Could PLS represent a UMN-predominant ALS syndrome?

Primary lateral sclerosis (PLS) is a motor neuron condition marked by pure upper motor neuron (UMN) degeneration. PLS represents around 3% of all motor neuron diseases. Classically the prognosis of PLS is less severe than those of amyotrophic lateral sclerosis (ALS). This explains the necessity to distinguish both conditions as early as possible. The key hallmark between the two diseases is the involvement of the lower motor neuron (LMN) system which is classically considered spared in PLS contrary to ALS. Although it seemed clinically easy to distinguish PLS from ALS with the aid of clinical and complementary examinations, there is a large body of evidence highlighting that the LMN system might be impaired in PLS. This led us to suggest that PLS might be considered as an almost pure UMN ALS phenotype.

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.

Epidemiological time-trend of amyotrophic lateral sclerosis (ALS) over two decades: The French population-based register of ALS in Limousin (FRALim register).

INTRODUCTION: Population-based registers are key to understanding disease patterns. Taking advantage of the long-standing operation of the French register of amyotrophic lateral sclerosis (ALS) in Limousin (FRALim register), we sought to determine the time trends in incidence, clinical features and survival of ALS patients from 2000 to 2020. METHODS: FRALim register included incident cases through multiple sources of ascertainment. A capture-recapture method was used to assess the exhaustiveness of case ascertainment. Crude and standardized incidences were calculated per 100,000 person-years of follow-up (PYFU). Time-period was divided (period 2000 to 2010 and period 2011 to 2020) to compare incidence rates and clinical features. Survival was analyzed using Kaplan-Meier method. Cox proportional hazards model was performed to calculate hazards for the time periods. RESULTS: Overall, 501 incident cases were identified during 21 years. The overall crude incidence was 3.26 (95% CI 2.97 to 3.55) per 100 000 PYFU. The exhaustiveness of the register was estimated at 98.8% (95% CI 97.4-99.6%) by capture-recapture analysis. Several fluctuations were observed without a consistent trend over the last two decades. The crude and standardized incidences were higher in males than females. The peak of incidence was observed in the 75-79 years age band. Almost one-third of the cases exhibited a bulbar onset. There were significant differences in clinical features between time periods. Four hundred and ninety-one cases were included in the survival analysis. The median survival time from diagnosis was 16.0 months (95% CI 14.3 to 17.7 months). Patients in the last decade experienced a lower risk of dying but the difference did not reach statistical significance (adjusted HR: 0.89 (95% CI 0.73 to 1.08, P=0.229). CONCLUSION: We provided reliable epidemiological data over two decades. We showed that incidence has been relatively stable, while clinical variability was observed. A slight improvement in survival time was found in the last decade but it was not statistically significant. Further quality register data are needed to improve our understanding of ALS epidemiological trends.

Therapeutic news in ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by death of motor neurons in the cortex and the spinal cord. This loss of motor neurons causes progressive weakness and amyotrophy. To date, the median duration of survival in patients with ALS, from first symptoms to death, is estimated to be 36 months. Currently the treatment is limited to two options: riluzole which prolongs survival for a few months and edaravone which is available in only a few countries and also has a small impact on disease progression. There is an urgent need for more effective drugs in this disease to significantly improve progression. Over the last 30 years, all trials have failed to find a curative drug for ALS. This is due, partially, to the heterogeneity of the clinical features and the pathophysiology of motor neuron death. We present in this review the various treatment options currently being developed for ALS, with an emphasis on the range of therapeutic approaches being explored, from old drugs tested in a new indication to innovative drugs obtained via biotechnology or gene therapy.

Phenotypic variability in amyotrophic lateral sclerosis.

Clinically, ALS phenotypes depend on the areas of the body that are affected, the different degrees of involvement of upper and lower motor neurons, the degrees of involvement of other systems, particularly cognition and behavior, and rates of progression. Phenotypic variability of ALS is characteristic and can be declined on the distribution of motor manifestations but also on the presence of extra-motor signs present in a variable manner in ALS patients. Neuropathologically, ALS is defined by the loss of UMN and LMN and the presence of two representative motor neuronal cytoplasmic inclusions, Bunina bodies and 43kDa Transactivation Response DNA Binding Protein (TDP-43) - positive cytoplasmic inclusions. The distribution of cytopathology and neuronal loss in patients is variable and this variability is directly related to phenotypic variability. Key regulators of phenotypic variability in ALS have not been determined. The functional decrement of TDP-43, and region-specific neuronal susceptibility to ALS, may be involved. Due to the selective vulnerability among different neuronal systems, lesions are multicentric, region-oriented, and progress at different rates. They may vary from patient to patient, which may be linked to the clinicopathological variability across patients.

Therapeutic patient education in Alzheimer's disease and related disorders: Clinical experience and perspectives.

Therapeutic patient education (TPE) is the process by which health professionals impart information to help patients self-manage their chronic disease: it is an essential part of treatment of long-term diseases and conditions. Memory loss and other cognitive disorders are usually considered as obstacles to TPE for patients with Alzheimer's disease or related disorders (ADRD). Over 100 patients with different forms of ADRD and caregivers have benefited from TPE programs since 2011 at the Limoges University Clinical and Research Memory Center. Participants report better understanding of the disease and improved relationships. TPE may prevent anxiety and depression in patient and in caregivers, and reduce burden of caregivers. General guidelines and perspectives for TPE in ADRD are outlined.

Staging amyotrophic lateral sclerosis: A new focus on progression.

Amyotrophic lateral sclerosis (ALS) is a heterogenous motoneuronal neurodegenerative condition with a panel of phenotypes exhibiting different clinical patterns. Two compounds are currently available for the treatment of ALS but the majority of trials have failed to show a positive effect on prognosis. One of the explanations which could be put forward involves the way efficacy is evaluated: clinicians agree that the ALSFRS-revised scale used in all trials does not fit with highlighting a positive effect. So, the development and validation of new tools allowing a reliable assessment of ALS has become a key issue in clinical research. Over the last three years, two functional scales (the King's College and MiToS staging systems) have been proposed. These scales rely on two different approaches to ALS: an anatomical and prognostic concept, and loss of autonomy. Both scales propose five stages. We will discuss below the contribution of these two scales to clinical evaluation and the questions which remain to be resolved in the future.

Hypermetabolism is a deleterious prognostic factor in patients with amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: The aim of this study was to investigate patients with amyotrophic lateral sclerosis in order to determine their nutritional, neurological and respiratory parameters, and survival according to metabolic level. METHODS: Nutritional assessment included resting energy expenditure (REE) measured by indirect calorimetry [hypermetabolism if REE variation (ΔREE) > 10%] and fat mass (FM) using impedancemetry. Neurological assessment included the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score. Survival analysis used the Kaplan-Meier method and multivariate Cox model. RESULTS: A total of 315 patients were analysed. Median age at diagnosis was 65.9 years and 55.2% of patients were hypermetabolic. With regard to the metabolic level (ΔREE: < 10%, 10-20% and >20%), patients with ΔREE > 20% initially had a lower FM(29.7% vs. 32.1% in those with ΔREE ≤10%; P = 0.0054). During follow-up, the median slope of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised tended to worsen more in patients with ΔREE > 20% (-1.4 vs. -1.0 points/month in those with ΔREE ≤10%; P = 0.07). Overall median survival since diagnosis was 18.4 months. ΔREE > 20% tended to increase the risk of dying compared with ΔREE ≤10% (hazard ratio, 1.33; P = 0.055). In multivariate analysis, an increased REE:FM ratio was independently associated with death (hazard ratio, 1.005; P = 0.001). CONCLUSIONS: Hypermetabolism is present in more than half of patients with amyotrophic lateral sclerosis. It modifies the body composition at diagnosis, and patients with hypermetabolism >20% have a worse prognosis than those without hypermetabolism.

Factors associated with spousal burden in Parkinson's disease.

Parkinson's disease is characterized by motor and non-motor symptoms, which can lead to progressive disability that, in turn, can lead to a burden on caregivers. Thus, the objective of this study was to determine correlations between intensity of disease burden and characteristics of patients and their spouses. The study included 38couples (patients and spouses) living at home with no severe comorbidities. The following patients' characteristics were measured: disease severity (MDS-UPDRS); cognitive status (MoCA); non-motor signs (NMSS); quality of life (PDQ-8); anxiety and depression (HADS); and levodopa equivalent dose. The Zarit Burden Interview, quality of life questionnaire (EQ-5D-VAS) and HADS were administered to spouses. The average caregiver burden score was 14.4±12.7, and correlated (in descending order) with severity of non-motor signs (R2=0.46, P<0.0001), anxiety and depression in caregivers and patients (R2=0.35, P<0.0001 and R2=0.26, P<0.0001, respectively), motor severity (R2=0.3, P<0.0001), patients' quality of life (R2=0.27, P=0.0125), levodopa equivalent dose (R2=0.13, P=0.0261) and duration of illness (R2=0.12, P=0.0307). The severity of non-motor signs, patients' and caregivers' mood, and motor disease severity are the main determinants of caregiver burden, making them important targets in the management of Parkinson's disease.

Current issues in ALS epidemiology: Variation of ALS occurrence between populations and physical activity as a risk factor.

Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease with a fatal outcome. This review aims to report key epidemiological features of ALS in relation to the hypothesis of variation between populations, to summarize environmental hypothesis and to highlight current issues that deserve much considerations. Epidemiological ALS studies have shown a variation of incidence, mortality and prevalence between geographical areas and different populations. These data could support the notion that genetic factors, especially populations' ancestries, along with environmental and lifestyle factors, play a significant role in the occurrence of the disease. To date, there is no strong evidence to confirm an association between a particular environmental factor and ALS. Physical activity (PA) has been extensively evaluated. Recent studies support with the best evidence level that PA in general population is not a risk factor for ALS. However, further research is needed to clarify the association of PA in some occupations and some athletic activities. Epidemiological research based on multicenter international collaboration is essential to provide new data on ALS especially in some regions of the world that are to date poorly represented in the ALS literature.

ALS and frontotemporal dementia belong to a common disease spectrum.

ALS is now understood to be a complex multisystem neurodegenerative disease because areas other than the motor cortices of the brain undergo degeneration. Frontotemporal dementia (FTD) may be associated with motor neuron disease, and the transactive response DNA-binding protein 43 (TDP-43) is a major pathological substrate underlying both diseases. The recent discovery of a gene that can cause both FTD, ALS and FTD-ALS, C9ORF72, has modified the way for considering these two pathologies. These findings would allow the development of potential biomarkers and therapeutic targets for these devastating diseases. This review summarizes the key points leading up to our current understanding of the genetic, clinical and neuropathological overlap between FTD and ALS.

Genetics of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease characterized by upper and lower motor neuron damage in the bulbar and spinal territories. Although the pathophysiology of ALS is still unknown, the involvement of genetic factors is no longer a subject of debate. Familial ALS (fALS) accounts for 10-20% of cases. Since the identification of the SOD1 gene, more than 20 genes have been described, of which four can explain >50% of familial cases. This review is an update focused on major aspects of the field of ALS genetics concerning both causative and susceptibility factors.

Evaluation of the application of the European guidelines for the diagnosis and clinical care of amyotrophic lateral sclerosis (ALS) patients in six French ALS centres.

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.