Supported Treadmill Ambulation for Amyotrophic Lateral Sclerosis: A Pilot Study

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a progressive neurodegenerative disease without effective therapies. Several studies have suggested that repetitive transcranial magnetic stimulation (rTMS) may have positive benefit in ALS. However, the efficacy and safety of this therapy remain uncertain. We aimed to determine the clinical efficacy and safety of rTMS for treating ALS. We searched the Cochrane Neuromuscular Disease Group Specialized Register (July 2010), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 2, 2010), MEDLINE (1966 to July 2010), EMBASE (1980 to July 2010), CINAHL (1937 to July 2010), Science Citation Index Expanded (January 1945 to June 2010), AMED (January 1985 to July 2010) and the Chinese Biomedical Database (1979 to September 2010). We also searched for ongoing studies on clinicaltrials.gov (September 2010). Randomised and quasi-randomised controlled trials assessing the therapeutic efficacy and safety of rTMS for patients with a clinical diagnosis of ALS.Comparisons eligible for inclusion were:1. rTMS versus no intervention;2. rTMS versus sham rTMS;3. rTMS versus physiotherapy;4. rTMS versus medications;5. rTMS + other therapies or drugs versus sham rTMS + the same therapies or drugs;6. different methods of application of rTMS such as high-frequency (> 1Hz) compared to low-frequency (≤ 1Hz) rTMS. Two authors independently selected papers, assessed risk of bias and extracted data. We resolved disagreements through discussion. We contacted study authors for additional information. Three randomised, placebo-controlled trials with a total of 50 participants were included in the review. All the trials were of poor methodological quality and were insufficiently homogeneous to allow the pooling of results. Moreover, the high rate of attrition further increased the risk of bias. None of the trials provided detailed data on the ALS Functional Rating Scale-Revised (ALSFRS-R) scores at six months follow-up which was pre-assigned as our primary outcome. One trial contained data in a suitable form for quantitative analysis of our secondary outcomes. No difference was seen between rTMS and sham rTMS using the ALSFRS-R scores and manual muscle testing (MMT) scores at 12 months follow-up in this trial. Additionally, none of the trials reported any adverse events associated with the use of rTMS. However, in view of the small sample size, the methodological limitations and incomplete outcome data, treatment with rTMS cannot be judged as completely safe. There is currently insufficient evidence to draw conclusions about the efficacy and safety of rTMS in the treatment of ALS. Further studies may be helpful if their potential benefit is weighed against the impact of participation in a randomised controlled trial on people with ALS.

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a progressive neurodegenerative disease without effective therapies. Several studies have suggested that repetitive transcranial magnetic stimulation (rTMS) may have positive benefit in ALS. However, the efficacy and safety of this therapy remain uncertain. This is the first update of a review published in 2011. To determine the clinical efficacy and safety of rTMS for treating ALS. On 30 July 2012, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL (2012, issue 7 in The Cochrane Library), MEDLINE (1966 to July 2012), EMBASE (1980 to July 2012), CINAHL (1937 to July 2012), Science Citation Index Expanded (January 1945 to July 2012), AMED (January 1985 to July 2012). We searched the Chinese Biomedical Database (1979 to August 2012). We also searched for ongoing studies on clinicaltrials.gov (August 2012). Randomised and quasi-randomised controlled trials assessing the therapeutic efficacy and safety of rTMS for patients with a clinical diagnosis of ALS.Comparisons eligible for inclusion were:1. rTMS versus no intervention;2. rTMS versus sham rTMS;3. rTMS versus physiotherapy;4. rTMS versus medications;5. rTMS + other therapies or drugs versus sham rTMS + the same therapies or drugs;6. different methods of application of rTMS such as high-frequency (> 1Hz) compared to low-frequency (≤ 1Hz) rTMS. Two authors independently selected papers, assessed risk of bias and extracted data. We resolved disagreements through discussion. We contacted study authors for additional information. Three randomised, placebo-controlled trials with a total of 50 participants were included in the review. All three trials compared rTMS with sham TMS. All the trials were of poor methodological quality and were insufficiently homogeneous to allow the pooling of results. Moreover, the high rate of attrition further increased the risk of bias. None of the trials provided detailed data on the ALS Functional Rating Scale-Revised (ALSFRS-R) scores at six months follow-up which was pre-assigned as our primary outcome. One trial contained data in a suitable form for quantitative analysis of our secondary outcomes. No difference was seen between rTMS and sham rTMS using the ALSFRS-R scores and manual muscle testing (MMT) scores at 12 months follow-up in this trial. Additionally, none of the trials reported any adverse events associated with the use of rTMS. However, in view of the small sample size, the methodological limitations and incomplete outcome data, treatment with rTMS cannot be judged as completely safe. There is currently insufficient evidence to draw conclusions about the efficacy and safety of rTMS in the treatment of ALS. Further studies may be helpful if their potential benefit is weighed against the impact of participation in a randomised controlled trial on people with ALS.

BackgroundThe study aimed to appraise the health-related quality of life (HRQoL) measured by the five-level EuroQol-5 dimensions (EQ-5D-5L) in amyotrophic lateral sclerosis (ALS), and to explore the associations between non-motor symptoms (mood changes, cognitive disturbances and sleep disturbances).MethodsEQ-5D-5L descriptive scores were converted into a single aggregated “health utility” score. A calibrated visual analog scale (EQ-VAS) was used for self-rating of current health status. Multiple logistic regression analysis was used to explore the factors associated with HRQoL.ResultsAmong the 547 enrolled ALS patients who were assessed using EQ-5D-5L, the highest frequency of reported problems was with usual activities (76.7%), followed by self-care (68.8%) and anxiety/depression (62.0%). The median health utility score was 0.78 and the median EQ-VAS score was 70. Clinical factors corresponding to differences in the EQ-5D-5L health utility score included age of onset, onset region, the ALS Functional Rating Scale-Revised (ALSFRS-R) score, and King’s College stages. Patients with depression, anxiety, and poor sleep had lower health utility scores. Patients with excessive daytime sleepiness and rapid eye movement sleep behavior disorder had lower EQ-VAS scores. Multivariate logistic analysis indicated that ALSFRS-R scores, depression, and anxiety were associated with health utility scores. After adjusting other parameters, ALSFRS-R score, stages, and depression were significantly associated with EQ-VAS scores (P < 0.05).ConclusionThis study examined HRQoL in ALS patients using the Chinese version of the EQ-5D-5L scale across different stages of the disease. We found that HRQoL is related to disease severity and to mood disturbances. Management of non-motor symptoms may help improve HRQoL in ALS patients.

Amyotrophic lateral sclerosis (ALS) is a degenerative neuromuscular disease with marked clinical heterogeneity. This heterogeneity can be partly captured by clinical measures, such as the forced vital capacity (FVC) and ALS Functional Rating Scale-Revised (ALSFRS-R). We aimed to further characterize the performance of these clinical measures, including their independence and additivity, in predicting mortality. We leveraged the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT ALS) database, which includes data from 23 clinical trials (n =2050). The primary exposures were baseline FVC and ALSFRS-R. The primary outcome was 1-y mortality. We performed correlation analyses, survival analyses and assessed classification performance using receiver operator characteristic (ROC) curves. FVC and ALSFRS-R were weakly correlated (r=0.31, p< .001). A 1-SD increase in FVC (hazard ratio [HR]: 0.66; 95% confidence interval [CI]: 0.59-0.74) and ALSFRS-R (HR: 0.75; 95% CI: 0.68-0.82) were associated with reduced risk of 1-y mortality. ROC analyses showed optimal predictive cutoffs at 80% for FVC (area under the curve [AUC]: 0.69) and 38 for ALSFRS-R (AUC: 0.67). After stratifying patients based on these cutoffs, we found a marked reduction (HR: 0.25; 95% CI: 0.19-0.33) in incident mortality for patients in the high FVC and high ALSFRS-R group relative to the low FVC and low ALSFRS-R group. ALSFRS-R and FVC are comparable predictors of survival that are only weakly correlated. When considered together, they synergistically predict survival. As such, consideration of both measures should be a routine part of prognostication in care of patients with ALS.

Amyotrophic lateral sclerosis (ALS) is a rare, devastating neurodegenerative disease that affects upper and lower motor neurons, resulting in muscle atrophy, spasticity, hyperreflexia, and paralysis. Inflammation plays an important role in the development of ALS, and associated with rapid disease progression. Current observational studies indicate the thinning of cortical thickness in patients with ALS is associated with rapid disease progression and cognitive changes. However, the effects of inflammatory cytokines on cortical thickness in patients with ALS are unclear. Here, we investigated the relationship between inflammatory cytokines and cortical thickness in patients with ALS. We evaluated 51 patients with ALS for inflammatory cytokines including interleukin (IL)-4, interferon (IFN)-α, IL-1β, IL-2, IL-5, IL-12, tumor necrosis factor (TNF)-α, IL-6, IL-10, IL-8, IL-17, and IFN-γ and analyzed the correlation between these indicators and the ALS functional rating scale-revised (ALSFRS-R) score or disease progression rate (ΔFS score). Twenty-six patients with ALS and 26 controls were studied using whole-cortex analysis, and post-hoc analyses were performed to examine the correlation between brain cortical thickness and ALSFRS-R or ΔFS scores. IL-4, IFN-α, IL-1β, and IL-2 levels were significantly correlated with ALSFRS-R scores, and the IL-2 level was significantly correlated with ΔFS scores. After controlling for age and sex, the ALS group had thinner cortexes in multiple clusters across the brain than the control group. Further analyses revealed that cortical thickness in the right superior temporal and lingual gyrus regions was inversely correlated with ΔFS scores. There was a significant positive correlation between the clusters in the right lingual cortex and IL-2 level. These results suggest cortical thickness was reduced in patients with ALS in motor and non-motor cortical areas. Inflammatory factors (especially IL-2) were correlated with cortical thickness, and both were related to the disease progression rate, suggesting IL-2 plays an important role in ALS.

Dear editors, Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease. It affects motor neurons in the brain and spinal cord resulting in bulbar palsy and respiratory failure. It also causes weakness of limbs. The disease usually progresses to fatal outcome within 2–4 years. Neural stem cell research for diagnosis and treatment of neurodegenerative disorders is highly promising. But more data are required to prove their efficacy. There is evidence regarding stem cell application in traumatic brain injury and other neurological disorders (Mouhieddine et al., 2014). Neurotrophic factors (NTFs) have been reported to increase the survival of motor neurons in ALS (Petrou et al., 2016). A culture-based method has been developed to promote the secretion of NTFs by mesenchymal stem cells (MSCs) (Petrou et al., 2016). NTFs have been shown to protect neurons in an animal model of neurodegenerative diseases (Chen et al., 2015). One phase I/II pilot trial (identifier {type:clinical-trial,attrs:{text:NCT00781872,term_id:NCT00781872}}NCT00781872) used intrathecal combined intravenous injections of bone marrow-derived MSCs in 34 patients with multiple sclerosis and ALS. Long-term (6–25 months) follow up observations did not show any severe adverse outcomes. MSCs transplantation was found to be a clinically feasible and relatively safe procedure (Karussis et al., 2010). Recently, in open-label proof-of-concept studies (Petrou et al., 2016), all patients enrolled between June 2011 and October 2014 were followed up from 3 months prior to transplantation to 6 months after transplantation. In six patients with early-stage ALS, MSC-secreting NTF (MSC-NTF) cells were intramuscularly administered in the phase I/II of the trial. Another six patients with more advanced diseases received intrathecal administration of MSC-NTF cells. In a phase IIa study, 14 patients who had early-stage ALS received a combined intramuscular and intrathecal transplantation of autologous MSC-NTF cells. The primary endpoints of the studies were tolerability and safety of this treatment. The secondary endpoint was the impact of such intervention on various clinical parameters, including the ALS Functional Rating Scale-Revised score and the respiratory function. In the phase I/II trial, the treatment was well tolerated by all included 12 patients over the study follow up period. A similar effect was shown in 14 patients in the phase IIa trial. The rate of deterioration in lung function and the ALS Functional Rating Scale-Revised score in the intrathecal (or intrathecal + intramuscular) group was found to be reduced (P < 0.04) in comparison with the pre-treatment phase. The result suggests the safety of intrathecal and intramuscular transplantation of MSC-NTF cells in patients with ALS (identifier {type:clinical-trial,attrs:{text:NCT01051882,term_id:NCT01051882}}NCT01051882 and {type:clinical-trial,attrs:{text:NCT01777646,term_id:NCT01777646}}NCT01777646) (Petrou et al., 2016). Bone marrow-derived MSCs have many advantages. For example, MSCs can be obtained safely from adult bone marrow; they can be cultured in vitro. Autologous MSCs can be administered safely without immunosuppressive therapy. Adult MSCs were shown to be associated with a low risk for induction of treatment-related malignant neoplasms (Karussis et al., 2010). We can focus on some other studies regarding the safety profile of stem cell transplant in the treatment of ALS. Animal studies have shown no clinically significant alteration of cytokine levels (involved in cell-mediated and humoral immunity) after MSC-NTF cell transplantation. Repeated injections of human MSC-NTF cells are found to be well tolerated in the studied animals (mice) (Gothelf et al., 2014). Pre-clinical and clinical trials have suggested that MSCs are safe and feasible as a therapeutic option. They are not immunogenic and have immunosuppressive features (Thomsen et al., 2014). Genetic stability and opportunity for cryopreservation for future use of MSCs are still in the research stage. Cryopreservation can preserve the biological behavior of MSCs including differentiation potential, growth capacity, and surface marker. Therefore, cryopreserved MSCs can be used safely in future (Wang et al., 2012). A meta-analysis of randomized controlled trials did not reveal any adverse effects of MSC transplants like infusion toxicity, any disorder of organ systems, infection, malignant transformation or fatal outcome (Dulamea, 2015). Another open-label phase I clinical trial showed the safety profile of two repeated intrathecal injections of autologous MSCs in ALS patients (Oh et al., 2015). Safety and Efficiency of Umbilical Cord-derived Mesenchymal Stem Cells (UC-MSC) in Patients with Alzheimer's Disease (SEMAD) [identifier {type:clinical-trial,attrs:{text:NCT01547689,term_id:NCT01547689}}NCT01547689] is an ongoing study, and hopefully, it will provide more definite results (https://clinicaltrials.gov/ct2/show/{type:clinical-trial,attrs:{text:NCT01547689,term_id:NCT01547689}}NCT01547689, last accessed on 27/03/2016). Before conclusion, we want to raise another issue about some biological markers of the efficacy of such therapy. The levels of vascular endothelial growth factor, angiogenin, and transforming growth factor-β were reported to be significantly higher in responders than in nonresponders after autologous MSC therapy in patients with ALS. The disease outcomes were evaluated by their scores on the revised ALS Functional Rating Scale (ALSFRS-R) (Kim et al., 2014). So this new treatment modality is hoped to be successful in ALS patients. More study results will enlighten us about it.

Treatment options for amyotrophic lateral sclerosis (ALS) remain suboptimal. Results from a phase 2 study of reldesemtiv in ALS suggested that it may slow disease progression. To assess the effect of reldesemtiv vs placebo on functional outcomes in ALS. A Study to Evaluate the Efficacy and Safety of Reldesemtiv in Patients With Amyotrophic Lateral Sclerosis (COURAGE-ALS) was a double-blind, placebo-controlled phase 3 randomized clinical trial conducted at 83 ALS centers in 16 countries from August 2021 to July 2023. The first 24-week period was placebo controlled vs reldesemtiv. All participants received reldesemtiv during the second 24-week period with a 4-week follow-up. Two interim analyses were planned, the first for futility and the second for futility and possible resizing. This was a hybrid decentralized trial with approximately half the trial visits performed remotely and the remaining visits in the clinic. Eligible participants met criteria for definite, probable, or possible ALS with lower motor neuron signs by modified El Escorial Criteria, ALS symptoms for 24 months or less, ALS Functional Rating Scale-Revised (ALSFRS-R) total score of 44 or less, and forced vital capacity of greater than or equal to 65% of predicted. Oral reldesemtiv, 300 mg, or placebo twice daily. The primary end point was change in ALSFRS-R total score from baseline to week 24. Of the 696 participants screened, 207 were screen failures. A total of 486 participants (mean [SD] age, 59.4 [10.9] years; 309 male [63.6%]) were randomized to reldesemtiv (n = 325) or placebo (n = 161); 3 randomized patients were not dosed. The second interim analysis at 24 weeks after randomization included 256 participants. The data monitoring committee recommended that the trial should end due to futility, and the sponsor agreed. The mean (SE) group difference in the ALSFRS-R score from baseline to week 24 was -1.1 (0.53; 95% CI, -2.17 to -0.08; P = .04, favoring placebo). Given excess missing data from early termination, the combined assessment assumed greater importance; it, too, failed to show a benefit from treatment with reldesemtiv (win probability was 0.44 for reldesemtiv and 0.49 for placebo, with a win ratio of 0.91; 95% CI of win ratio, 0.77-1.10; P = .11). This randomized clinical trial failed to demonstrate efficacy for reldesemtiv in slowing functional decline in ALS. ClinicalTrials.gov Identifier: NCT04944784.

Background:Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron diseases. Until now, it lacks effective drugs for its treatment, and the median survival time of ALS is reported as only 20 to 48 months after the onset of symptoms. Acupuncture served as part of traditional Chinese therapy, has been widely applied to clinical practice for patients with ALS but lacks studies to verify its efficacy. This study provides a protocol of systematic review, with which we will comprehensively verify the effects of acupuncture on ALS with evidence-based studies.Methods:The eligible studies will be collected from 4 English databases (the MEDLINE via PubMed, the Cochrane Library, EMBASE, the Web of Science, and Ovid database), and 4 Chinese databases (China Science and Technology Journal Database, Chinese Biomedical Literature Database, Wan-fang Database, China National Knowledge Infrastructure) from October 2000 to October 2022. The primary outcome measure is the change in amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R) scores. We will use RevMan V.5.3 software to calculate the data synthesis and will conduct meta-analysis based on the collected data.Results:The primary outcome measure is the change in ALSFRS-R scores, and secondary outcome measures included changes in forced vital capacity, grasping power, pinch strength, modified Norris Scale, ALS assessment questionnaire-40, and time to activity of daily living-independent will be measured and comprehensively assessed to evaluate the effect of acupuncture on ALS from this systematic review and meta-analysis.Conclusion:The systematic review and meta-analysis will assess the effect of acupuncture in the treatment of ALS with up-to-date clinical evidence.PROSPERO registration number:PROSPERO CRD 42019124785.

[Objective] Few studies have comprehensively investigated the non-motor symptoms of amyotrophic lateral sclerosis (ALS). We aimed to investigate this aspect of ALS. [Methods] We held a nationwide webinar, titled “ALS Café,” and distributed self-report questionnaires to ALS patients. In addition to the frequency of non-motor symptoms such as fatigue, pain, sleep disorders, defecation disorders, sialorrhea, and sexual problems, we evaluated the quality of life (QoL), ALS Functional Rating Scale-Revised (ALSFRS-R), and Patient Health Questionnaire-9 (PHQ-9). [Results] The average age of the 33 respondents (19 male, 14 female) was 60.8 ± 11.2; 96.7% of respondents had some non-motor symptoms. The median ALSFRS-R was 32.0, and seven (21.2%) of the respondents had a PHQ-9 score of 10 or higher. Fatigue was the most common non-motor symptom (81.8%), followed by pain (60.6%), defecation disorders (57.6%), sleep disorders (48.5%), sialorrhea (48.5%), and sexual problems (24.2%). Fatigue was more frequent in females (P = 0.03). Among the non-motor symptoms, pain was the most common factor affecting QoL, followed by fatigue. More than 90% of ALS patients answered that they had never consulted a physician/counselor about sexual problems. Patients with pain had higher PHQ-9 scores than those without (P = 0.01). There was no correlation between the ALSFRS-R score and QoL and PHQ-9. [Conclusions] Most patients with amyotrophic lateral sclerosis had non-motor symptoms, and fatigue and pain were the most common. We showed that many non-motor symptoms affected QoL without correlating with ALSFRS-R score. Attention should be paid to those even if the motor symptoms of ALS are mild.

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.

Improvement of a decreased anti-oxidative activity by edaravone in amyotrophic lateral sclerosis patients

Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited treatment options. Pridopidine, a selective sigma-1 receptor agonist, was evaluated in Regimen D of the HEALEY ALS Platform Trial. Although the primary endpoint (ALS Functional Rating Scale-Revised (ALSFRS-R) total score accounting for survival at 24 weeks) was not met, a predefined subgroup analysis suggested slowed disease progression in ALS patients with definite and early disease (<18 months from onset). This report presents an exploratory analysis that further investigates pridopidine in rapidly progressing participants with definite/probable ALS and early-disease, where treatment effects may be more pronounced. Methods: The randomized, double-blind, placebo-controlled phase 2 trial assigned participants to pridopidine 45 mg bid or placebo, and placebo patients were shared across four trial regimens. The primary outcome was ALSFRS-R total score, with secondary outcomes assessing respiratory, bulbar, and speech functions. Results: Of 163 participants randomized to Regimen D, 72 met subgroup criteria (pridopidine: n = 37; shared placebo: n = 35). At week 24, pridopidine slowed ALSFRS-R total score decline (32%; Δ2.90, p = 0.03) and slowed decline of ALSFRS-R respiratory function (62%; Δ1.20, p = 0.03) and dyspnea (88%; Δ0.85, p = 0.005). ALSFRS-R-Bulbar function stabilized, with articulation and speaking rate declines reduced by 93% (Δ0.43, p = 0.0007) and 70% (Δ0.43, p = 0.002), respectively. Pridopidine was well-tolerated, with a safety profile comparable to placebo. All p values are nominal. Conclusion: Post hoc subgroup analysis suggests therapeutic benefits of pridopidine in patients that had definite/probable ALS and with early-disease progression, supporting further evaluation in a Phase 3 trial.

Background and PurposeMutations in the FIG4 gene have been linked to amyotrophic lateral sclerosis (ALS) type 11 in Caucasian populations. The purpose of this study was to identify FIG4 variants in a cohort of 15 familial ALS (FALS) indexes and 275 sporadic ALS (SALS) patients of Han Chinese origin.MethodsAll 23 exons of FIG4 were sequenced using targeted next-generation sequencing. An extensive literature review was performed to detect genotype-phenotype associations of FIG4 mutations.ResultsNo FIG4 variants were identified in the FALS patients. One novel heterozygous missense variant (c.352G>T [p.D118Y]) and one novel heterozygous nonsense variant (c.2158G>T [p.E720X]) in FIG4 were identified in two SALS patients. The p.E720X variant is interpreted as likely pathogenic while the p.D118Y variant is a variant of uncertain significance. The patient carrying the p.E720X mutation developed lower-limb-onset slowly progressive ALS, and survived for 11.5 years. The patient harboring the FIG4 p.D118Y variant also presented with progressive ALS, with the score on the ALS Functional Rating Scale–Revised (ALSFRS-R) decreasing by 0.4 per month. The rate of decrease in the ALSFRS-R scores from symptom onset to diagnosis seemed to be lower in the patients carrying FIG4 variants than the no-FIG4-mutation ALS patients in this study.ConclusionsOur findings suggest that ALS patients carrying FIG4 mutations are not common in the Chinese population and are more likely to exhibit slow progression.

Fatigue may be underestimated symptom in amyotrophic lateral sclerosis (ALS). The self-administered checklist individual strength (CIS20-R) was used to measure both physical and mental fatigue in ALS. Fatigue was measured in 51 consecutive patients with ALS using the fatigue severity scale (FSS) and the CIS20-R (four dimensions: subjective fatigue experience, concentration, motivation, activity). The questionnaire scores were compared with disease and progression parameters [revised ALS functional rating scale (ALS-FRS-R), MRC sum score, slow vital capacity (slow VC)]. Patients had follow-ups at six and 12 months. At baseline (mean age: 57.9 years ± 12.3, mean disease duration: 15.8 months ± 12.7) clinical relevant fatigue was seen in 49% in FSS and 40% in CIS20-R. FSS and CIS20-R (except the subscale for concentration) were steadily increasing in the course of the disease. CIS1 (subjective fatigue) but not FSS showed a correlation to the ALS-FRS-R and the progression of the ALS-FRS-R after 12 months. There was a moderate positive correlation between FSS and CIS20-R. The CIS20-R is a sensitive tool to detect clinically relevant fatigue in early stages of ALS. Both physical and mental (motivation) dimensions of fatigue steadily increase during the course of the disease in ALS.

To prospectively assess the incidence of both symptomatic and asymptomatic venous thromboembolism (VTE) in patients with amyotrophic lateral sclerosis (ALS) and to identify risk factors. Fifty outpatients with ALS were recruited consecutively and prospectively evaluated with bilateral venous duplex ultrasonography (VDU) of the proximal leg veins at enrollment and 6 and 12 months. The primary outcome measure was clinically important VTE, defined as asymptomatic proximal deep vein thrombosis (DVT) by screening VDU, symptomatically proven DVT or pulmonary embolism (PE), or fatal PE. For each patient, person-days of follow-up were recorded from enrollment until the date of VTE, death, loss to follow-up, or final 12-month visit. During the 1-year follow-up period, VTE was detected in 4 patients (1 symptomatic DVT, 1 symptomatic PE, and 2 asymptomatic DVTs) over 13,011 person-days of follow-up, representing an 11.2% 1-year incidence. Subjects with leg-onset ALS or significant leg weakness had a 1-year VTE incidence rate of 35.8% and 35.5%, respectively. VTE risk was significantly increased for those patients with decreased lower extremity Revised ALS Functional Rating Scale subscore (p = 0.03), decreased Lower Extremity Activity Scale score (p = 0.02), and decreased average lower limb Medical Research Council scale strength score (p = 0.03). Our data suggest that clinically important VTE is common in patients with ALS, particularly those with leg weakness and reduced mobility. Given these results, the potential benefits of routine VTE screening and primary prophylaxis in high-risk patients with ALS with leg weakness should be explored in future studies. In the meantime, physicians should have a low threshold for considering VTE in patients with ALS with leg weakness.