Amyotrophic Lateral Sclerosis Outcome Research Articles

Motor band sign is specific for amyotrophic lateral sclerosis and corresponds to motor symptoms.

Magnetic resonance imaging can detect neurodegenerative iron accumulation in the motor cortex, called the motor band sign. This study aims to evaluate its sensitivity/specificity and correlations to symptomatology, biomarkers, and clinical outcome in amyotrophic lateral sclerosis. This prospective study consecutively enrolled 114 persons with amyotrophic lateral sclerosis and 79 mimics referred to Karolinska University Hospital, and also 31 healthy controls. All underwent 3-Tesla brain susceptibility-weighted imaging. Three raters independently assessed motor cortex susceptibility with total and regional motor band scores. Survival was evaluated at a median of 34.2 months after the imaging. The motor band sign identified amyotrophic lateral sclerosis with a sensitivity of 59.6% and a specificity of 91.1% versus mimics and 96.8% versus controls. Higher motor band scores were more common with genetic risk factors (p = 0.032), especially with C9orf72 mutation, and were associated with higher neurofilament light levels (std. β 0.22, p = 0.019). Regional scores correlated strongly with focal symptoms (medial region vs. gross motor dysfunction, std. β -0.64, p = 0.001; intermediate region vs. fine motor dysfunction, std. β -0.51, p = 0.031; lateral region vs. bulbar symptoms std. β -0.71, p < 0.001). There were no associations with cognition, progression rate, or survival. In a real-life clinical setting, the motor band sign has high specificity but relatively low sensitivity for identifying amyotrophic lateral sclerosis. Associations with genetic risk factors, neurofilament levels and somatotopic correspondence to focal motor weakness suggest that the motor band sign could be a suitable biomarker for diagnostics and clinical trials in amyotrophic lateral sclerosis.

Feasibility assessment of using the MiToS staging system for conducting economic evaluation in amyotrophic lateral sclerosis

ABSTRACT Objectives This study assessed the feasibility of using the Milano-Torino staging (MiToS) system for conducting economic evaluation to measure health outcomes in amyotrophic lateral sclerosis (ALS). Methods A Markov model was developed using the MiToS system and evaluated with a hypothetical treatment versus standard of care. Health utilities and transition probabilities were derived from the literature. Four-time horizons (1, 5, 10, and 20 years) were examined. Treatment effects of 20–35% relative risk reduction (RRR) of progressing to the next MiToS stage were assessed. Three patient distribution scenarios were tested: (1) all patients began in stage 0; (2) patient distribution based on real-world TONiC study; (3) distribution based on the PRO-ACT database. Health outcomes (quality-adjusted life-years [QALYs], life-years [LYs]) were reported with a 3% discount rate. Results A time horizon of 10 years fully captured treatment benefits: incremental QALYs were 0.28–0.60, 0.21–0.45, and 0.26–0.55 for scenarios 1–3, respectively; incremental LYs were 0.56–1.17, 0.46–0.97, and 0.53–1.11, respectively. Conclusion MiToS-based staging can be used for conducting economic analyses in ALS. Estimated incremental QALY and LY gains were meaningful within the context of ALS, for hypothetical treatments with RRR of 20–35%.

Does repetitive nerve stimulation predict clinical outcomes in amyotrophic lateral sclerosis? A cross-sectional study

Does repetitive nerve stimulation predict clinical outcomes in amyotrophic lateral sclerosis? A cross-sectional study

Evaluating the Effect of Sodium Phenylbutyrate and Taurursodiol on Survival Outcomes in Amyotrophic Lateral Sclerosis Using a Propensity Score–Matched Cohort From the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) Database (S33.005)

Evaluating the Effect of Sodium Phenylbutyrate and Taurursodiol on Survival Outcomes in Amyotrophic Lateral Sclerosis Using a Propensity Score–Matched Cohort From the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) Database (S33.005)

Symptoms timeline and outcomes in amyotrophic lateral sclerosis using artificial intelligence

Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative motor neuron disease. Although an early diagnosis is crucial to provide adequate care and improve survival, patients with ALS experience a significant diagnostic delay. This study aimed to use real-world data to describe the clinical profile and timing between symptom onset, diagnosis, and relevant outcomes in ALS. Retrospective and multicenter study in 5 representative hospitals and Primary Care services in the SESCAM Healthcare Network (Castilla-La Mancha, Spain). Using Natural Language Processing (NLP), the clinical information in electronic health records of all patients with ALS was extracted between January 2014 and December 2018. From a source population of all individuals attended in the participating hospitals, 250 ALS patients were identified (61.6% male, mean age 64.7 years). Of these, 64% had spinal and 36% bulbar ALS. For most defining symptoms, including dyspnea, dysarthria, dysphagia and fasciculations, the overall diagnostic delay from symptom onset was 11 (6–18) months. Prior to diagnosis, only 38.8% of patients had visited the neurologist. In a median post-diagnosis follow-up of 25 months, 52% underwent gastrostomy, 64% non-invasive ventilation, 16.4% tracheostomy, and 87.6% riluzole treatment; these were more commonly reported (all Ps < 0.05) and showed greater probability of occurrence (all Ps < 0.03) in bulbar ALS. Our results highlight the diagnostic delay in ALS and revealed differences in the clinical characteristics and occurrence of major disease-specific events across ALS subtypes. NLP holds great promise for its application in the wider context of rare neurological diseases.

The Expression of Active CD11b Monocytes in Blood and Disease Progression in Amyotrophic Lateral Sclerosis.

Monocytes expressing the inflammation suppressing active CD11b, a beta2 integrin, may regulate neuroinflammation and modify clinical outcomes in amyotrophic lateral sclerosis (ALS). In this single site, retrospective study, peripheral blood mononuclear cells from 38 individuals living with ALS and 20 non-neurological controls (NNC) were investigated using flow cytometry to study active CD11b integrin classical (CM), intermediate (IM) and non-classical (NCM) monocytes during ALS progression. Seventeen ALS participants were sampled at the baseline (V1) and at two additional time points (V2 and V3) for longitudinal analysis. Active CD11b+ CM frequencies increased steeply between the baseline and V3 (ANOVA repeated measurement, p < 0.001), and the V2/V1 ratio negatively correlated with the disease progression rate, similar to higher frequencies of active CD11b+ NCM at the baseline (R = −0.6567; p = 0.0031 and R = 0.3862; p = 0.0168, respectively). CD11b NCM, clinical covariates and neurofilament light-chain plasma concentration at the baseline predicted shorter survival in a multivariable and univariate analysis (CD11b NCM—HR: 1.05, CI: 1.01–1.11, p = 0.013. Log rank: above median: 43 months and below median: 21.22 months; p = 0.0022). Blood samples with the highest frequencies of active CD11b+ IM and NCM contained the lowest concentrations of soluble CD11b. Our preliminary data suggest that the levels of active CD11b+ monocytes and NCM in the blood predict different clinical outcomes in ALS.

Improving clinical trial outcomes in amyotrophic lateral sclerosis.

Individuals who are diagnosed with amyotrophic lateral sclerosis (ALS) today face the same historically intransigent problem that has existed since the initial description of the disease in the 1860s — a lack of effective therapies. In part, the development of new treatments has been hampered by an imperfect understanding of the biological processes that trigger ALS and promote disease progression. Advances in our understanding of these biological processes, including the causative genetic mutations, and of the influence of environmental factors have deepened our appreciation of disease pathophysiology. The consequent identification of pathogenic targets means that the introduction of effective therapies is becoming a realistic prospect. Progress in precision medicine, including genetically targeted therapies, will undoubtedly change the natural history of ALS. The evolution of clinical trial designs combined with improved methods for patient stratification will facilitate the translation of novel therapies into the clinic. In addition, the refinement of emerging biomarkers of therapeutic benefits is critical to the streamlining of care for individuals. In this Review, we synthesize these developments in ALS and discuss the further developments and refinements needed to accelerate the introduction of effective therapeutic approaches.

Gastrostomy and mechanical ventilation in amyotrophic lateral sclerosis: how best to support the decision-making process?

The unfavourable outcome of amyotrophic lateral sclerosis (ALS) confronts patients with challenging decisions regarding life-sustaining measures. The decision-making process is usually triggered by medical consultations and patient-dependent factors. This may largely depend on the physician's depth of knowledge and professional experience. This paper presents an overview of the life-sustaining methods used in ALS and their effects on disease progression, survival and quality of life of patients and their caregivers. It is intended to aid physicians in their discussions with patients. We interrogate all the positive and negative facets of life-sustaining measures that may allow for optimisation of the decision-making process and care provision.

Multiple doses of cell therapy and neurorehabilitation in amyotrophic lateral sclerosis: A case report.

Cell therapy, along with intensive rehabilitation has been shown to significantly improve outcomes in amyotrophic lateral sclerosis (ALS), in addition to standard therapy. We present a 40-years-old male ALS patient, suffering for the past four years, who underwent multiple doses of cell therapy at our institution. Along with riluzole treatment and lithium co-administration, his treatment involved multiple intrathecal transplants of autologous bone marrow-derived mononuclear cells, followed by multidisciplinary neurorehabilitation. The outcome measures of ALSFunctional Rating Scale Revised score remained stable, and importantly, Six Minute Walk Test distance improved from 475.2 m to 580.8 m, over a span of 16 months. Improved outcomes are indicative of slowing down of disease progression. Multiple doses of intrathecal autologous cell therapy along with rehabilitation and lithium, in addition to standard riluzole treatment is a novel approach for decelerating disease progression and qualitatively improving living conditions for ALS patients and their caregivers.

Prognostic value of time to generalization in 71 Chinese patients with sporadic amyotrophic lateral sclerosis.

Background:It is important to determine prognostic factors for the outcome of amyotrophic lateral sclerosis (ALS) at an early stage. The time taken for symptoms to spread from spinal or bulbar regions to both (time to generalization; TTG) is considered a strong predictor of survival; however, this has rarely been studied in Asian populations. The aim of this retrospective study was to evaluate potential factors affecting prognosis in Chinese patients with sporadic ALS, with a focus on the association between TTG and overall survival.Methods:Seventy-one patients with sporadic ALS who were hospitalized at Chinese PLA General Hospital from 2009 to 2016 were followed up until December 2017. Survival analysis was performed using univariate Kaplan-Meier log-rank and multivariate Cox proportional hazards models. The clinical data of the patients were recorded and analyzed. Variables studied were age at symptom onset, sex, site of symptom onset, diagnostic latency, TTG, diagnostic category, ALS Functional Rating Scale-revised score, percent predicted forced vital capacity (FVC%), and disease progression rate (DPR) at diagnosis.Results:The mean age at onset was 54 (SD = 10.2) years, and the median survival time from symptom onset was 41 months (95% confidence interval: 34–47). By univariate analysis, factors independently affecting survival were age at symptom onset (Log rank = 15.652, P < 0.0001), TTG (Log rank = 14.728, P < 0.0001), diagnostic latency (Log rank = 11.997, P = 0.001), and DPR (Log rank = 6.50, P = 0.011). In the Cox multivariate model, TTG had the strongest impact on survival time (hazard ratio = 0.926, P = 0.01).Conclusions:TTG can be used as an effective indicator of prognosis in patients with sporadic ALS.

Apathy and its impact on patient outcome in amyotrophic lateral sclerosis.

Apathy is one of the most common behavioural symptoms of amyotrophic lateral sclerosis (ALS), yet there are few studies that have investigated the relationship between apathy and quality of life (QOL) as they are experienced by the patient. A cohort of 60 ALS patients were evaluated using the Apathy Evaluation Scale which measured cognitive, behavioural, emotional and non-specific symptoms of apathy combined with the Personal Wellbeing Index, a multidimensional measure of QOL. The relationship between patient-rated apathy and QOL scores, controlling for potential clinical and psychological confounders were analysed using univariate and multivariate methods. Apathy was identified in 30% of ALS patients. Patients with apathy reported higher levels of depression (p=0.0001). Compared to non-apathetic patients, patients with apathy had lower overall QOL (p=0.001), most pronounced in the domains related to achievements in life (p=0.001) and community-connectedness (p=0.0001). Of the cognitive, behavioural, emotional and non-specific manifestations of apathy, only the emotional symptoms explained a significant amount of variance in achievements in life (p=0.003) and community-connectedness (p=0.001). As such, emotional manifestations of apathy may underlie worse QOL in ALS patients presenting with behavioural impairment. Patient-reported outcomes, particularly those assessing psychosocial functioning may be important for demonstrating the efficacy of interventions designed to improve QOL in ALS patients with behavioural impairment.

Plasma level of club-cell (CC-16) predicts outcome in amyotrophic lateral sclerosis.

The club cell protein (CC-16) is a biomarker associated with respiratory distress and pulmonary inflammation. We evaluated CC-16 as a candidate biomarker for respiratory failure in amyotrophic lateral sclerosis (ALS). We studied 81 ALS patients and 30 matched controls. We used an ALS-related measure of functional capacity, and tested forced vital capacity (FVC) and the amplitude of the diaphragmatic response by phrenic nerve stimulation (PhrenAmpl). Plasma CC-16 levels were measured in venous blood. Kaplan-Meier survival curves were plotted to evaluate risk to non-invasive ventilation and death in patients with abnormal CC-16 levels. CC-16 levels were significantly raised in ALS patients (10.56ng/mL±6.84 vs 8.34ng/mL±3.10, P=.02), and in 17% of them, CC-16 level was above the upper cutoff value (mean+2.5SD). CC-16 levels did not correlate with age, onset region, disease duration, functional status, FVC, and PhrenAmpl. In patients with increased CC-16 level, the risk of non-invasive was greater in the following 6months (P=.01) and tended to have higher mortality in the following 30months (P=.07). We propose that increased CC-16 levels is a marker of lung inflammatory response that associated with ventilatory insufficiency are related to impending respiratory failure, not fully predicted by conventional respiratory tests. The latter are limited by the moment of testing.

Plasma Neurofilament Heavy Chain Levels correlate with disease severity and progression on multiple clinical outcomes in Amyotrophic Lateral Sclerosis (ALS) (S3.004)

Plasma Neurofilament Heavy Chain Levels correlate with disease severity and progression on multiple clinical outcomes in Amyotrophic Lateral Sclerosis (ALS) (S3.004)

Long-Term Outcome of Amyotrophic Lateral Sclerosis in Korean Subjects.

ObjectiveTo report the latest long-term outcome of amyotrophic lateral sclerosis (ALS) and to analyze the predictors of prognosis.MethodsSubjects who were diagnosed with ALS between January 2005 and December 2009 at a single institute were followed up until death or up to December 2014. Data regarding age, sex, date of onset, date of diagnosis, presence of bulbar symptoms on onset, date of initiation of non-invasive ventilation (NIV), and the date of tracheostomy were collected. Survival was assessed using Kaplan-Meier curves and multivariate analyses of the risk of death were performed using the Cox proportional hazards model.ResultsAmong 212 suspicious subjects, definite ALS was diagnosed in 182 subjects. The survival rate at 3 and 5 years from onset was 61.5% and 40.1%, respectively, and the survival rate at 3 and 5 years post-diagnosis was 49.5% and 24.2%, respectively. Further, 134 patients (134/182, 73.6%) were initiated on NIV, and among them, 90 patients (90/182, 49.5%) underwent tracheostomy. Male gender and onset age of ≥65 years were independent predictors of adverse survival.ConclusionThe analysis of long term survival in ALS showed excellent outcomes considering the overall poor prognosis of this disease.

Clinical and demographic factors and outcome of amyotrophic lateral sclerosis in relation to population ancestral origin.

To review how the phenotype and outcome of amyotrophic lateral sclerosis (ALS) change with variations in population ancestral origin (PAO). Knowledge of how PAO modifies ALS phenotype may provide important insight into the risk factors and pathogenic mechanisms of the disease. We performed a systematic review and meta-analysis of the literature concerning differences in phenotype and outcome of ALS that relate to PAO. A review of 3111 records identified 78 population-based studies. The 40 that were included covered 40 geographical areas in 10 subcontinents. Around 12,700 ALS cases were considered. The results highlight the phenotypic heterogeneity of ALS at time of onset [age, sex ratio (SR), bulbar onset], age at diagnosis, occurrence of comorbidities in the first year after diagnosis, and outcome (survival). Subcontinent is a major explanatory factor for the variability of the ALS phenotype in population-based studies. Some markers of ALS phenotype were homogeneously distributed in western countries (SR, mean age at onset/diagnosis) but their distributions in other subcontinents were remarkably different. Other markers presented variations in European subcontinents (familial ALS, bulbar onset) and in other continents. As a consequence, ALS outcome strongly varied, with a median survival time from onset ranging from 24 months (Northern Europe) to 48 months (Central Asia). This review sets the scene for a collaborative study involving a wide international consortium to investigate, using a standard methodology, the link between ancestry, environment, and ALS phenotype.

Impact of disease, cognitive and behavioural factors on caregiver outcome in amyotrophic lateral sclerosis

Up to 50% of patients with amyotrophic lateral sclerosis (ALS) show mild to moderate cognitive-behavioural change alongside their progressive functional impairment. This study examines the relative impact of patients’ disease symptoms, behavioural change and current executive function and social cognition abilities on psychosocial outcomes in spouse caregivers of people with ALS. Thirty-five spouse caregivers rated their own levels of depression and anxiety, subjective burden and marital satisfaction. Caregivers also rated their partner’s everyday behaviour. The patients were assessed for disease severity and cognitive function, with composite scores derived for executive function and social cognition. Regression analyses revealed that caregiver burden was predicted by the severity of patients’ limb involvement and behavioural problems. Depression was predicted by patients’ limb involvement, while behavioural problems and patient age predicted caregiver anxiety. Current marital satisfaction was predicted by patient behavioural problems beyond the level of pre-illness marital satisfaction. In conclusion, the study highlights the potential impact of ALS patients’ functional impairment and behavioural change on ALS caregivers’ psychosocial functioning. Clinical communication with ALS families should emphasise both physical and psychological challenges presented by the disease.

Ethnic differences in the phenotype and outcome of Amyotrophic Lateral Sclerosis: A meta-analysis of population-based studies (P4.143)

Ethnic differences in the phenotype and outcome of Amyotrophic Lateral Sclerosis: A meta-analysis of population-based studies (P4.143)

Head injury does not alter disease progression or neuropathologic outcomes in ALS.

To study the effects of head injury on disease progression and on neuropathologic outcomes in amyotrophic lateral sclerosis (ALS). Patients with ALS were surveyed to obtain head injury history, and medical records were reviewed. Linear regression was performed to determine if head injury was a predictor for mean monthly decline of Amyotrophic Lateral Sclerosis Functional Rating Scale-revised (ALSFRS-R), while controlling for confounders. Head injury history was obtained from family members of ALS autopsy cases. The frequency of tau proteinopathy, brain TDP-43 inclusions, and pathologic findings of Alzheimer disease (AD) were examined in ALS cases with head injury compared to cases without. Logistic regression was performed with each neuropathologic diagnosis as an outcome measure and head injury as a predictor variable. No difference was seen in rate of decline of the ALSFRS-R between patients with head injury (n = 24) and without (n = 76), with mean monthly decline of -0.9 for both groups (p = 0.18). Of 47 ALS autopsy cases (n = 9 with head injury, n = 38 without), no significant differences were seen in the frequency of tau proteinopathy (11% with head injury; 24% without), TDP-43 in the brain (44% with head injury; 45% without), or AD pathology (33% with head injury; 26% without). Independent logistic regression models showed head injury was not a predictor of tau pathology (p = 0.42) or TDP-43 in the brain (p = 0.99). Head injury was not associated with faster disease progression in ALS and did not result in a specific neuropathologic phenotype. The tau pathology described with chronic traumatic encephalopathy was found in ALS autopsy cases both with and without head injury.

Predictors of Outcome in Amyotrophic Lateral Sclerosis (P2.076)

Predictors of Outcome in Amyotrophic Lateral Sclerosis (P2.076)

Survival in ALS with home mechanical ventilation non-invasively and invasively: A 15-year cohort study in west Denmark

Our objective was to describe patient characteristics, survival and long-term outcome in amyotrophic lateral sclerosis (ALS) patients treated with non-invasive and invasive home mechanical ventilation (HMV). A single-centre cohort study over a 15-years period (1998–2012) was performed. All ALS patients admitted to the centre were enrolled in the study. All patients were offered treatment with non-invasive and/or invasive HMV. The patients were divided into four groups: 1) no treatment; 2) treatment with non-invasive HMV; 3) treatment with non-invasive HMV followed by invasive HMV by tracheostomy; and 4) treatment with invasive HMV by tracheostomy. Patient characteristics and effects on survival were studied. Four hundred and thirty-one patients with ALS were admitted to a referral respiratory care unit (RCU) in the period January 1998 to June 2012. The average treatment time in the groups was: 1) 22.9 months (range 1–164); 2) 25.8 months (range 1–145); 3) 56.8 months (range 14–207); and 4) 33.8 months (range 6–88). Non-invasive HMV followed by invasive HMV is a possible treatment of respiratory symptoms in ALS and has a significant effect on survival.