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Objective: To analyze disease-modifying effects of percutaneous endoscopic gastrostomy (PEG) insertion for supporting nutrition, noninvasive ventilation (NIV), and tracheostomy-assisted ('invasive') ventilation (TIV) in amyotrophic lateral sclerosis (ALS)., Methods: We retrospectively analyzed survival in a large population-based incident cohort that was prospectively followed up in our center. Analysis considered several known ALS-related prognostic variables., Results: In this population, PEG and NIV in multivariable analysis significantly correlated to survival as computed by disease onset to death/tracheostomy. NIV was associated with better survival while PEG was associated with reduced survival. Other independent prognostic factors were age at ALS onset, diagnostic delay, and flail arm/leg and pure upper motor neuron (PUMN) phenotypes. The length of survival after TIV was significantly associated with age at ALS onset (inverse correlation) whereas other variables did not. The length of survival after TIV correlated to age at ALS onset in such a way that each additional year of age at ALS onset decreased survival by about 0.7 months. Patients who underwent both TIV and NIV did not experience a better survival than those who underwent TIV alone., Conclusion: The lack of effect of enteral nutrition on ALS survival probably reflected the timing of PEG insertion in patients with more severe disease. By contrast, patients who used mechanical ventilation had an increased overall survival compared with non-ventilated ones. The study also provided new information showing that the combined use of NIV and TIV did not may prolong ALS survival as compared to TIV alone.

Spurred by patient interest, ALSUntangled herein examines the potential of the Portable Neuromodulation Stimulator (PoNS™) in treating amyotrophic lateral sclerosis (ALS). The PoNS™ device, FDA-approved for the treatment of gait deficits in adult patients with multiple sclerosis, utilizes translingual neurostimulation to stimulate trigeminal and facial nerves via the tongue, aiming to induce neuroplastic changes. While there are early, promising data for PoNS treatment to improve gait and balance in multiple sclerosis, stroke, and traumatic brain injury, no pre-clinical or clinical studies have been performed in ALS. Although reasonably safe, high costs and prescription requirements will limit PoNS accessibility. At this time, due to the lack of ALS-relevant data, we cannot endorse the use of PoNS as an ALS treatment.

Introduction : Clinical trials location is determined by many factors, including the availability of patient populations, regulatory environment, scientific expertise, and cost considerations. In clinical drug development of amyotrophic lateral sclerosis (ALS), where genetic differences have been described and may be related to geographic setting, this could have implications for the clinical interpretation of results in underrepresented geographic settings. Objective : The aim of this study was to review country participation in ALS clinical research based on available data from clinical trial registries and databases. Methods : We performed a scoping review with available information about clinical trials on ALS in ClinicalTrials.gov (CT), EU clinical trials register (EudraCT), WHO International Clinical Trials Registry Platform (ICTRP) and Web of Science (WOS). Inclusion criteria were clinical trials in phase 2 and 3 to treat ALS, recruiting or active not recruiting, from 23/06/2018 to 23/06/2023. Results : The total number of clinical trials identified were 188; 54 studies in CT, 38 in EudraCT, 47 in ICTRP and 49 in WOS. We identified 77 clinical trials after deleting duplicates and applying exclusion criteria. The countries with most studies conducted were the US with 35 studies (10.9%), followed by the United Kingdom, Belgium, France and Germany with 21 studies each one of them (6.5%). Conclusion : The data obtained in our review showed a non-homogeneous distribution in clinical trials at the international level, which may influence the interpretation of the results obtained.

ALS is a neurodegenerative disease characterized by loss of motor neurons, resulting in progressive weakness and wasting of muscles. The average survival time is 2-5 years, mostly due to respiratory failure. Since current therapies can prolong survival time by only a few months, multidisciplinary care remains the cornerstone of the management of ALS. At the ALS Expert Centre of University Hospitals Leuven, a large proportion of Belgian ALS patients are seen for diagnosis and a significant number is also in follow-up with the multidisciplinary team. In this retrospective study, we compared the outcome of incident patients who were in follow-up at our site with patients who were not in follow-up. We included 659 patients of which 557 (84.5%) received specialized care at the ALS Expert Centre. After adjusting for clinically relevant prognostic parameters, multidisciplinary follow-up significantly prolonged survival ( p  = 0.004; HR = 0.683; CI 95% [0.528 - 0.884]). This increase in survival is mainly driven by patients with spinal onset ( p  = 0.035; HR = 0.746; CI 95% [0.568 - 0.980]), since no significant increased survival time was observed in patients with bulbar onset ( p  = 0.28; HR = 0.778; CI 95% [0.495 - 1.223]). These data confirm that multidisciplinary follow-up contributes to a better outcome of patients, emphasizing the importance of multidisciplinary specialized care in ALS.

Objective: Delays in amyotrophic lateral sclerosis (ALS) diagnosis can result in compromised disease management and unnecessary costs. We examined the extent of ALS misdiagnosis in the US and Europe., Methods: Data were collected via the Adelphi ALS Disease Specific Programme™, a cross-sectional survey of physicians and a medical chart review of their consulting patients with ALS in France, Germany, Italy, Spain, the UK (EU5), and the US. Between July 2020 and March 2021, eligible physicians (primary speciality neurology, active involvement in managing patients with ALS) abstracted data from patients (≥18 years old) with confirmed ALS., Results: Overall, 138 physicians completed the survey (EU5 107, US 31), with data reviewed from 795 patient medical charts (EU5 568, US 227); 278 (35.0%) patients (EU5 183 [32.2%], US 95 [41.9%]) had received ≥1 initial misdiagnosis based on symptoms later attributed to ALS. Mean (SD) time from symptom onset to first healthcare professional consultation was 3.8 (5.2) months (EU5 4.3 [4.8] months, US 2.6 [5.8] months). Mean (SD) time from symptom onset to ALS diagnosis was 8.2 (12.5) months (EU5 9.6 [14.0] months, US 5.0 [6.8] months) and increased to 10.4 (17.9) for patients with a misdiagnosis (compared with 6.9 [7.2] for patients with no misdiagnosis). Physician-identified barriers to timely ALS diagnosis included the similarity of symptoms to other conditions and delayed referral to neurologists., Conclusions: Misdiagnosis of ALS is frequent, with a protracted diagnostic pathway. Targeted education of patients and physicians about signs and symptoms and benefits of prompt referral to multidisciplinary care are needed.

Objective: This article presents an updated analysis of the LIGALS register, a prospective study conducted over a ten-year period (2009-2018) in Liguria, Italy, aimed at evaluating the incidence, prevalence, clinical presentation, and management of amyotrophic lateral sclerosis (ALS)., Methods: We calculated the mean annual crude incidence rate of ALS, assessed the point prevalence of ALS on January 1, 2018, and analyzed demographic factors, clinical characteristics, and clinical management strategies. Data analysis included Cox regression analysis to identify predictors of survival., Results: The mean annual crude incidence rate of ALS was 3.16/100,000 per year (CI 95%) while the point prevalence of ALS on January 1, 2018, was 9.31/100,000 population (CI 95%). Among the patients, 6.5% were familial ALS, while 93.5% were sporadic cases. Clinical management strategies, including percutaneous endoscopic gastrostomy (PEG) and noninvasive ventilation (NIV), were employed. The study observed a stable frequency of NIV initiation and PEG placement over time, with a growing trend toward earlier PEG positioning. The mean survival from symptom onset was 39 months, whereas from diagnosis, it was 26 months. Cox regression analysis identified several predictors of survival, including gender, age at onset and diagnosis, site of onset, diagnostic category, phenotype, and diagnostic delay., Conclusions: This comprehensive analysis provides valuable insights into the long-term trends in ALS epidemiology and clinical management in Liguria, Italy. It underscores the importance of continued research efforts in understanding and addressing the challenges posed by ALS, particularly in terms of early diagnosis and optimizing clinical interventions to improve patient outcomes.

Objective: The study aims to analyze the quality of studies that make economic evaluations for amyotrophic lateral sclerosis (ALS). Assessing the quality of studies can guide policy-making and planning. Methods: One of the most recognized checklists "The Consensus on Health Economic Criteria" (CHEC)-list designed by Evers et al. in 2005 aims to answer two important questions: is the methodology of the study appropriate, and are the results of the study valid? We reviewed studies focusing on ALS and its economic costs, and evaluated the studies with (CHEC)-list. Results: We examined 25 articles in terms of their cost evaluation and quality. It is seen that they mainly focus on medical costs, ignoring social care costs. When the quality of the studies is examined, it is seen that the studies overall achieve high scores in terms of their purpose and research question, but some of the studies score low in terms of ethical dimension, comprehensiveness of expenditure items, their application of sensitivity analyses and their study design. Conclusions: The main recommendation of our study for future cost evaluation studies is that they should focus on the questions in the checklist that are scored low overall by the 25 articles, and consider the social care costs as well as medical costs. Our recommendations when designing cost studies can be applied to other chronic diseases with long-term economic costs like ALS.

Objective : The identification of effective therapeutics for ALS necessitates valid and responsive outcome measures to track disease progression and therapeutic gain in clinical trial settings. The Amyotrophic Lateral Sclerosis-Health Index (ALS-HI) is a multifaceted, disease-specific patient-reported outcome measure (PRO) designed to measure ALS symptomatic disease burden in adults with ALS. Methods: Through a national cross-sectional study of individuals with ALS, we identified the most important symptoms in ALS. These symptoms were incorporated into the ALS-HI, a measure that quantifies the multifaceted disease burden in ALS. We performed factor analysis, qualitative patient interviews, test-retest reliability assessment, and known groups analysis to evaluate and validate the ALS-HI. Results: The cross-sectional study included 497 participants with ALS who identified the most important symptoms to include in the ALS-HI. Fifteen participants beta tested the ALS-HI and found it to be clear, easy to use, and relevant. Twenty-one participants engaged in a test-retest reliability study, which indicated the reliability of the instrument (intraclass correlation coefficient = 0.952 for full instrument). The final ALS-HI and its subscales demonstrated a high internal consistency (Cronbach's α = 0.981 for full instrument) and an ability to differentiate between groups with dissimilar disease severity. Conclusions: This research supports use of the ALS-HI as a valid, sensitive, reliable, and relevant PRO to assess the multifactorial disease burden faced by adults with ALS. The ALS-HI has potential as a mechanism to track disease progression and treatment efficacy during therapeutic trials.

Objective: We endeavor to draw attention to what appears to be a gap in the management of ALS patients and the potential uncertainty of clinical drug trial research results in the absence of a structured approach to ensure nutritional adequacy. Methods: A selective literature review was curated to focus on the barriers to measure the adequacy of daily nutritional intake in the context of physical challenges and functional impairments facing ALS patients. The consequences of a negative energy (calorie) balance are highlighted and discussed from the perspective of clinical drug trials and daily ALS care. Conclusion: We propose that by redirecting the emphasis away from the exclusive focus on symptoms to the fundamental principles of maintaining adequate nutritional intake, we will mitigate the consequences of nutrition as an uncontrolled variable to improve global efforts in battling ALS.

Introduction/Aims . Primary lateral sclerosis (PLS) is exceedingly rare and has been an enigmatic disease. Recent progress has drastically changed this perception, with early biomarkers being investigated and potential medications for PLS emerging at the preclinical stage. The aim of this paper is to describe a study of PLS natural history and discuss the limitations and proposed solutions to the study of a rare and slowly progressive disease. Methods . The PLS Natural History Study is a 30-site, 24-month, prospective study that is supported by multiple funding sources. The study aims to enroll 50 early PLS (disease duration ≤4 years) and 50 definite PLS (disease duration 4 to 15 years) participants using modified PLS Diagnostic Criteria. Smartphone-based assessments including semi-quantitative and quantitative measures and patient-reported outcomes are utilized. In-person quantitative measures are also completed during site visits. The change in the PLS Functional Rating Scale score is the primary outcome. The study utilizes the NeuroBANK ® patient-centric data capture and management platform. The biostatistical analysis plan has been developed. Results . In one year, 28 participants have been recruited. Enrollment has been much slower than anticipated due to the COVID-19 pandemic, the rarity of PLS, and potential study competition for internal resources from ALS clinical trials. Discussion . We discuss the need for more innovative methods to enroll and study individuals with such rare diseases and propose a number of mechanisms by which more efficient enrollment could be facilitated.

Objective: Expert consensus guidelines recommend referral of people with amyotrophic lateral sclerosis (ALS) to ALS health charities for support. Limited research indicates that patients and families value interaction with these volunteer sector organizations. We investigated how patient support from Canadian ALS health charities (ALS Societies) is experienced by those affected by ALS, and whether patient-centered outcomes validate recommendations for referral., Methods: Data were drawn from the ALS Talk Project, an asynchronous online focus group study. Patients and family caregivers were recruited from regions across Canada. Seven groups met online for 14 weeks between January and July 2020. Seventy-eight participants made statements about ALS Societies. Data were qualitatively analyzed using directed content analysis and the constant-comparative approach., Results: Participants viewed ALS Societies as integral to the healthcare system. The Societies acted as patient navigators and filled perceived care gaps, including psychological support. They provided critical practical assistance, particularly equipment loans and peer support groups; comprehensive disease-related and real-life information; and personal connections. They facilitated knowledge of research, emerging therapies, and research opportunities. Delayed referral to ALS Society supports and information resources was a concern for some participants., Conclusions: ALS Societies provide patients with critical practical, informational, and emotional support and play an overarching role as patient/research navigators. Patient-centred outcomes support patient referral to ALS Societies. Communication about the services provided should be a standard component of clinical care, with choice of access left to individuals. Clinical conversations should be supplemented with information resources developed by these voluntary sector organizations.

Objective: The ALS Functional Rating Scale-Revised (ALSFRS-R) is the most frequent primary outcome measure in ALS trials. The reliable and accurate performance of this instrument is critical. The Barrow Neurological Institute Clinical Research Organization (BNI-CRO) has been performing evaluator training and certification for the ALSFRS-R since 2011. Here we evaluate the impact of evaluator training and participant practice., Methods: Training records were reviewed for evaluators trained and certified by the BNI-CRO at least twice since 2011. We determined the impact of training intervals on ease of recertification. We also assessed whether the mode of training impacted successful vignette scoring. For self-reported participant assessment, remote training was provided by BNI CRO personnel; we determined whether there was a practice effect on reliable assessment., Results: 117 evaluators completed at least two training sessions either via interactive in-person training, interactive remote training, or by completing a self-training module. Poorer performance on retraining was noted when the interval between pieces of training was 2 years or greater. Mode of training also impacted performance; interactive in-person and remote sessions were associated with better performance than the use of self-training modules. For participant self-assessment, week-week variability in ALSFRS-R scores declined over time as the study progressed., Conclusions: Standard training of evaluators has an impact on the performance of the ALSFRS-R, with shorter intervals between training positively impacting performance. Interactive training sessions allowing for real-time questions also are associated with better performance. Continued training is important to maintain a high-quality ALSFRS-R assessment.

Our research project computed the direct health costs of patients with amyotrophic lateral sclerosis (ALS) in a Spanish multidisciplinary unit and explored the main factors associated. Besides analyzing a context with universal health care provision, we used an administrative health care dataset from the most crucial center unit treating ALS in Catalonia (80% of total patients). Our results show that the direct health cost of caring for an ALS patient in our unit was 5,158€per patient/year. This cost was not influenced by the onset of the disease, sex or age, but it increased if the patient lived near our center since this facilitates the frequency of follow-up visits. Finally, the higher the educational level, the lower the direct health costs.

The Covid-19 pandemic has impacted healthcare. Our aim was to identify how amyotrophic lateral sclerosis (ALS) care in the UK has been affected by the pandemic by exploring the experiences of people living with ALS (plwALS), healthcare professionals (HCPs) working with plwALS, and ALS care centers. Three surveys were carried out to explore the experiences of plwALS, HCPs and ALS care centers during the pandemic. Quantitative data were analyzed using descriptive and inferential statistics and triangulated with the qualitative data which were analyzed thematically. Responses from 53 plwALS, 73 HCPs and 23 ALS care centers were analyzed. Five main themes were identified: keeping safe, losses, negative emotions, delivering care and alternative care delivery in a pandemic. PlwALS and HCPs felt that care was sub-optimal as a result of the pandemic. Changes to care included longer waiting times and face-to-face appointments being canceled or replaced by virtual consultations. While benefits of virtual consultations were reported, concerns were raised about incomplete clinical assessments and the disruption of provision of testing and interventions. ALS care has changed as a result of the pandemic. Patients have had a lack of face-to-face contact with HCPs and have experienced delays to investigations and treatments. PlwALS and HCPs were concerned about the impact of this change, but the long-term implications remain unclear. We propose recommendations for HCPs caring for plwALS, that will promote continuity of evidenced based care in the context of a pandemic.

Objective: Uniform data collection is fundamental for multicentre clinical trials. We aim to determine the variability, between ALS trial centers, in the prevalence of unexpected or implausible improvements in the revised ALS functional rating scale (ALSFRS-R) score, and its associations with individual patient and item characteristics. Methods: We used data from two multicentre studies to estimate the prevalence of an unexpected increase or implausible improvement in the ALSFRS-R score, defined as an increase of 5 points or more between two consecutive, monthly visits. For each patient with a 5-point or more increase, we evaluated the individual contribution of each ALSFRS-R item. Results: Longitudinal ALSFRS-R scores, originating from 114 trial centers enrolling a total of 1,240 patients, were analyzed. A 5-point or more increase in ALSFRS-R total score was found in 151 (12.2%) patients, with prevalence per study center ranging from 0% to 83%. Bulbar onset, faster disease progression at enrollment, and a lower ALSFRS-R score at baseline were associated with a sudden 5-point or more increase in the ALSFRS-R total score. ALSFRS-R items 2 (saliva), 9 (stairs), 10 (dyspnea), and 11 (orthopnea) were the primary drivers when a 5-point or more increase occurred. Conclusions: Sudden 5-point or more increases in ALSFRS-R total scores between two consecutive visits are relatively common. These sudden increases were not found to occur with equal frequency in trial centers; which underscores the need for amending existing standard operating procedures toward a universal version and monitoring of data quality during the study, in multicentre research.

Background: Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA). Objective: To assess the feasibility of clinical studies on the effect of therapy in children (<18 years) with ALS in Europe. Methods: The EMA database was searched for submitted PIPs in ALS. A questionnaire was sent to 58 European ALS centers to collect the prevalence of pediatric ALS during the past ten years, the recruitment potential for future pediatric trials, and opinions of ALS experts concerning a waiver for ALS. Results: Four PIPs were identified; two were waived and two are planned for the future. In total, 49 (84.5%) centers responded to the questionnaire. The diagnosis of 44,858 patients with ALS was reported by 46 sites; 39 of the patients had an onset < 18 years (prevalence of 0.008 cases per 100,000 or 0.087% of all diagnosed patients). The estimated recruitment potential (47 sites) was 26 pediatric patients within five years. A majority of ALS experts (75.5%) recommend a waiver should apply for ALS due to the low prevalence of pediatric ALS. Conclusions: ALS with an onset before 18 years is extremely rare and may be a distinct entity from adult ALS. Conducting studies on the effect of disease-modifying therapy in pediatric ALS may involve lengthy recruitment periods, high costs, ethical/legal implications, challenges in trial design and limited information.

Objective: To describe current practices and barriers and support needs in gastrostomy indication and decision-making amongst rehabilitation physicians of ALS care teams in the Netherlands., Methods: Cross-sectional online survey of rehabilitation physicians of ALS care teams in the Netherlands. Survey items covered current practices in timing of indication (i.e. indicators and criteria), goals , initiating discussion about gastrostomy , and criteria for preferred method of placement ; and barriers and support needs in indication and decision-making. Descriptive analysis was used for quantitative responses, thematic, and content analysis for qualitative data., Results: Twenty-nine physicians (41%) of 27 ALS care teams (71%) responded. Timing of indication : physicians agreed on important indicators but not cutoff values/criteria. Goals : optimizing nutritional status (100%), ensuring safe food-intake (72%), and reducing effort of meals (59%). Initiating discussion about gastrostomy : 52% introduces the topic early after diagnosis, 48% at indication. Criteria for method of placement included physician preference (69%), availability of service (21%), lower complication risk (17%), contraindication (59%), and patient preference (24%). Reported barriers (69% of respondents) were: patient readiness (52%), timing of indication (31%), and organizational barriers (18%). Support needs (62%): evidence-based timing of indication (35%) and tailored patient education (31%)., Conclusions: There is practice variation in the timing of first introduction of gastrostomy and preferred method of placement, but agreement on goals and indicators . More evidence on optimal timing of gastrostomy placement is needed. However, until then early and regular discussion of the topic of gastrostomy and better patient information may promote patient readiness and support patient choice.

A roundtable convened in July 2020 examined issues concerning respiratory support in amyotrophic lateral sclerosis (ALS), with reference to the potential for an early-phase orally administered medication that might either postpone the introduction of noninvasive ventilation (NIV) and/or enhance the benefits to be gained from it. Attention was also given to the impact of the COVID-19 pandemic on usual practice in the assessment and management of ALS-related respiratory difficulties. Implementation of NIV marks a step-change in clinical status for patients and a major increase in burden for caregivers. All means to ease this transition should be explored: an oral therapy that supported respiratory function and patients' independence and sense of well-being would aid discussions to facilitate the eventual successful introduction of NIV. Assessment of a candidate oral therapy that might support respiratory function in ALS patients would be aided by the development of improved patient-reported outcome measures for robust quantification of treatment effect and quality of life. Such instruments could also be used to monitor patients' status during the COVID-19 pandemic, averting some of the risks of face-to-face assessment plus the patient burden and costs of traditional methods. Several oral candidate therapies have recently failed to meet their primary endpoints in clinical trials. However, understanding of the underlying physiology and appropriate trial design have grown and will inform future developments in this field.

Objective: To evaluate how Amyotrophic Lateral Sclerosis (ALS) patients' mortality rates change, based on different levels of forced vital capacity (FVC) and disease duration, providing a scheme of mortality rates of a real population of ALS patients to improve the design of future RCTs. Methods : One random spirometry for each ALS patient was selected during four time intervals from disease onset: (1) ≤12 months; (2) ≤18 months; (3) ≤24 months; (4) ≤36 months. Date of spirometry corresponded to date of trial entry, while time interval onset-spirometry to disease duration at enrollment. Mortality rates from inclusion were computed at different time intervals. Based on progression rates, patients were stratified in slow, intermediate and fast progressors. Survival from recruitment was calculated depending on FVC, disease duration and progression rate. Results : We included 659 patients in group 1, 888 in group 2, 1019 in group 3 and 1102 in group 4. Mortality rates were higher in each group at reducing the FVC cutoff used for recruitment ( p  < 0.001). Median survival decreased when lowering FVC and disease duration cutoffs ( p  < 0.001); a higher median disease progression rate of included patients led to lower median survival from recruitment. The proportion of recruited fast progressors raised when shortening disease duration and lowering FVC cutoff. Conclusions : This is a simple model for setting eligibility criteria, based on mortality rates of patients depending on FVC and disease duration, to select the best population for RCTs, tailored to trials' primary endpoints and duration.

Objectives : Mindfulness-based interventions seem to be effective in promoting QOL of ALS patients and caregivers, but most require substantial time. In the Langerian approach, mindfulness can be easily promoted with mental tasks and short lectures. This study aims to explore the impact of an ALS-specific online Langerian mindfulness training program on QOL of ALS patients. Methods: We developed and tested with an Randomized Controlled Trial (RCT) a 5-week active learning mindfulness program. Participants were recruited from the ALS clinic at Penn State Health and online and were randomly assigned to either the mindfulness group or a wait-list control group. The primary outcome was the patient's QOL after the treatment. 3 and 6-month follow-ups, together with anxiety, depression, care burden, and physical function, assessed at all times for both patients and caregivers, were explored as secondary outcomes. Results: 47 ALS patients and 27 caregivers were recruited. Among the ALS patients, the experimental group reported higher levels of QOL at the end of the treatment (d = 0.54). Moreover, they showed lower values of depression, anxiety, and negative emotions, compared to the controls, over time. The caregivers from the mindfulness group reported lower scores of care burden, depression, and anxiety, with higher values of energy and emotional well-being over time. Conclusions: This small RCT provides preliminary evidence that this intervention leads to an increase of QOL and a reduction in psychological comorbidities in ALS patients and caregivers. Given the relatively short time commitment, it may be easily implemented by the ALS community.

Objectives: The aim of this study was to investigate how nutritional management services for people with Amyotrophic Lateral Sclerosis (pwALS) are structured in the UK, in order to gain insight into current practice and identify key barriers and enablers to delivering and providing services. Methods : A three-part, sequential mixed-methods study was conducted that comprised (i) a thematic analysis of data from five focus groups (with 47 ALS health professionals from 41 UK organizations and four service user representatives), (ii) a nationwide cross-sectional survey (281 ALS healthcare professionals) and (iii) a freedom of information request (251 organizations). Results : UK nutritional management services for pwALS are coordinated from specialist ( n  = 22) and non-specialist care centers ( n  = 89), with national variability in the organization and delivery of services. Multidisciplinary working was highlighted to facilitate the coordination of nutritional care. However, the need to provide evidence-based continuing education for HCPs was evident. Overall, the lack of clear guidelines on the nutritional management of people with ALS was identified as a key barrier to the delivery of effective nutritional care, as was the lack of transparency and consistency in the commissioning of nutritional services. Further concerns over the timeliness of the dietetic intervention and equity of access and provision were raised. Conclusions : Our findings suggest that development of guidelines for nutritional management, particularly at diagnosis and pre-gastrostomy, could drive standardization of high quality nutritional care for pwALS. Such guidance has the potential to reduce inequalities in geographical provision by providing clarity for those commissioning specialist nutrition services.

Objective : Amyotrophic lateral sclerosis (ALS) is a multisystem neurodegenerative disorder which includes cognitive and behavioral symptoms akin to frontotemporal dementia (FTD). Despite the necessity of caregiver intervention to assist with the management of cognitive and behavioral symptoms, there has been a lack of research on the topic. A focus on caregiver coping may offer a promising foundation to guide the development of interventions as part of ALS care. Accordingly, the aim of the present study was to examine the relationships between caregiver coping, psychological morbidity and burden of care in the context of ALS cognitive and behavioral symptoms. Methods : Fifty-five patient-caregiver dyads were recruited from specialized ALS and FTD clinics. Specific coping strategies were examined using the COPE Inventory/Brief COPE and psychological morbidity and burden were assessed using the Depression, Anxiety, and Stress Scale-21 and Zarit Burden Interview. The relationship between coping, psychological morbidity and burden of care were analyzed using univariate and multivariate methods. Results : High-burden caregivers were more likely to be caring for patients with a diagnosis of ALS-FTD ( p =.0001). Caregivers used problem-focused strategies (particularly planning) more frequently ( M  = 71.4, SD = 15.3) compared to emotion-focused ( M  = 60.8, SD = 12.3) and dysfunctional coping strategies ( M  = 42.2, SD = 8.6). A diagnosis of ALS-FTD ( p =.0001) and problem-focused strategies ( p =.024) emerged as significant predictors of caregiver burden. Caregiver anxiety, depression and stress were not predictive of caregiver burden ( p =.151). Conclusions : Timely provision of caregiver support optimizing problem-focused coping strategies as part of multidisciplinary ALS care, particularly for caregivers of ALS-FTD patients may mitigate caregiver burden.

Objective: The ALSFRS-R is limited by multidimensionality, which originates from the summation of various subscales. This prevents a direct comparison between patients with identical total scores. We aim to evaluate how multidimensionality affects the performance of the ALSFRS-R in clinical trials. Methods: We simulated clinical trial data with different treatment effects for the ALSFRS-R total score and its subscales (i.e. bulbar, fine motor, gross motor and respiratory). We considered scenarios where treatment reduced the rate of ALSFRS-R subscale decline either uniformly (i.e. all subscales respond identically to treatment) or non-uniformly (i.e. subscales respond differently to treatment). Two main analytical strategies were compared: (1) analyzing only the total score or (2) utilizing a subscale-based test (i.e. alternative strategy). For each analytical strategy, we calculated the empirical power and required sample size. Results: Both strategies are valid when there is no treatment benefit and provide adequate control of type 1 error. If all subscales respond identically to treatment, using the total score is the most powerful approach. As the differences in treatment responses between subscales increase, the more the total score becomes affected. For example, to detect a 40% reduction in the bulbar rate of decline with 80% power, the total score requires 1380 patients, whereas this is 336 when using the alternative strategy. Conclusions: Ignoring the multidimensional structure of the ALSFRS-R total score could have negative consequences for ALS clinical trials. We propose determining treatment benefit on a subscale level, prior to stating whether a treatment is generally effective.

We describe the telemedicine experience of an Italian ALS tertiary Center during COVID-19 pandemic. A total of 144 visits were scheduled between 6th March and 6th April 2020. These mostly consisted of neurological or psychological visits (139, 96.5%). One hundred thirty-nine (96.5%) visits were performed as telemedicine and mostly via phone call (112, 80.6%). Three (2.1%) visits were considered as urgent and maintained as outpatient care. Additionally, patients were still able to telephone, being put through directly to their neurologists. Many requests of contact were addressed at getting information about the scheduled visits or examinations (45, 43.3%). Globally, patients and caregivers were satisfied with the telemedicine service. However, the majority (85, 65.9%) would prefer a face-to-face visit. In conclusion, telemedicine could be considered a good complement to face-to-face care, even after social restrictions have been eased.

The HeadUp collar (previously known as the Sheffield Support Snood) provides support for neck weakness caused by amyotrophic lateral sclerosis (ALS) and has shown to be superior to alternative options in a small cohort of patients from one single center. Here we report the assessment of the HeadUp collar in a larger cohort of patients, exploring the use in other neurological conditions and expanding to other centers across the UK and Ireland. An interventional cross-sectional study design was implemented to investigate the usability and acceptability of the HeadUp collar. A total of 139 patients were recruited for the study, 117 patients had a diagnosis of ALS and 22 patients presented with neck weakness due to other neurological conditions. Participants were assessed at baseline, fitted a HeadUp collar and followed-up one month later. The performance of the HeadUp collar was rated favorably compared to previously worn collars in terms of the ability to eat, drink and swallow. Findings suggest that the collar also permitted a more acceptable range of head movements whilst maintaining a good level of support. We conclude that the HeadUp collar is a suitable option for patients with neck weakness due to ALS and other neurological conditions.

Objective: To investigate the role of arterial blood gas (ABG) analysis parameters (blood carbon dioxide, pCO2; oxygen, pO2; carbonate, HCO3 - ; standard base excess, SBE) in monitoring respiratory function and ventilation compliance after noninvasive mechanical ventilation (NIV) adaptation, predicting survival in ALS patients. Methods : We selected the first ABG performed after NIV start in ALS patients followed from 2000 to 2015 in Turin ALS Center. Correlations between ABG parameters and survival were calculated. Risk for death/tracheostomy was computed at modifying ABG parameters by using Cox regression models, adjusted for the main prognostic factors. Kaplan-Meier curves were then performed and compared. Results : A total of 186 post-NIV ABGs were included. HCO3 - and SBE showed a significant correlation with survival after NIV (respectively, R = -0.183, p  = 0.018 and R = -0.200, p  = 0.010). Risk for death/tracheostomy after NIV was significantly higher at increasing HCO3 - and SBE blood levels, especially when HCO3 - was >29 mmol/L and SBE >4 mmol/L (respectively, HR 1.466, 95% CI 1.068-2.011, p  = 0.018 and HR = 1.411, 95% CI 1.030-1.32, p  = 0.032). Survival in NIV was higher in patients with HCO3 - < 29.0 mmol/L and SBE < 4.0 mmol/L. Conclusions : HCO3 - and SBE blood levels are markers of ventilation compliance, tolerance and efficacy, being able to predict survival after NIV start in ALS.

Background : Although noninvasive ventilation (NIV) improves survival and quality of life (QOL) in ALS, use of NIV is suboptimal. Objective: To determine compliance with "early" NIV initiation, requisite for the feasibility of a large study of early NIV initiation, and examine factors impacting compliance. Methods : Seventy-three ALS participants with forced vital capacities (FVC) >50% were enrolled. Participants with FVC over 80% (Group 1) were initiated on NIV early (FVC between 80 and 85%). Participants with FVC between 50 and 80% (Group 2) started NIV at FVC between 50 and 55%. Symptom surveys, QOL scores, and NIV compliance (machine download documenting use ≥4 hours/night >60% of time) were collected following NIV initiation. Results : 53.6% of Group 1 and 50% of Group 2 were compliant 28 days following NIV initiation, with increased compliance over time. Participants who were unmarried, had lower income, lower educational attainment, or limited caregiver availability were less likely to be compliant. Bothersome symptoms in non-compliant participants included facial air pressure, frequent arousals with difficulty returning to sleep, and claustrophobia. Both compliant and noncompliant participants felt improved QOL with NIV; improvement was significantly greater in compliant participants. Conclusions : These data suggest ALS patients can comply with NIV early in their disease, and potentially benefit as evidenced by improved QOL scores, supporting both feasibility and need for a study comparing early versus late NIV initiation. Moreover, modifiable symptoms were identified that could be optimized to improve compliance. Further studies are needed to determine the impact of "early" intervention on survival and QOL.

Background: Teleneurology is an effective tool for the rapid evaluation of patients in remote locations with a well-established use in stroke and epilepsy. To date its adoption for Amyotrophic Lateral Sclerosis (ALS) care is still in a preliminary stage. We evaluated the feasibility of multidisciplinary assessment of patients with ALS, using telememedicine during the emergency determined by the COVID-19 pandemic. Methods: All patients included in this survey had received a diagnosis of ALS according to international criteria after a complete clinical and paraclinical assessment during 2019. A structured questionnaire was used by the neurologist with the patient or the caregiver. A video interaction was offered but refused by all patients because they did not feel comfortable or did not have smartphone. Results : Out of 31 clinical interviews 8 were completed directly with the patients and 23 with patients' caregivers. In a successive survey, most of patients were satisfied with the neurological interview (85%), the possibility to interact directly with the clinician being at home (85%) and reduction of economic and time costs because they avoided unnecessary travel to the clinic. Most of subjects expressed their willingness to continue to be included in remote evaluation programs (90%). Notably, none of the patients presented index symptoms of Covid-19 infection. Conclusion : Our study indicates that telemedicine is a valid tool to triage patients with ALS to increase practice outreach and efficiency. Delivery of care via telemedicine was effective and successful in people with ALS in the dramatic and sudden crisis determined by Covid-19 outbreak.

Objective: To evaluate whether a blended (face-to-face and online) psychosocial support program for caregivers of patients with Amyotrophic Lateral Sclerosis (ALS) and Progressive Muscular Atrophy (PMA), aimed at enhancing feeling of control over caregiving, reduces psychological distress. Methods: A randomized controlled trial using a wait-list control design was conducted. Caregiver-patient dyads were randomly assigned to either the support program ( n  = 74) or to a wait-list control group ( n  = 74). The support program, based on Acceptance and Commitment Therapy, consists of 1 face-to-face contact, 6 online guided modules and 1 telephone contact. Participants filled in questionnaires at baseline, 3 and 6 months. Caregivers' feeling of control over caregiving was assessed using two self-efficacy measures. Primary outcome was caregivers' psychological distress. Secondary outcomes included caregiver burden, caregiver quality of life and patients' quality of life and psychological distress. Intention-to-treat and per-protocol analyses were performed using linear mixed models. Results: The support program had no effect on the primary or secondary outcomes, despite a significant positive effect on the intervening variable self-efficacy with regard to control over thoughts. Almost half of the caregivers did not complete the intervention with the most frequently reported reason being lack of time. Caregivers who completed the intervention evaluated the support program positively. Conclusions: The support program did not reduce distress of partners of patients with ALS/PMA but may be beneficial by increasing feeling of control over the caregiving situation. The high level of intervention drop outs may have limited the ability to detect an intervention effect. Trial registration: Netherlands Trial Registry NTR5734, registered 28 March 2016.

Neuroinflammation, meaning the establishment of a diffuse inflammatory condition in the CNS, is one of the main hallmarks of amyotrophic lateral sclerosis (ALS). Recently, a crucial role of regulatory T cells (Tregs) in this disease has been outlined. Tregs are a T cell subpopulation with immunomodulatory properties. In this review, we discuss the physiology of Tregs and their role in ALS disease onset and progression. Evidence has demonstrated that in ALS patients Tregs are dramatically and progressively reduced in number and are less effective in promoting immune suppression. In addition, Tregs levels correlate with the rate of disease progression and patient survival. For this reason, Tregs are now considered a promising therapeutic target for neuroprotection in ALS. In this review, the clinical impact of these cells will be discussed and an overview of the current clinical trials targeting Tregs is also provided.

Objective : Amyotrophic lateral sclerosis (ALS) has profound effects on people with ALS (PALS) and caregivers. There is a paucity of research detailing and comparing PALS and caregiver day-to-day perspectives of ALS. Methods : A survey developed collaboratively by The ALS Association and a panel of experts in ALS care was designed to broadly sample the experience of PALS and caregivers with respect to physical and emotional symptoms, the efficacy of treatment approaches, and goals for future treatments. Specific physical symptoms assessed consisted of fatigue, pain, weakness, shortness of breath, difficulty sleeping, speech problems, depression and other mood changes, and cognitive changes. PALS, caregivers of living patients with ALS (C-LPALS), and caregivers of deceased patients with ALS (C-DPALS) were contacted by email to participate in a 30-minute online survey. Results : 887 PALS, 444 C-LPALS, and 193 C-DPALS responded to the survey. In comparison to PALS, C-LPALS perceived that PALS had significantly higher rates of all surveyed symptoms except for pain and weakness. Caregivers self-reported higher stress levels than PALS ( p  < 0.001). 35% (135/383) of caregivers reported experiencing a devastating or near devastating financial impact of ALS and 64% (247/383) of caregivers felt their own health had worsened. Caregivers were significantly less likely to perceive a positive response to treatment in comparison to PALS ( p  < 0.001). Conclusions : PALS and caregivers report a number of symptoms beyond weakness that affect daily life which may be targets of future interventions. There are opportunities to improve services and care for caregivers to reduce the burden of illness.

There are a number of physical restrictions that develop in the course of amyotrophic lateral sclerosis (ALS). While loss of speech and motor control may be partially compensated by the support of assistive devices, swallowing difficulty and respiratory insufficiency require medical interventions (percutaneous endoscopic gastrostomy, noninvasive, and invasive ventilation). Based on the data collected within the NEEDSinALS study, we found major differences in personal satisfaction with the financing, healthcare provision, medical infrastructure, and regulations of German and Polish ALS patients, despite minor differences in economic burden caused by the disease. In order to explain this phenomenon, we thoroughly reviewed the legal basis, structure and organization of the healthcare systems in Germany and Poland to determine the range of obstacles in the everyday lives of patients and their caregivers that are attempting to attain an assistive device or care after the start of medical interventions.

Objective : We aimed to provide an overview of telehealth used in the care for patients with amyotrophic lateral sclerosis (ALS), and identify the barriers to and facilitators of its implementation. Methods : We searched Pubmed and Embase to identify relevant articles. Full-text articles with original research reporting on the use of telehealth in ALS care, were included. Data were synthesized using the Consolidation Framework for Implementation Research. Two authors independently screened articles based on the inclusion criteria. Results : Sixteen articles were included that investigated three types of telehealth: Videoconferencing, home-based self-monitoring and remote NIV monitoring. Telehealth was mainly used by patients with respiratory impairment and focused on monitoring respiratory function. Facilitators for telehealth implementation were a positive attitude of patients (and caregivers) toward telehealth and the provision of training and ongoing support. Healthcare professionals were more likely to have a negative attitude toward telehealth, due to the lack of personal evaluation/contact and technical issues; this was a known barrier. Other important barriers to telehealth were lack of reimbursement and cost-effectiveness analyses. Barriers and facilitators identified in this review correspond to known determinants found in other healthcare settings. Conclusions : Our findings show that telehealth in ALS care is well-received by patients and their caregivers. Healthcare professionals, however, show mixed experiences and perceive barriers to telehealth use. Challenges related to finance and legislation may hinder telehealth implementation in ALS care. Future research should report the barriers and facilitators of implementation and determine the cost-effectiveness of telehealth.

Objective: The Ljubljana ALS Centre, established in 2002, is the only tertiary center for amyotrophic lateral sclerosis (ALS) in Slovenia. The aim of our study was to evaluate the impact of therapeutic interventions and improvements in the multidisciplinary care on the survival of our patients. Methods: All patients diagnosed with ALS at our center during years 2003-2005 (early group) and 2011-2012 (late group) were included in this retrospective cohort study ( n  = 124). Kaplan-Meier survival analysis and multiple regression analysis with Cox proportional hazards model were performed to compare survival and to evaluate the differences between the two cohorts. Results: Median survival from the time of diagnosis was 13.0 (95% CI 10.2-15.8) months in the early group and 21.8 (95% CI 17.2-26.4) months in the late group ( p  = 0.005). In the Cox proportional hazards analysis, the late group of patients was associated with better survival independently of all other prognostic factors (hazard ratio (HR)=0.51, 95% CI = 0.32-0.81, p  = 0.004). Survival was also associated with patients' age, use of noninvasive ventilation (NIV) and gastrostomy. The model fit significantly improved when the interaction between the NIV use and the observed time period was added to the model (HR = 0.34, 95% CI = 0.12-0.96, p  = 0.041). Conclusions: Our findings suggest that improvements in the multidisciplinary care were beneficial for survival of our patients with ALS. The survival benefit in the late group of our patients could be partially explained by the improvements in the NIV use at our center.

Objective: To assess the role of premorbid type 2 diabetes in patients with amyotrophic lateral sclerosis (ALS) in China. Methods: We compared data from ALS patients with premorbid type 2 diabetes (T2D) and ALS patients without T2D with regard to the age of onset of ALS. In addition, survival was compared between these two groups of patients using propensity score matching (PSM). Results: Among 1331 consecutive sporadic ALS patients, 100 (7.5%) were labeled as ALS-T2D and 1231 were labeled as ALS-control according to the presence or absence of premorbid T2D. The mean age of onset in patients in the ALS-T2D group was 57.0 years, with a 4.4-year delay compared to that in the ALS-control group [57.0 (SD, 9.6) years vs 52.6 (SD, 10.3) years, respectively; p  = 0.000]. This 4.4-year delay was significant after adjusting for sex and the site of onset in a multiple linear regression model. Additionally, after comparison with matched pairs, a nonsignificant increase in survival was observed among the ALS patients with premorbid T2D. Conclusions: The results support the protective role of diabetes in ALS. It is possible to infer that these beneficial effects occur mainly in the preclinical and early stages of the disease course.

Objective : Patient engagement in research is increasingly recognized as important across many countries and fields. In 2008, we conducted surveys that suggested a need for improved patient engagement in ALS research. We decided to create an ALS Clinical Research Learning Institute (ALS-CRLI) to facilitate direct interactions between researchers and people with ALS and their caregivers, toward ultimately improving engagement. Methods : Initially modeled after a similar program in Parkinson's disease, our ALS-CRLI is a multi-day collection of formal courses for people with ALS and their caregivers, moderated by clinicians, scientists and patient advocates. Previous graduates (called ALS Research Ambassadors) engage with the current class participants before, during and after the courses. Prior to the courses, Research Ambassadors serve as "mentors" to the participants, offering guidance and setting expectations. Feedback during the courses is used to change the way researchers design and advertise studies, and feedback after the courses is used to improve the agenda for subsequent ALS-CRLIs. Funding is provided by patient advocacy groups including the ALS Association and ALS Hope Foundation. Research Ambassadors are provided with ongoing mentoring and notifications about opportunities for engagement via regular teleconferences with the Northeast ALS Consortium's Patient Education and Advocacy Committee and their own Facebook page. Engagement and advocacy efforts are tracked using a tool on the Northeast ALS Consortium's website. Results and Conclusions : We have now held 15 ALS-CRLIs at various locations within the United States, resulting in over 320 graduated ALS Research Ambassadors. From these engagements, researchers have been prompted to formally include patients in the design process, to design more patient-centric trials and to create new ways to help patients find trials. Research ambassadors are improving awareness and clearing up misconceptions about participation in research, improving research availability, and helping to create more patient-centric trial designs. In addition, we are now creating an ALS-CRLI Toolkit that will facilitate ALS-CRLIs throughout the world. This will be housed on the Northeast ALS Consortium website.

Introduction : Susceptibility to amyotrophic lateral sclerosis (ALS) is associated with smoking in some studies, but it is not clear which aspect of smoking behavior is related. Using detailed records of lifetime smoking we investigated the relationship between smoking and ALS in a UK population. Methods : In this retrospective case-control study, smoking status was collected using environmental questionnaires from people diagnosed with ALS between 2008 and 2013 and from age, sex and geographically matched controls. Categorical measures of smoking behavior were: smoking at the time of survey and smoking initiation; continuous measures were intensity (cigarettes per day), duration (years from starting to stopping or time of survey), cigarette pack years, and comprehensive smoking index (CSI), a measure of lifetime smoking. We used logistic regression to assess the risk of ALS with different combinations of smoking variables adjusted for age at survey, gender, level of education, smoking status and alcohol initiation, selecting the best model using the Akaike Information Criterion. Results : There were 388 records with full smoking history. The best-fitting model used CSI and smoking status at the time of survey. We found a weak association between current smoking and risk of ALS, OR 3.63 (95% CI 1.02-13.9) p value 0.05. Increase in CSI score did not increase risk of ALS: OR 0.81 (95% CI 0.58-1.11) p value 0.2. Conclusion : There is weak evidence of a positive effect of current smoking on the risk of ALS which does not show dose-dependence with higher levels of lifetime smoking and maybe a false positive result.

Objective: To evaluate the use of telehealth as part of specialized care for patients with amyotrophic lateral sclerosis (ALS) and the user experiences of patients and healthcare professionals. Methods: Fifty patients with ALS were recruited from a single specialist center and used telehealth, consisting of an ALS-app for self-monitoring and messaging, alerts for symptom-worsening, and nurse practitioner follow-up. Patients self-monitored their well-being (daily report), body weight (weekly) and functional status (monthly). The use of the telehealth service was evaluated through adoption rate, dropout rate and adherence to self-monitoring. User-experiences were collected through online surveys among 23 patients and nine healthcare professionals, and interviews with 12 patients. Results: The adoption rate was 80%, dropout rate 4% and median follow-up was 11 months. Good adherence was seen in 49% of patients for well-being, 83% for body weight and 87% for functional assessment. For patients who discontinued using telehealth due to the end-of-life phase, median time between last measurement and death was 19 days. The majority of patients experienced using telehealth as easy, helpful, not burdensome, and reported satisfaction with flexible clinic visits and the continuity of care. Healthcare professionals reported that telehealth was of added value in ALS-care. Conclusions: ALS-care supplemented by home-monitoring and nurse practitioner follow-up was shown to be suitable and widely accepted by patients and healthcare professionals in our ALS clinic. Success factors were low self-monitoring burden, a user-friendly platform and the provision of personalized feedback. Further research is needed to replicate these findings in other ALS clinics.

Objective: The rates of decline in respiratory measurements, including Peak Cough Flow (PCF) have not been established in Amyotrophic Lateral Sclerosis (ALS). Additionally, optimal prescription of cough adjuncts which aim to increase cough strength are unknown. The primary aim of this study was to quantify declines in respiratory function in ALS using PCF, Sniff Nasal Inspiratory Pressure (SNIP) and Slow Vital Capacity (SVC). Secondary aims were to measure respiratory morbidity, audit the characteristics of those prescribed cough adjuncts, and compare outcomes between treated and untreated cohorts. Methods: A prospective, longitudinal, observational, cohort study evaluated respiratory measures, morbidity, and physical function in ALS patients at three monthly intervals, over one year. Patient and disease characteristics of those prescribed cough adjuncts were profiled at the time of device prescription. Results: one hundred and eight participants with mean age 62.1 ± 11.5 years participated. PCF declined rapidly at a rate of 124.8L/min/year ( p  < 0.001). SNIP, SVC (%predicted), and ALSFRS-R also declined significantly at rates of 18.72cmH 2 O, 17.49%, and 9.62 units per year respectively ( p  < 0.001). Thirty-two (29.6%) patients reported 56 incidences of chest infection and 21 died. Patients prescribed a cough adjunct (44.4%) had significantly lower average PCF, SNIP, SVC percent predicted, and ALSFRS-R ( p  < 0.001). Conclusions: This study identified a rapid rate of decline in PCF, a similar decline in SNIP, and slower declines in SVC and ALSFRS-R. Cough adjunct prescription was triggered by declining respiratory measures and recommended PCF thresholds, but also by respiratory symptoms. Chest infections were common in patients regardless of cough adjunct prescription and should be closely monitored.

Objective: There are conflicting data on nutritional factors influencing survival in amyotrophic lateral sclerosis (ALS) patients after percutaneous endoscopic gastrostomy (PEG) placement. We performed an observational cross-sectional study evaluating body mass index (BMI) categories and cholesterol levels as prognostic factors for survival after PEG. Moreover, we assessed body composition in a subgroup of patients to better explain the influence of BMI on survival. Methods: Neurological and nutritional parameters were evaluated at the time of PEG implantation in 47 consecutive patients. Moreover, body composition was evaluated in a subgroup of 22 patients by bioelectrical impedance analysis. Survival was calculated as the time from the PEG placement to death. Results: Underweight patients had a significantly increased risk of death as compared to normal-weight patients using Cox regression analysis [HR = 3.37 (1.29-8.81); p  = 0.04]. Similarly, older age at the onset of symptoms significantly increased the risk of death [HR = 1.07 (1.02-1.12); p  = 0.001]. Neither overweight/obesity nor hypercholesterolemia affected survival. All ALS patients showed an altered body composition compared to the general population. In addition, a BMI <18.5 kg/m 2 identified patients with a significant reduction of body cell mass (BCM) and phase angle (PhA) compared to patients with normal BMI taken as the reference value. Conclusions: In the later stages of the disease, only a BMI < 18.5 kg/m 2 and older age at symptom onset had a prognostic value on survival. Dyslipidemia did not affect survival. The low BCM and PhA characterizing underweight patients support the role of BMI as a predictor of survival.

Objective : Spirometry is commonly used as screening tool for respiratory insufficiency in neuromuscular diseases. Despite the well-known effects of reference standards on spirometric outcomes, its standardization is overlooked in current guidelines. We aim to illustrate the effect of spirometric reference values on prognostication, medical decision-making, and trial eligibility in the applied setting of amyotrophic lateral sclerosis (ALS). Methods : We selected 4,651 patients with 32,022 FVC measurements from the PRO-ACT dataset. The FVC estimates were standardized according to five reference standards: Knudson '76, Knudson '83, ECSC, NHANES III, and GLI-2012. (Generalized) linear mixed-effects and Cox proportional hazard models were used to evaluate longitudinal patterns and time-to-event outcomes. Results : The mean population %predicted FVC varied between 78.5% (95% CI 78.0-79.1) and 88.5% (95% CI 87.9-89.1). The unstandardized liters provided the worst fit on the survival data (AIC 20573, c-index 0.760), whereas the GLI provided the best fit (AIC 20374, c-index 0.780, p  < 0.001). The mean population rate of decline in %predicted FVC could vary as much as 11.4% between reference standards. The median time-to-50% predicted FVC differed by 2.9 months between recent (14.5 months, 95% CI 14.4-16.1) and early reference standards (17.4 months, 95% CI 16.1-18.2). Conclusion : Independent of technique, device, or evaluator, spirometric reference values affect the utility of spirometry in ALS. Standardization of reference values is of the utmost importance to optimize clinical decision-making, improve prognostication, enhance between-center comparison and unify patient selection for clinical trials.

Objective : To systematically review quantitative and qualitative literature on optimal provision of noninvasive ventilation (NIV) for patients with amyotrophic lateral sclerosis/motor neuron disease (MND). Methods : A systematic search of electronic databases, together with supplementary search methods was used to identify relevant literature from the last 20 years. Studies of any empirical design with an English abstract were eligible for inclusion. Data from documents meeting our criteria were extracted and synthesized using narrative and thematic synthesis. A patient pathway of care model was used to integrate data and provide a process perspective to the findings. Results : While the importance of individualizing care was highlighted, factors optimizing use for all patients include: specialized multi-disciplinary team service provision; determining need using respiratory function tests in addition to symptom report; providing adequate information for patients and their family; paying attention to the role of carers in decision-making; adequately managing secretions; considering the most advantageous place of initiation; optimizing the interface, machine mode, and settings for patient comfort and effectiveness; providing supportive interventions where appropriate; regular monitoring and adjustment of settings; and providing opportunities for ongoing discussion of patient wishes. Conclusions : Optimizing use of NIV in people with MND requires consideration of multiple factors as part of a process throughout the patient pathway. Current guidelines predominantly focus on the initiation of NIV and may underplay psychosocial factors. We have made evidence-based recommendations for each step in the pathway, which may help improve optimal uptake, usage, quality of life, and survival outcomes in patients with MND.

Objective : Previous studies suggest a positive impact of telehealth in the care of people with motor neuron disease/amyotrophic lateral sclerosis (MND/ALS). This study reports the development of self-reported questions for telemonitoring, using a tablet-based device Careportal ® , in the care of patients with MND on noninvasive ventilation (NIV) and its initial impact. Methods : The study consisted of a question development phase and an evaluation phase of the use of Careportal ® . The development phase employed a modified Delphi process. The evaluation phase involved a 24-week pilot study with 13 patients (median age = 66; median illness duration = 14 m), who were using NIV. The participants completed overnight oximetry and self-report questions via Careportal ® each week, generating interventions where required. Patient-ventilator interaction (PVI) data were monitored and the revised ALS functional rating scale (ALSFRS-R) was completed. Results : Telemonitoring encompassing the newly developed 26-item symptom questions showed good feasibility and validity. During the evaluation phase, 61 interventions were made for 10 patients, including seven patients who had routine clinic appointments during the trial to optimize care. ALSFRS-R showed significant illness deteriorations. Blood oxygen saturation (SpO 2 ) levels were maintained, time ventilated and inspiratory pressures increased during the trial. Conclusions : The MND OptNIVent question set together with weekly ventilator and oximetry monitoring facilitated the maintenance of ventilation and SpO 2 levels despite illness progression. The use of the question set, and devices, such as Careportal ® , facilitate care and may further enable a single point of contact for patients from which clinicians may offer proactive interventions to optimize care.

Objective: To model the effects of demographic change under various scenarios of possible future treatment developments in ALS. Methods: Patients diagnosed with ALS at the King's College Hospital Motor Nerve Clinic between 2004 and 2017, and living within the London boroughs of Lambeth, Southwark, and Lewisham (LSL), were included as incident cases. We also ascertained incident cases from the Canterbury region over the same period. Future incidence of ALS was estimated by applying the calculated age- and sex-specific incidence rates to the UK population projections from 2020 to 2116. The number of prevalent cases for each future year was estimated based on an established method. Assuming constant incidence, we modelled four possible future prevalence scenarios by altering the median disease duration for varying subsets of the population, to represent the impact of new treatments. Results: The total number of people newly diagnosed with ALS per year in the UK is projected to rise from a baseline of 1415 UK cases in 2010 to 1701 in 2020 and 2635 in 2116. Overall prevalence of ALS was predicted to increase from 8.58 per 100,000 persons in 2020 to 9.67 per 100,000 persons in 2116. Halting disease progression in patients with C9orf72 mutations would yield the greatest impact of the modelled treatment scenarios, increasing prevalence in the year 2066 from a baseline of 9.50 per 100,000 persons to 15.68 per 100,000 persons. Conclusions: Future developments in treatment would combine with the effects of demographic change to result in more people living longer with ALS.

Objective : To estimate amyotrophic lateral sclerosis (ALS) prevalence, 5-year survival, and explore factors associated with survival in a Medicare population. Methods : A validated administrative claims algorithm was used to classify individual's ages 18-89 years at index date (first claim with a diagnosis of motor neuron disease or ALS between 1 January 2007 and 31 December 2011) with Medicare Advantage prescription drug coverage into mutually exclusive categories: ALS, no ALS, and possible ALS. Crude prevalence and cumulative survival from index date to the date of death, disenrollment or end of the study were calculated. Cox-proportional hazards were used to estimate and explore factors associated with survival. Results : Of 2631 eligible individuals, the algorithm identified 1271 (48 %), 1157 (44 %), 203 (8 %) as ALS, no ALS and possible ALS, respectively. The 5-year period prevalence and the 2011 point prevalence of ALS were 20.5 and 11.8 per 100,000, respectively. Evidence of death was documented in 81%, 35%, and 1.6% of the ALS, no ALS or possible ALS groups, respectively. Unadjusted median survival time was 388, 542 and 1473 days for the ALS, no ALS and possible ALS groups, respectively. Seeing a psychiatrist or neurologist at the index visit, having respiratory or genitourinary comorbidities, and the number of pre-index acute inpatient admissions were associated with shorter survival. Conclusions : Surveillance data from a Medicare population demonstrated a higher prevalence of ALS. Results highlight the need for effective ALS treatment options and resources for patients with ALS who will likely face limited therapeutic choices and care options at the end of life.

Objective: This study aims (1) to assess physicians' attitudes toward different palliative end-of-life (EOL) practices in amyotrophic lateral sclerosis (ALS) care, including forgoing artificial nutrition and hydration (FANH), continuous sedation until death (CSD), and withdrawing invasive ventilation (WIV), and toward physician-assisted dying (PAD) including physician-assisted suicide and euthanasia and (2) to explore variables influencing these attitudes., Methods: We used two clinical vignettes depicting ALS patients in different stages of their disease progression to assess the influence of suffering (physical/psycho-existential) on attitudes toward WIV and the influence of suffering and prognosis (short-term/long-term) on attitudes toward FANH, CSD, and PAD., Results: 50 physicians from European ALS centers and neurological departments completed our survey. Short-term prognosis had a positive impact on attitudes toward offering FANH (p = 0.014) and CSD (p = 0.048) as well as on attitudes toward performing CSD (p = 0.036) and euthanasia (p = 0.023). Predominantly psycho-existential suffering was associated with a more favorable attitude toward WIV but influenced attitudes toward performing CSD negatively. Regression analysis showed that religiosity was associated with more reluctant attitudes toward palliative EOL practices and PAD, whereas training in palliative care was associated with more favorable attitudes toward palliative EOL practices only., Conclusion: ALS physicians seem to acknowledge psycho-existential suffering as a highly acceptable motive for WIV but not CSD. Physicians appear to be comfortable with responding to the patient's requests, but more reluctant to assume a proactive role in the decision-making process. Palliative care training may support ALS physicians in these challenging situations.

Objective: As declining respiratory muscle function commonly leads to disability and death in amyotrophic lateral sclerosis (ALS), respiratory measurements such as slow vital capacity (SVC) may predict disease progression. This study evaluated the relationship between SVC and symptoms measured by the revised ALS Functional Rating Scale (ALSFRS-R)., Methods: About 453 ALS placebo-treated patients from the EMPOWER trial (NCT01281189) were evaluated. Correlations between %predicted SVC and individual respiratory ALSFRS-R subdomain items, respiratory subdomain score (maximum score of 12), and total ALSFRS-R score (maximum score of 48) were evaluated using the Pearson correlation coefficient. Pearson's chi-squared test was used to evaluate changes from baseline to week 48 in ALSFRS-R respiratory symptom and respiratory subdomain scores in patients with baseline %predicted SVC above/below the median at baseline and with more slowly/more rapidly decreasing %predicted SVC., Results: The %predicted SVC showed significant correlations with dyspnea, orthopnoea, respiratory insufficiency, respiratory subdomain score, and total ALSFRS-R score (all p < 0.0001). Patients with baseline SVC values < median were significantly more likely than those with baseline SVC ≥ median to have a change in total ALSFRS-R respiratory subdomain score from 12 to <12 (40.9% vs. 30.2%, p = 0.0358) and from ≥10 to <10 (41.6% vs. 24.4%, p = 0.0005). Additionally, patients with smaller declines in SVC over time were significantly more likely to have smaller decreases in their respiratory subdomain scores (p < 0.0001)., Conclusions: The higher correlation between %predicted SVC and specific ALSFRS-R symptom scores in patients with rapidly versus more slowly progressing disease reinforces the importance of continually monitoring respiratory function throughout the disease course.

Objectives: Propose an empirical amyotrophic lateral sclerosis (ALS) staging approach called Fine'til 9 (FT9) based on how many of the patient's ALS functional rating scale (ALSFRS-R) subscores are 9 or less (of normal 12). Gain insights into progression of ALS by applying Markov models to ALS stages by multiple systems (King's, Milan-Torino system (MITOS) and FT9)., Methods: Patients from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) dataset were staged using ALSFRS-R responses. Risks of progression through stages and death were estimated, as were effects of prognostic variables on these risks., Results: A total of 29,947 time points in 3199 patients from the PRO-ACT dataset were assigned stages. Although the three systems were moderately correlated, MITOS stages were heavily skewed toward advanced disease, whereas King's and FT9 stages were more balanced. Non-sequential progression was observed with King's system. Markov models adequately described transitions from stage to stage in the first year of observation, but underestimated risks beyond that point. Regardless of staging method, initial rate of ALSFRS-R decline had a powerful effect on rate of progression through sequential stages, whereas age predominantly influenced stage-specific mortality., Conclusion: King's and FT9 are more sensitive to observed progression of disease in clinical trials than MITOS. FT9 can partition the course similar to King's, and may have advantages of sequential progression and easy applicability to retrospective data. Markov transition intensity estimates may be of value for counseling, health economic studies, and research design. In particular, this framework permits estimation of multidimensional effects of variables (including treatment) on outcome.

Objective: To identify differences in demographics, disease characteristics, treatments, and co-morbidities between patients with "amyotrophic lateral sclerosis (ALS) reversals" and those with typically progressive ALS., Methods: Cases of possible ALS reversals were found in prior publications, in the Duke ALS clinic, through self-referral or referral from other Neurologists, and on the internet. Of 89 possible reversals identified, 36 cases were included because chart or literature review confirmed their diagnosis and a robust, sustained improvement in at least one objective measure. Controls were participants in the Pooled Resource Open-Access ALS Clinical Trials database and the National ALS Registry. Cases and controls were compared using descriptive statistics., Results: ALS reversals were more likely to be male, have limb onset disease, and initially progress faster. The prevalences of myasthenia gravis (MG) and purely lower motor neuron disease in cases were higher than estimates of these prevalences in the general population. The odds of taking curcumin, luteolin, cannabidiol, azathioprine, copper, glutathione, vitamin D, and fish oil were greater for cases than controls., Conclusions: When compared to patients with typically progressive ALS, patients with reversals differed in their demographics, disease characteristics, and treatments. While some of these patients may have had a rare antibody-mediated ALS mimicker, such as atypical myasthenia gravis, details of their exams, EMGs and family histories argue that this was unlikely. Instead, our data suggest that ALS reversals warrant evaluation for mechanisms of disease resistance and that treatments associated with multiple ALS reversals deserve further study.