Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative syndrome hallmarked by adult-onset loss of motor neurons. We performed exome sequencing of 252 familial ALS (fALS) and 827 control individuals. Gene-based rare variant analysis identified an exome-wide significant enrichment of eight loss-of-function (LoF) mutations in TBK1 (encoding TANK-binding kinase 1) in 13 fALS pedigrees. No enrichment of LoF mutations was observed in a targeted mutation screen of 1,010 sporadic ALS and 650 additional control individuals. Linkage analysis in four families gave an aggregate LOD score of 4.6. In vitro experiments confirmed the loss of expression of TBK1 LoF mutant alleles, or loss of interaction of the C-terminal TBK1 coiled-coil domain (CCD2) mutants with the TBK1 adaptor protein optineurin, which has been shown to be involved in ALS pathogenesis. We conclude that haploinsufficiency of TBK1 causes ALS and fronto-temporal dementia.
Weight loss is a common phenomenon and an independent prognostic factor in amyotrophic lateral sclerosis (ALS). Several potential causal mechanisms, including intrinsic hypermetabolism and deficient food intake, have been discussed. We investigated the influence of fasting serum glucose, cholesterol, and triglyceride levels at time of diagnosis on survival in ALS. Serum cholesterol (LDL, HDL, and LDL/HDL ratio), triglycerides, and glucose were investigated in 488 patients (age of onset = 57.6 ± 12.6 years) in relation to survival and revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALS-FRS) data. High serum levels of both fasting cholesterol and triglycerides had a significantly positive effect on survival (p < 0.05). We found a median prolonged life expectancy by 14 months for patients with serum triglyceride levels above the median of 1.47 mmol/l. The results suggest that the lipid metabolism and the nutritional status of ALS patients are important prognostic factors. These parameters should be thoroughly monitored during the clinical management of these patients. In case of progressive loss of body weight, a diet rich in lipids and calories should be considered. However, the final decision whether a lipid-rich diet should be recommended to ALS patients can only be based on a double-blind placebo-controlled interventional trial. Our results further imply that lipid-lowering drugs, e.g., statins, should be applied carefully in ALS patients although individual risk considerations must be made.
ObjectiveWeight loss has been identified as a negative prognostic factor in amyotrophic lateral sclerosis, but there is no evidence regarding whether a high‐caloric diet increases survival. Therefore, we sought to evaluate the efficacy of a high‐caloric fatty diet (HCFD) for increasing survival.MethodsA 1:1 randomized, placebo‐controlled, parallel‐group, double‐blinded trial (LIPCAL‐ALS study) was conducted between February 2015 and September 2018. Patients were followed up at 3, 6, 9, 12, 15, and 18 months after randomization. The study was performed at 12 sites of the clinical and scientific network of German motor neuron disease centers (ALS/MND‐NET). Eligible patients were randomly assigned (1:1) to receive either HCFD (405kcal/day, 100% fat) or placebo in addition to riluzole (100mg/day). The primary endpoint was survival time, defined as time to death or time to study cutoff date.ResultsTwo hundred one patients (80 female, 121 male, age = 62.4 ± 10.8 years) were included. The confirmatory analysis of the primary outcome survival showed a survival probability of 0.39 (95% confidence interval [CI] = 0.27–0.51) in the placebo group and 0.37 (95% CI = 0.25–0.49) in the HCFD group, both after 28 months (point in time of the last event). The hazard ratio was 0.97, 1‐sided 97.5% CI = −∞ to 1.44, p = 0.44.InterpretationThe results provide no evidence for a life‐prolonging effect of HCFD for the whole amyotrophic lateral sclerosis population. However, post hoc analysis revealed a significant survival benefit for the subgroup of fast‐progressing patients. ANN NEUROL 2020;87:206–216
IMPORTANCEIntravenous edaravone is approved as a disease-modifying drug for patients with amyotrophic lateral sclerosis (ALS), but evidence for efficacy is limited to short-term beneficial effects shown in the MCI186-ALS19 study in a subpopulation in which efficacy was expected.OBJECTIVE To evaluate the long-term safety and effectiveness of intravenous edaravone therapy for patients with ALS in a real-world clinical setting. DESIGN, SETTING, AND PARTICIPANTS Multicenter, propensity score-matched cohort study conducted between June 2017 and March 2020 at 12 academic ALS referral centers associated with the German Motor Neuron Disease Network. Of 1440 patients screened, 738 were included in propensity score matching. Final analyses included 324 patients with ALS comprising 194 patients who started intravenous edaravone treatment (141 received Ն4 consecutive treatment cycles; 130 matched) and 130 propensity score-matched patients with ALS receiving standard therapy. All patients had probable or definite ALS according to the El Escorial criteria, with disease onset between December 2012 and April 2019.Subgroups were defined by applying the MCI186-ALS19 study inclusion criteria to evaluate whether patients would have been considered eligible (EFAS) or ineligible (non-EFAS). EXPOSURES Intravenous edaravone plus riluzole vs riluzole only.MAIN OUTCOMES AND MEASURES Patient characteristics and systematic safety assessment for patients who received at least 1 dose of intravenous edaravone. Effectiveness assessment of edaravone was conducted among patients who received at least 4 treatment cycles compared with propensity score-matched patients with ALS who received only standard therapy. Primary outcome was disease progression measured by decrease in the ALS Functional Rating Scale-Revised (ALSFRS-R) score. Secondary outcomes were survival probability, time to ventilation, and change in disease progression before vs during treatment. To account for the matched design, patients receiving edaravone and their corresponding matched controls were regarded as related samples in disease progression analyses; stratification for propensity score quintiles was used for survival probability and time to ventilation analyses.RESULTS A total of 194 patients started intravenous edaravone treatment; 125 (64%) were male, and the median age was 57.5 years (IQR, 50.7-63.8 years). Potential adverse effects were observed in 30 cases (16%), most notably infections at infusion sites and allergic reactions. Disease progression among 116 patients treated for a median of 13.9 months (IQR, 8.9-13.9 months) with edaravone did not differ from 116 patients treated for a median of 11.2 months (IQR, 6.4-20.0 months) with standard therapy (ALSFRS-R points/month, −0.91 [95% CI, −0.69 to −1.07] vs −0.85 [95% CI, −0.66 to −0.99]; P = .37). No significant differences were observed in the secondary end points of survival probability, time to ventilation, and change in disease progression. Similarly, outcomes between patients treated with edaravone and matched p...
Weight loss is an independent prognostic factor in amyotrophic lateral sclerosis (ALS). We investigated whether the body weight of ALS patients who previously lost weight can be stabilized by a high-caloric diet. For this purpose we compared two different high-caloric food supplements: one with high fat content and one with high carbohydrate content. Twenty-six patients were randomly allocated to one of the therapeutic groups. Body weight, ALS functional rating scale-revised (ALSFRS-R), static vital capacity (SVC), bioelectrical impedance analysis (BIA), metabolic serum parameters, and adverse events were investigated. Results showed that body weight of ALS patients could be stabilized in both therapeutic groups after 12 weeks of therapy (p = 0.008). The effect was greater in the group with high fat supplement though not statistically significant (p = 0.37). In conclusion, high-caloric food supplements with high fat as well as high carbohydrate content are both suitable to stabilize the body weight of ALS patients. The effect of a high fat diet might be more pronounced. Since body weight is an independent prognostic factor in ALS it is possible that a high-caloric food supplement improves survival in ALS. However, this hypothesis can only be tested by conducting a placebo-controlled double-blinded trial of sufficient power.
In this review, we summarize the most important recent developments in the treatment of amyotrophic lateral sclerosis (ALS). In terms of disease-modifying treatment options, several drugs such as dexpramipexole, pioglitazone, lithium, and many others have been tested in large multicenter trials, albeit with disappointing results. Therefore, riluzole remains the only directly disease-modifying drug. In addition, we discuss antisense oligonucleotides (ASOs) as a new and potentially causal treatment option.Progress in symptomatic treatments has been more important. Nutrition and ventilation are now an important focus of ALS therapy. Several studies have firmly established that noninvasive ventilation improves patients’ quality of life and prolongs survival. On the other hand, there is still no consensus regarding best nutritional management, but big multicenter trials addressing this issue are currently ongoing. Evidence regarding secondary symptoms like spasticity, muscle cramps or sialorrhea remains generally scarce, but some new insights will also be discussed. Growing evidence suggests that multidisciplinary care in specialized clinics improves survival.
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