were included in the study. The median mREE was 1503 kcal/24 h (range, 1290-1698 kcal/24 h), which was higher than all predictive equations (P < 0.0001). Depending on the predictive equation, REE variation >10% and 20% was found in 35.2% to 76.3% and 14.6% to 53.3% of patients with ALS, respectively. Patients with an REE variation >20% with HB 1919 and HB 1984 had a lower survival. Moreover, with this same threshold and the Mifflin formula, patients had higher functional and respiratory evolutions and lower survival. CONCLUSIONS: The increase in metabolic rate is present according to the different cREE formulas used compared with IC. In clinical practice, REE formulas (e.g., HB 1919, HB 1984, or Mifflin) can be used as a reference value compared with IC to screen patients with ALS with an REE variation >20% and a higher evolving risk.

Resting energy expenditure equations in amyotrophic lateral sclerosis, creation of an ALS-specific equation.

INTRODUCTION: Resting energy expenditure (REE) formulas for healthy people (HP) are used to calculate REE (cREE) in amyotrophic lateral sclerosis (ALS) patients. In 50-60% of ALS cases an increase of measured REE (mREE) in indirect calometry (IC) compared to cREE is found. The aims here were (i) to assess the accuracy of cREE assessed using 11 formulas as compared to mREE and (ii) to create (if necessary) a specific cREE formula for ALS patients. METHOD: 315 Patients followed in the ALS expert center of Limoges between 1996 and 2014 were included. mREE assessed with IC and cREE calculated with 11 predictive formulas (Harris Benedict (HB) 1919, HB 1984, WSchofield, De Lorenzo, Johnstone, Mifflin, WHO/FAO, Owen, Fleisch, Wang and Rosenbaum) were determined at the time of diagnosis. Fat free mass (FFM) and fat mass (FM) were measured with impedancemetry. A Bland and Altman analysis was carried out. The percentage of accurate prediction ±10% of mREE, and intraclass correlation coefficients (ICC) were calculated. Using a derivation sample, a new REE formula was created using multiple linear regression according to sex, age, FFM and FM. Accuracy of this formula was assessed in a validation sample. RESULTS: ICC ranged between 0.60 and 0.71 (moderate agreement), and percentage of accurate prediction between 27.3% and 57.5%. Underestimation was found from 31.7% to 71.4% of cases. According to these unsatisfactory results we created an ALS-specific formula in a derivation sample (130 patients). ICC and percentage of accurate prediction increased in a validation sample (143 patients) to 0.85 (very good agreement) and 65.0% respectively, with 17.5% underestimation. CONCLUSION: REE formulas for HP underestimate REE in ALS patients compared to mREE. Our new ALS-specific formula produced better results than formulas for HP. This formula can be used to estimate REE in ALS patients if IC is not accessible.

Validity of medico-administrative data related to amyotrophic lateral sclerosis in France: A population-based study.

The accuracy of French medico-administrative data concerning amyotrophic lateral sclerosis (ALS) is to date unknown. We aimed to assess the validity of hospital discharge data (HDD) and health insurance data (HID) related to ALS. A retrospective population-based study was performed. The French register of ALS in Limousin (FRALim) was used as gold standard (2000-2013 period). All patients discharged from the regional hospitals with a 'G12.2' code in their HDD (according to the International Classification of Disease-10th version) or having a G12 HID code were considered. In the study period, the register included a total of 322 incident ALS patients. Among 451 subjects identified through HDD, 290 were true incident ALS cases, corresponding to 90.1% (95% CI 86.3-93.1) sensitivity and 64.3% (95% CI 59.7-68.7) positive predictive value (PPV). A total of 184 subjects were identified through HID, 142 of which were true ALS cases. This corresponded to 44.1% (95% CI 38.6-49.7) sensitivity and 75.5% (95% CI 68.7-81.5) PPV. The combination of both HDD and HID led to 93.8% (95% CI 90.6-96.2) sensitivity and 60.8% (95% CI 56.3-65.1) PPV. This study shows that French HDD and HID, even if combined, are not per se suitable for accurate and exhaustive direct identification of ALS cases.

Exploring the diagnosis delay and ALS functional impairment at diagnosis as relevant criteria for clinical trial enrolment.

Objectives were: i) to describe the phenotypic heterogeneity of incident amyotrophic lateral sclerosis (ALS) patients diagnosed in 2012 in French ALS centres; ii) to look at the associations between ALSFRS-R score and ALSFRS-R slope (ΔFS) at time of diagnosis with diagnosis delay, ALS phenotypes and Airlie House diagnosis criteria (AHDC); iii) to describe the rate of progression on ΔFS, according to diagnosis delay. METHODS: Incident ALS cases diagnosed in French ALS centres were included. The rate of progression was evaluated as follows: ΔFS = (48 - ALSFRS-R at time of diagnosis)/duration from onset to diagnosis (months). Fast and slow progressors were defined by ΔFS >1 and <0.5, respectively. RESULTS: At time of diagnosis, 476 patients were classified into eight phenotypes: bulbar (33.0%), spinal lumbar (28.2%), spinal cervical (23.1%), flail leg (4.4%), ALS/FTD (4.2%), possible flail arm (4.0%), respiratory (2.1%), dropped-head (1.0%). Median ΔFS (n = 358/476) was 1.0 [0.5-2.0]. ΔFS was associated with AHDC (p = 0.009), but not with clinical phenotype (p = 0.902). Stratification on diagnosis delay (<12 months or ≥18 months) allowed to differentiate fast progressors from slow progressors. CONCLUSION: At time of inclusion in therapeutic trial closed to diagnosis, ΔFS or diagnosis delay may discriminate the rate of progression.

Novel UBQLN2 mutations linked to amyotrophic lateral sclerosis and atypical hereditary spastic paraplegia phenotype through defective HSP70-mediated proteolysis.

Mutations in UBQLN2 have been associated with rare cases of X-linked juvenile and adult forms of amyotrophic lateral sclerosis (ALS) and ALS linked to frontotemporal dementia (FTD). Here, we report 1 known (c.1489C>T, p.Pro497Ser, P497S) and 3 novel (c.1481C>T, p.Pro494Leu, P494L; c.1498C>T, p.Pro500Ser, P500S; and c.1516C>G, p.Pro506Ala, P506A) missense mutations in the PXX domain of UBQLN2 in familial motor neuron diseases including ALS and spastic paraplegia (SP). A novel missense mutation (c.1462G>A, p.Ala488Thr, A488T) adjacent to this hotspot UBQLN2 domain was identified in a sporadic case of ALS. These mutations are conserved in mammals, are absent from ExAC and gnomAD browsers, and are predicted to be deleterious by SIFT in silico analysis. Patient lymphoblasts carrying a UBQLN2 mutation showed absence of ubiquilin-2 accumulation, disrupted binding with HSP70, and impaired autophagic pathway. Our results confirm the role of PXX repeat in ALS pathogenesis, show that UBQLN2-linked disease can manifest like a SP phenotype, evidence a highly reduced disease penetrance in females carrying UBQLN2 mutations, which is important information for genetic counseling, and underline the pivotal role of ubiquilin-2 in proteolysis regulation pathways.

[Epidemiology of amyotrophic lateral sclerosis]. / Épidémiologie de la sclérose latérale amyotrophique. Près de 6 000 cas en France, majoritairement sporadiques et sans facteurs de risque identifiés.

Epidemiology of amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis (ALS) is the most common motorneuron disease. The incidence of ALS in France is 2.5/100 000 persons-years of follow-up, or 1,500 cases per year. The peak incidence is between 65 and 75 years. The prevalence of ALS is 8/100 000, or 6 000 cases in France with a sex ratio close to 1. The average survival time is close to 36 months after the onset of symptoms, with a large variation between patients. The main prognostic factors are the age of onset, initial site of involvement, the time to diagnosis, respiratory status and nutritional status. 5 to 10% of cases are family related to a mutation of the four major genes SOD1, FUS, TARDP and C9ORF72. In sporadic forms an interaction between a genetic susceptibility factor and an environmental factor is suspected. There is to date no association between exogenous risk factor for sporadic ALS occurrence of which could be demonstrated reproducibly with the notable exception of smoking.

Épidémiologie de la sclérose latérale amyotrophique. La sclérose latérale amyotrophique est la plus fréquente des maladies du motoneurone. Son incidence en France est de 2,5/100 000 personnes-années, soit 1 500 cas par an. Le pic d'incidence est compris entre 65 et 75 ans. Sa prévalence est de 8/100 000, soit 6 000 cas en France, avec un sex-ratio proche de 1. La durée moyenne de survie est proche de 36 mois après le début des premiers symptômes avec une importante variation selon les patients. Les principaux facteurs pronostiques sont l'âge de début, le siège initial de l'atteinte, le délai diagnostique, le statut respiratoire et l'état nutritionnel. Cinq à 10 % des cas sont familiaux, liés à une mutation des quatre principaux gènes SOD1, FUS, TARDP et C9ORF72. Dans les formes sporadiques, une interaction entre un facteur de susceptibilité génétique et un facteur environnemental est suspectée. Il n'existe à ce jour aucune association entre un facteur de risque exogène et la survenue d'une sclérose latérale amyotrophique sporadique qui ait pu être démontrée de manière reproductible, à l'exception notable du tabagisme qui favoriserait la survenue de la maladie.

Stratification of ALS patients' survival: a population-based study.

The natural history of amyotrophic lateral sclerosis (ALS) and patient risk stratification are areas of considerable research interest. We aimed (1) to describe the survival of a representative cohort of French ALS patients, and (2) to identify covariates associated with various patterns of survival using a risk classification analysis. ALS patients recruited in the FRALim register (2000-2013) were included. Time-to-death analyses were performed using Kaplan-Meier method and Cox model. A recursive partitioning and amalgamation (RECPAM) algorithm analysis identified subgroups of patients with different patterns of survival. Among 322 patients, median survival times were 26.2 and 15.6 months from time of onset and of diagnosis, respectively. Four groups of patients were identified, depending on their baseline characteristics and survival (1) ALSFRS-R slope >0.46/month and definite or probable ALS (median survival time (MST) 10.6 months); (2) ALSFRS-R slope >0.46/month and possible or probable laboratory-supported ALS (MST: 18.1 months); (3) ALSFRS-R slope ≤0.46/month and definite or probable ALS (MST: 22.5 months), and (4) ALSFRS-R slope ≤0.46/month and possible or probable laboratory-supported ALS (MST: 37.6 months). Median survival time is among the shortest ever reported by a worldwide population-based study. This is probably related to the age structure of the patients (the oldest identified to date), driven by the underlying population (30 % of subjects older than 60 years). Further research in the field of risk stratification could help physicians better anticipate prognosis of ALS patients, and help improve the design of randomized controlled trials.

[Epidemiology, clinical spectrum of ALS and differential diagnoses]. / Épidémiologie, spectre clinique de la SLA et diagnostics différentiels.

Amyotrophic Lateral Sclerosis (ALS) is the most common motor neuron disease in adults. Its incidence in France is estimated at 2.5 per 100,000 population and its prevalence between 5 and 8 per 100,000 inhabitants. Good prognostic factors are age of early onset, a longer time to diagnosis, initial damage to the spinal onset, early management of undernutrition and restrictive respiratory failure. The diagnosis of ALS is primarily clinical and is based on the evidence of involvement of the central motor neuron and peripheral neuron (NMP) in different territories or spinal or bulbar. The EMG confirms the achievement of NMP, shows the extension to clinically preserved areas and allows to exclude some differential diagnoses. The clinical spectrum of ALS is broad: conventional forms beginning brachial, lower limb or bulbar onsets, rarer forms to start breathing, pyramidal forms, forms with cognitive and behavioural impairment. In 5-10% of cases, ALS is familial. In 15% of cases, it is associated with frontotemporal degeneration rather than orbito-frontal type. The main differential diagnoses are guided by the clinic: combining pure motor neuropathy with or without conduction block, post-polio syndrome, cramp-fasciculation syndrome, myasthenia gravis, paraneoplastic syndromes, Sjögren syndrome, retroviral infections, some endocrine disorders, some metabolic diseases, genetic diseases (Kennedy and SMA) and inclusion body myositis.

Searching for a link between the L-BMAA neurotoxin and amyotrophic lateral sclerosis: a study protocol of the French BMAALS programme.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is the most common motor neurone disease. It occurs in two forms: (1) familial cases, for which several genes have been identified and (2) sporadic cases, for which various hypotheses have been formulated. Notably, the ß-N-methylamino-L-alanine (L-BMAA) toxin has been postulated to be involved in the occurrence of sporadic ALS. The objective of the French BMAALS programme is to study the putative link between L-BMAA and ALS. METHODS AND ANALYSIS: The programme covers the period from 1 January 2003 to 31 December 2011. Using multiple sources of ascertainment, all the incident ALS cases diagnosed during this period in the area under study (10 counties spread over three French regions) were collected. First, the standardised incidence ratio will be calculated for each municipality under concern. Then, by applying spatial clustering techniques, overincidence and underincidence zones of ALS will be sought. A case-control study, in the subpopulation living in the identified areas, will gather information about patients' occupations, leisure activities and lifestyle habits in order to assess potential risk factors to which they are or have been exposed. Specimens of drinking water, food and biological material (brain tissue) will be examined to assess the presence of L-BMAA in the environment and tissues of ALS cases and controls. ETHICS AND DISSEMINATION: The study has been reviewed and approved by the French ethical committee of the CPP SOOM IV (Comité de Protection des Personnes Sud-Ouest & Outre-Mer IV). The results will be published in peer-reviewed journals and presented at national and international conferences.