Prediction of survival in amyotrophic lateral sclerosis: a nationwide, Danish cohort study

Kjældgaard, Anne Lene; Pilely, Katrine; Olsen, Karsten Skovgaard; Jessen, Anders Hedegaard; Lauritsen, Anne Øberg; Pedersen, Stephen Wørlich; Svenstrup, Kirsten; Karlsborg, Merete; Thagesen, Helle; Blaabjerg, Morten; Theódórsdóttir, Ásta; Elmo, Elisabeth Gundtoft; Møller, Anette Torvin; Bonefeld, Lone; Berg, Mia; Garred, Peter; Møller, Kirsten

doi:10.1186/s12883-021-02187-8

Cited by 26 publications

(18 citation statements)

References 21 publications

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“…Previous studies have identified ΔFS as a biomarker of ALS survival collected cross‐sectionally at baseline 6,18,22,23 . The present findings are in concordance with previous studies, confirming that a faster rate of disease progression at baseline (ΔFS ≥1.1) is associated with greater functional disability and muscle weakness.…”

Section: Discussionsupporting

confidence: 92%

Clinical and neurophysiological biomarkers of disease progression in amyotrophic lateral sclerosis

et al. 2022

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Introduction/Aims Rate of disease progression (ΔFS), measured as change in the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS‐R) and body mass index (BMI), are predictors of survival in amyotrophic lateral sclerosis (ALS). Our aim in this study was to assess the utility of these clinical biomarkers along with neurophysiological measures, such as the split hand index (SI), in monitoring disease progression. Methods Clinical trial data were collected from 107 patients recruited into the Tecfidera in ALS trial. The prognostic utility of clinical and neurophysiological measures, including ΔFS, BMI, SI, and neurophysiological index (NPI), were assessed cross‐sectionally and longitudinally (40 weeks). The outcome measures of disease severity and progression included: (i) ALSFRS‐R score; (ii) Medical Research Council (MRC) score; and (iii) forced vital capacity and sniff nasal inspiratory pressure. Results Fast‐progressor ALS patients (ΔFS ≥1.1) exhibited significantly lower ALSFRS‐R and total MRC scores at baseline. A baseline ΔFS score ≥1.1 was associated with a greater reduction in ALSFRS‐R (P = .002) and MRC (P = .002) scores over 40 weeks. Baseline BMI <25 was also associated with faster reduction of ALSFRS‐R and MRC scores. SI and NPI were associated with disease severity at baseline, but not with subsequent rate of disease progression. Discussion Implementation of the assessed clinical and neurophysiological biomarkers may assist in patient management and stratification into clinical trials.

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Section: Discussionsupporting

confidence: 92%

Clinical and neurophysiological biomarkers of disease progression in amyotrophic lateral sclerosis

et al. 2022

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“…The limitations inherent to the ALSFRS-R also influence composite end points, and post hoc analysis may become necessary to reconstruct the single score effects 36. Survival and ALSFRS-R scores are independently interrelated37 and it remains to specifically assess whether and to what extent combining these two measures provide a basis for medical decision-making 38. While symptom progression influences both functional decline and survival, these two end points are differently impacted by the possibility that a patient completes the study.…”

Section: Discussionmentioning

confidence: 99%

Review of disease-modifying drug trials in amyotrophic lateral sclerosis

Tornese

Lalli

Cocco

et al. 2022

J Neurol Neurosurg Psychiatry

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We analysed clinical trials of pharmacological interventions on patients with amyotrophic lateral sclerosis (ALS), and compared study quality and design features. The systematic review included articles published in PubMed and trials registered in ClinicalTrials.gov. Included studies were randomised double-blind placebo-controlled clinical trials assessing a disease-modifying pharmacological intervention. Studies were excluded if primary end points were safety or dose finding. A total of 28 735 articles and 721 current trials were identified. 76 published articles and 23 ongoing trials met inclusion criteria; they referred to distinct populations comprising 22 817 participants with ALS. Most articles and all current trials had parallel group design; few articles had cross-over design. A run-in observation period was included in about 20% of published studies and ongoing trials. Primary end points included functional assessment, survival, muscle strength, respiratory function, biomarkers and composite measures. Most recent trials had only functional assessment and survival. Risk of bias was high in 23 articles, moderate in 35, low in 18. A disease modification effect was observed for 10 interventions in phase II studies, two of which were confirmed in phase III. Three confirmatory phase III studies are currently underway. The present review provides cues for the design of future trials. Functional decline and survival, as single or composite measures, stand as the reference end points. Post hoc analyses should not be performed, particularly in studies using composite end points. There is a general agreement on diagnostic criteria; but eligibility criteria must be improved. Run-in observations may be used for censoring patients but are discouraged for refining participants’ eligibility. The ALS Functional Rating Scale-Revised needs improvement for use as an ordinal measure of functional decline.

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“…Age of onset, region of onset and El Escorial criteria are prognostic factors [4,32,33] but were not found to be influential in our study concerning any progression group, regardless of their differences between groups (Table 5). Although progression rate is a good prognostic marker of survival [10,34], the discordance between predictors of survival and disease progression has been noted before [24,[35][36][37][38]. In fact, the functional decline based on ALSFRS-R total score is strongly associated with survival but is not a strong predictor [36], which is evidenced by some of the most severely disabled patients being amongst the longest survivors.…”

Section: Discussionmentioning

confidence: 99%

Dynamic Bayesian networks for stratification of disease progression in amyotrophic lateral sclerosis

Gromicho

Leão

Santos

et al. 2022

Euro J of Neurology

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Background and purpose Progression rate is quite variable in amyotrophic lateral sclerosis (ALS); thus, tools for profiling disease progression are essential for timely interventions. The objective was to apply dynamic Bayesian networks (DBNs) to establish the influence of clinical and demographic variables on disease progression rate. Methods In all, 664 ALS patients from our database were included stratified into slow (SP), average (AP) and fast (FP) progressors, according to the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS‐R) rate of decay. The sdtDBN framework was used, a machine learning model which learnt optimal DBNs with both static (gender, age at onset, onset region, body mass index, disease duration at entry, familial history, revised El Escorial criteria and C9orf72) and dynamic (ALSFRS‐R scores and sub‐scores, forced vital capacity, maximum inspiratory pressure, maximum expiratory pressure and phrenic amplitude) variables. Results Disease duration and body mass index at diagnosis are the foremost influences amongst static variables. Disease duration is the variable that better discriminates the three groups. Maximum expiratory pressure is the respiratory test with prevalent influence on all groups. ALSFRS score has a higher influence on FP, but lower on AP and SP. The bulbar sub‐score has considerable influence on FP but limited on SP. Limb function has a more decisive influence on AP and SP. The respiratory sub‐score has little influence in all groups. ALSFRS‐R questions 1 (speech) and 9 (climbing stairs) are the most influential in FP and SP, respectively. Conclusions The sdtDBN analysis identified five variables, easily obtained during clinical evaluation, which are the most influential for each progression group. This insightful information may help to improve prognosis and care.

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Prediction of survival in amyotrophic lateral sclerosis: a nationwide, Danish cohort study

Cited by 26 publications

References 21 publications

Clinical and neurophysiological biomarkers of disease progression in amyotrophic lateral sclerosis

Clinical and neurophysiological biomarkers of disease progression in amyotrophic lateral sclerosis

Review of disease-modifying drug trials in amyotrophic lateral sclerosis

Dynamic Bayesian networks for stratification of disease progression in amyotrophic lateral sclerosis

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