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

Abstract Introduction Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with great heterogeneity. Biological prognostic markers are needed for the patients to plan future supportive treatment, palliative treatment, and end-of-life decisions. In addition, prognostic markers are greatly needed for the randomization in clinical trials. Objective This study aimed to test the ALS Functional Rating Scale-Revised (ALSFRS-R) progression rate (ΔFS) as a prognostic marker of survival in a Danish ALS cohort. Methods The ALSFRS-R score at test date in association with duration of symptoms, from the onset of symptoms until test date, (defined as ΔFS’) was calculated for 90 Danish patients diagnosed with either probable or definite sporadic ALS. Median survival time was then estimated from the onset of symptoms until primary endpoint (either death or tracheostomy). ΔFS’ was subjected to survival analysis using Cox proportional hazards modelling, log-rank test, and Kaplan-Meier survival analysis. Results and conclusions Both ΔFS’ and age was found to be strong predictors of survival of the Danish ALS cohort. Both variables are easily obtained at the time of diagnosis and could be used by clinicians and ALS patients to plan future supportive and palliative treatment. Furthermore, ΔFS’, is a simple, prognostic marker that predicts survival in the early phase of disease as well as at later stages of the disease.

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Sensory cortex hyperexcitability predicts short survival in amyotrophic lateral sclerosis

Neurology ◽

10.1212/wnl.0000000000005424 ◽

2018 ◽

Vol 90 (18) ◽

pp. e1578-e1587 ◽

Cited By ~ 8

Author(s):

Toshio Shimizu ◽

Kota Bokuda ◽

Hideki Kimura ◽

Tsutomu Kamiyama ◽

Yuki Nakayama ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Multivariate Analysis ◽

Action Potential ◽

Median Nerve ◽

Rating Scale ◽

Sensory Cortex ◽

Peak Amplitude ◽

Short Survival ◽

Sporadic Als ◽

Lateral Sclerosis

ObjectiveTo investigate somatosensory cortex excitability and its relationship to survival prognosis in patients with amyotrophic lateral sclerosis (ALS).MethodsA total of 145 patients with sporadic ALS and 73 healthy control participants were studied. We recorded compound muscle action potential and sensory nerve action potential of the median nerve and the median nerve somatosensory evoked potential (SEP), and we measured parameters, including onset-to-peak amplitude of N13 and N20 and peak-to-peak amplitude between N20 and P25 (N20p-P25p). Clinical prognostic factors, including ALS Functional Rating Scale–Revised, were evaluated. We followed up patients until the endpoints (death or tracheostomy) and analyzed factors associated with survival using multivariate analysis in the Cox proportional hazard model.ResultsCompared to controls, patients with ALS showed a larger amplitude of N20p-P25p in the median nerve SEP. Median survival time after examination was shorter in patients with N20p-P25p ≥8 μV (0.82 years) than in those with N20p-P25p <8 μV (1.68 years, p = 0.0002, log-rank test). Multivariate analysis identified a larger N20p-P25p amplitude as a factor that was independently associated with shorter survival (p = 0.002).ConclusionSensory cortex hyperexcitability predicts short survival in patients with ALS.

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MERIDIAN: A phase 2, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of pegcetacoplan in patients with amyotrophic lateral sclerosis

10.5327/1516-3180.744 ◽

2021 ◽

Author(s):

Frederico Mennucci de Haidar Jorge ◽

Angela Genge ◽

Ammar Al- Chalabi ◽

Orla Hardiman ◽

Alice Shen ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Rating Scale ◽

Phase 2 ◽

Efficacy And Safety ◽

Open Label ◽

Double Blind ◽

Double Blind Placebo ◽

Sporadic Als ◽

The Difference ◽

Lateral Sclerosis

Introduction: Inflammation underlies the pathogenesis of numerous neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). In ALS, the complement system has been implicated in the neuropathology of disease and disease progression. Pegcetacoplan, a subcutaneously administered C3 complement inhibitor, is being investigated in hematology, nephrology, and neurology. The current clinical study (NCT04579666) is investigating whether pegcetacoplan can improve survival and function in people diagnosed with apparent sporadic ALS. Objectives and Methodology: Evaluate the efficacy and safety of pegcetacoplan compared to placebo among people diagnosed with ALS in a global, multicenter, randomized, double-blind, placebo-controlled, phase 2 study. Approximately 228 patients diagnosed with apparent sporadic ALS, ≥18 years of age and with an ALS Functional Rating Scale-Revised (ALSFRS-R) score ≥30, slow vital capacity (SVC) ≥60% of the predicted value at screening, and with symptom onset within 72 weeks before screening, are eligible for enrollment. After screening, patients will be randomized 2:1 to treatment groups receiving either subcutaneous pegcetacoplan (1080 mg) or placebo twice weekly for a duration of 52 weeks. The primary efficacy endpoint is the difference in the Combined Assessment of Function and Survival (CAFS) ranked score at 52 weeks after treatment initiation. Additional, secondary functional efficacy (ALSFRS-R, percent SVC, muscle strength, quality of life, and caregiver burden) and safety endpoints will be analyzed at 52 weeks. After the placebo-controlled period, all patients will have the option to receive pegcetacoplan in an open-label period for an additional 52 weeks. Results: This ongoing study is currently enrolling participants. Conclusions: Results of this study will determine the role of complement and C3 inhibition in patients with ALS.

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SMN1 copy number as a modifying factor of survival in Serbian patients with sporadic amyotrophic lateral sclerosis

Srpski arhiv za celokupno lekarstvo ◽

10.2298/sarh180801069b ◽

2018 ◽

Vol 146 (11-12) ◽

pp. 646-652

Author(s):

Milos Brkusanin ◽

Irena Jeftovic-Velkova ◽

Vladimir Jovanovic ◽

Stojan Peric ◽

Jovan Pesovic ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Copy Number ◽

Rating Scale ◽

Cox Regression ◽

Diagnostic Delay ◽

Susceptibility Genes ◽

Sporadic Amyotrophic Lateral Sclerosis ◽

Cox Regression Analysis ◽

Sporadic Als ◽

Lateral Sclerosis

Introduction/Objective. Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. The majority of cases are apparently sporadic ALS (SALS) with variants in susceptibility genes or sometimes in high-risk ALS genes. Two ALS susceptibility genes are SMN1, whose functional loss causes spinal muscular atrophy (SMA), and a nearly identical SMN2 gene, which modulates SMA severity. In this study we examined the association of copy number variations (CNVs) of SMN1 and SMN2 genes and two additional genes, SERF1 and NAIP, residing in the same genomic region (i.e. 5q13.2 segmental duplication), with SALS in patients from Serbia. Methods. Multiplex ligation-dependent probe amplification was used to determine CNVs of each gene in a clinically well-characterised group of 153 Serbian SALS patients and 153 controls. Results. Individual association between SMN1, SMN2, SERF1 or NAIP CNVs and SALS susceptibility or survival was not found. Survival curves based on the multivariable Cox regression analysis showed that three SMN1 copies, lower ALS Functional Rating Scale Revised (ALSFRS-R) score at the time of diagnosis, faster decline of the ALSFRS-R score over time, and shorter diagnostic delay result in shorter survival of Serbian SALS patients. Conclusion. Clinical variables might be complemented with the SMN1 copy number to improve prediction of survival in Serbian SALS patients.

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Creatine Kinase and Progression Rate in Amyotrophic Lateral Sclerosis

Cells ◽

10.3390/cells9051174 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1174 ◽

Cited By ~ 1

Author(s):

Marco Ceccanti ◽

Valeria Pozzilli ◽

Chiara Cambieri ◽

Laura Libonati ◽

Emanuela Onesti ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Rating Scale ◽

Axonal Damage ◽

Mouse Strains ◽

Disease Rate ◽

Progression Rate ◽

Predisposing Factor ◽

Slow Progressors ◽

Als Patients ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with no recognized clinical prognostic factor. Creatinine kinase (CK) increase in these patients is already described with conflicting results on prognosis and survival. In 126 ALS patients who were fast or slow disease progressors, CK levels were assayed for 16 months every 4 months in an observational case-control cohort study with prospective data collection conducted in Italy. CK was also measured at baseline in 88 CIDP patients with secondary axonal damage and in two mouse strains (129SvHSD and C57-BL) carrying the same SOD1G93A transgene expression but showing a fast (129Sv-SOD1G93A) and slow (C57-SOD1G93A) ALS progression rate. Higher CK was found in ALS slow progressors compared to fast progressors in T1, T2, T3, and T4, with a correlation with Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) scores. Higher CK was found in spinal compared to bulbar-onset patients. Transgenic and non-transgenic C57BL mice showed higher CK levels compared to 129SvHSD strain. At baseline mean CK was higher in ALS compared to CIDP. CK can predict the disease progression, with slow progressors associated with higher levels and fast progressors to lower levels, in both ALS patients and mice. CK is higher in ALS patients compared to patients with CIDP with secondary axonal damage; the higher levels of CK in slow progressors patients, but also in C57BL transgenic and non-transgenic mice designs CK as a predisposing factor for disease rate progression.

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Brain Cortical Complexity Alteration in Amyotrophic Lateral Sclerosis: A Preliminary Fractal Dimensionality Study

BioMed Research International ◽

10.1155/2020/1521679 ◽

2020 ◽

Vol 2020 ◽

pp. 1-6

Author(s):

Jian-Hua Chen ◽

Nao-Xin Huang ◽

Tian-Xiu Zou ◽

Hua-Jun Chen

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Disease Progression ◽

Gray Matter ◽

Rating Scale ◽

Structural Complexity ◽

Fractal Dimensionality ◽

Clinical Parameters ◽

Precentral Gyrus ◽

Duration Of Symptoms ◽

Lateral Sclerosis

Objective. Fractal dimensionality (FD) analysis provides a quantitative description of brain structural complexity. The application of FD analysis has provided evidence of amyotrophic lateral sclerosis- (ALS-) related white matter degeneration. This study is aimed at evaluating, for the first time, FD alterations in a gray matter in ALS and determining its association with clinical parameters. Materials and Methods. This study included 22 patients diagnosed with ALS and 20 healthy subjects who underwent high-resolution T1-weighted imaging scanning. Disease severity was assessed using the revised ALS Functional Rating Scale (ALSFRS-R). The duration of symptoms and rate of disease progression were also assessed. The regional FD value was calculated by a computational anatomy toolbox and compared among groups. The relationship between cortical FD values and clinical parameters was evaluated by Spearman correlation analysis. Results. ALS patients showed decreased FD values in the left precentral gyrus and central sulcus, left circular sulcus of insula (superior segment), left cingulate gyrus and sulcus (middle-posterior part), right precentral gyrus, and right postcentral gyrus. The FD values in the right precentral gyrus were positively correlated to ALSFRS-R scores (r=0.44 and P=0.023), whereas negatively correlated to the rate of disease progression (r=−0.41 and P=0.039). Meanwhile, the FD value in the left circular sulcus of the insula (superior segment) was negatively correlated to disease duration (r=−0.51 and P=0.010). Conclusions. Our results suggest an ALS-related reduction in structural complexity involving the gray matter. FD analysis may shed more light on the pathophysiology of ALS.

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The Impact of Lifetime Alcohol and Cigarette Smoking Loads on Amyotrophic Lateral Sclerosis Progression: A Cross-Sectional Study

Life ◽

10.3390/life11040352 ◽

2021 ◽

Vol 11 (4) ◽

pp. 352

Author(s):

Aliona Cucovici ◽

Andrea Fontana ◽

Andrei Ivashynka ◽

Sergio Russo ◽

Valentina Renna ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Alcohol Consumption ◽

Cigarette Smoking ◽

Multicenter Study ◽

Alcohol Drinking ◽

Rating Scale ◽

Progression Rate ◽

Cross Sectional ◽

The Impact ◽

Lateral Sclerosis

Background—Amyotrophic lateral sclerosis (ALS) is a devastating and untreatable motor neuron disease; smoking and alcohol drinking may impact its progression rate. Objective—To ascertain the influence of smoking and alcohol consumption on ALS progression rates. Methods—Cross-sectional multicenter study, including 241 consecutive patients (145 males); mean age at onset was 59.9 ± 11.8 years. Cigarette smoking and alcohol consumption data were collected at recruitment through a validated questionnaire. Patients were categorized into three groups according to ΔFS (derived from the ALS Functional Rating Scale-Revised and disease duration from onset): slow (n = 81), intermediate (80), and fast progressors (80). Results—Current smokers accounted for 44 (18.3%) of the participants, former smokers accounted for 10 (4.1%), and non-smokers accounted for 187 (77.6%). The age of ALS onset was lower in current smokers than non-smokers, and the ΔFS was slightly, although not significantly, higher for smokers of >14 cigarettes/day. Current alcohol drinkers accounted for 147 (61.0%) of the participants, former drinkers accounted for 5 (2.1%), and non-drinkers accounted for 89 (36.9%). The log(ΔFS) was weakly correlated only with the duration of alcohol consumption (p = 0.028), but not with the mean number of drinks/day or the drink-years. Conclusions: This cross-sectional multicenter study suggested a possible minor role for smoking in worsening disease progression. A possible interaction with alcohol drinking was suggested.

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Serum asymmetric dimethyl arginine level correlates with the progression and prognosis of amyotrophic lateral sclerosis

10.1101/2021.07.01.21259228 ◽

2021 ◽

Author(s):

Kensuke Ikenaka ◽

Yasuhiro Maeda ◽

Hotta Yuji ◽

Seiichi Nagano ◽

Keita Kakuda ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Disease Progression ◽

Rating Scale ◽

Proportional Hazards Model ◽

Cox Proportional Hazards Model ◽

No Production ◽

Adma Level ◽

Neurofilament Light Chain ◽

Sporadic Als ◽

Lateral Sclerosis

Objective: To investigate the association between serum asymmetric dimethylarginine (ADMA) levels and the progression and prognosis of amyotrophic lateral sclerosis (ALS), and to compare cerebrospinal fluid (CSF) and serum ADMA levels with other biomarkers of ALS. Methods: Serum ADMA levels of patients with sporadic ALS (n = 68) and disease control patients (n = 54) were measured using liquid chromatography tandem mass spectrometry. Serum samples were obtained at the time of patient registration for diagnosis. Correlations of ADMA level and other markers (nitric oxide (NO) and neurofilament light chain (NFL) levels) were analyzed. Changes in the ALS Functional Rating Scale Revised (ALSFRSR) score from the onset of disease (ALSFRSR preslope) was used to assess disease progression. Survival was evaluated using the Cox proportional hazards model and Kaplan Meier analysis. Results: The concentration of ADMA in CSF was substantially higher in patients with ALS than in disease controls. Serum ADMA level correlated with CSF ADMA level (r = 0.591, p < 0.0001), and was independently associated with the ALSFRSR preslope (r = 0.505. p < 0.0001). Patients with higher serum ADMA levels had less favorable prognoses. CSF ADMA level significantly correlated with CSF NfL level (r = 0.456, p = 0.0002) but not with NO level (r = 0.194, p = 0.219). Conclusion: ADMA level is an independent biomarker of ALS disease progression and prognosis, and reflects the degree of motor neuron degeneration. The increased ADMA level in ALS patients was not associated with the inhibition of NO production.

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Coffee and Tea Consumption Impact on Amyotrophic Lateral Sclerosis Progression: A Multicenter Cross-Sectional Study

Frontiers in Neurology ◽

10.3389/fneur.2021.637939 ◽

2021 ◽

Vol 12 ◽

Author(s):

Aliona Cucovici ◽

Andrei Ivashynka ◽

Andrea Fontana ◽

Sergio Russo ◽

Letizia Mazzini ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Rating Scale ◽

Coffee Consumption ◽

Black Tea ◽

Cross Sectional Study ◽

Progression Rate ◽

Tea Consumption ◽

Sectional Study ◽

Cross Sectional ◽

Lateral Sclerosis

Background/objectives: Amyotrophic lateral sclerosis (ALS) is a devastating and still untreatable motor neuron disease. The causes of ALS are unknown, but nutritional factors may impact the rate of disease progression. We aimed to ascertain the influence of coffee and tea consumption on ALS progression rate.Subjects/methods: In this multicenter cross-sectional study, we recruited 241 patients, 96 females, and 145 males; the mean age at onset was 59.9 ± 11.8 years. According to El Escorial criteria, 74 were definite ALS, 77 probable, 55 possible, and 35 suspected; 187 patients had spinal onset and 54 bulbar. Patients were categorized into three groups, according to their ΔFS (derived from ALS Functional Rating Scale-Revised score and disease duration from onset): slow (81), intermediate (80), and fast progressors (80).Results: Current coffee consumers were 179 (74.3%), 34 (14.1%) were non-consumers, and 22 (9.1%) were former consumers, whereas six (2.5%) consumed decaffeinated coffee only. The log-ΔFS was weakly correlated with the duration of coffee consumption (p = 0.034), but not with the number of cup-years, or the intensity of coffee consumption (cups/day). Current tea consumers were 101 (41.9%), 6 (2.5%) were former consumers, and 134 (55.6%) were non-consumers. Among current and former consumers, 27 (25.2%) consumed only green tea, 51 (47.7%) only black tea, and 29 (27.1%) both. The log-ΔFS was weakly correlated only with the consumption duration of black tea (p = 0.028) but not with the number of cup-years.Conclusions: Our study does not support the hypothesis that coffee or tea consumption is associated with the ALS progression rate.

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Long-term survival analysis of masitinib in amyotrophic lateral sclerosis

Therapeutic Advances in Neurological Disorders ◽

10.1177/17562864211030365 ◽

2021 ◽

Vol 14 ◽

pp. 175628642110303

Author(s):

Jesus S. Mora ◽

Walter G. Bradley ◽

Delia Chaverri ◽

María Hernández-Barral ◽

Javier Mascias ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Survival Analysis ◽

Phase Iii ◽

Progression Rate ◽

Term Survival ◽

Risk Of Death ◽

Severe Impairment ◽

Phase Iii Study ◽

Lateral Sclerosis

Background: A randomized, placebo-controlled phase III study (AB10015) previously demonstrated that orally administered masitinib (4.5 mg/kg/day) slowed rate of functional decline, with acceptable safety, in amyotrophic lateral sclerosis (ALS) patients having an ALS Functional Rating Scale-revised (ALSFRS-R) progression rate from disease onset to baseline of <1.1 points/month. Here we assess long-term overall survival (OS) data of all participants from study AB10015 and test whether a signal in OS is evident in an enriched patient population similar to that prospectively defined for confirmatory study AB19001. Methods: Survival status of all patients originally randomized in AB10015 was collected from participating investigational sites. Survival analysis (using the multivariate log-rank test and Cox proportional hazards model, with stratification factors as covariates) was performed on the intention-to-treat population and enriched subgroups, which were defined according to initial randomization, baseline ALSFRS-R progression rate and baseline disease severity. Results: A significant survival benefit of 25 months ( p = 0.037) and 47% reduced risk of death ( p = 0.025) was observed for patients receiving 4.5 mg/kg/day masitinib ( n = 45) versus placebo ( n = 62) in an enriched cohort with ⩾2 on each baseline ALSFRS-R individual component score (i.e. prior to any complete loss or severe impairment of functionality) and post-onset ALSFRS-R progression rate <1.1 (i.e. exclusion of very fast progressors) [median OS of 69 versus 44 months, respectively; hazard ratio, 0.53 [95% CI (0.31–0.92)]]. This corresponds to the population enrolled in confirmatory phase III study, AB19001. Conclusions: Analysis of long-term OS (75 months average follow-up from diagnosis) indicates that oral masitinib (4.5 mg/kg/day) could prolong survival by over 2 years as compared with placebo, provided that treatment starts prior to severe impairment of functionality. This trial was registered at www.ClinicalTrials.gov under identifier NCT02588677 (28 October 2015).

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Decremental Responses to Repetitive Nerve Stimulation in Amyotrophic Lateral Sclerosis

European Neurology ◽

10.1159/000494670 ◽

2018 ◽

Vol 80 (3-4) ◽

pp. 151-156 ◽

Cited By ~ 1

Author(s):

Fangfang Hu ◽

Jiaoting Jin ◽

Li Kang ◽

Rui Jia ◽

Xing Qin ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Diagnostic Delay ◽

Deltoid Muscle ◽

Clinical Results ◽

Progression Rate ◽

Repetitive Nerve Stimulation ◽

Sporadic Als ◽

Compound Muscle Action Potentials ◽

Als Patients ◽

Lateral Sclerosis

Introduction: To illuminate the mechanism of neuromuscular junction involvement by analyzing the features of a slow-rate repetitive nerve simulation (RNS) and EMG in amyotrophic lateral sclerosis (ALS) patients. Methods: We retrospectively analyzed relationship between clinical features and the decremental response in RNS in 184 sporadic ALS patients. Results: (1) 44.3 and 43.5% of compound muscle action potentials (CMAP) decrement were more than –10% in deltoid muscle (Del) and Trap; (2) ALS patients were divided into RNS positive (RNS+) and RNS negative (RNS–) group according to decremental percentage of RNS greater or less than –10%. The diagnostic delay time was shorter and ALSFRS-r score was lower in RNS+ than RNS– group (p < 0.05), progression rate had no difference. The incidence of RNS+ decrement was higher in cervical enlargement onset and definite diagnostic degrees (p < 0.05); (3) In EMG+ group, the CMAP amplitude was lower (Axillary: 3.1 ± 1.91 vs. 5.92 ± 2.896, p = 0.000; Accessory: 2.68 ± 1.349 vs. 3.65 ± 1.53, p = 0.002), decremental percentage of RNS was higher (Axillary: –10.85 ± 7.508 vs. –5.43 ± 8.425, p = 0.000; Accessory: –13.11 ± 7.539 vs. –8.03 ± 5.999, p = 0.000) compared with needle EMG– group whether in Del or Trap; (4) Decremental response of RNS was positively correlated with the CMAP amplitude in Axillary and Accessory nerves (R = 0.201, p < 0.0001; R = 0.103, p < 0.0001). Conclusions: Our clinical results support the mechanism of decremental phenomenon of RNS is immature sprouts and unstable conduction by the degenerating axons in ALS patients. The more serious the axon damage, the more significant the RNS decremental response. But decremental response dose not effect disease progression.

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