Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised Score Research Articles

Loss of appetite is associated with a loss of weight and fat mass in patients with amyotrophic lateral sclerosis

Objective: Weight loss in amyotrophic lateral sclerosis (ALS) is associated with faster disease progression and shorter survival. It has different possible causes, including loss of appetite. Our objective is to determine the prevalence and impact of loss of appetite on change in body weight and composition in patients with ALS. Methods: We conducted a prospective case-control study, comparing demographic, clinical, appetite and prognostic features between 62 patients with ALS and 45 healthy non-neurodegenerative disease (NND) controls. To determine the impact of loss of appetite on weight throughout disease course, we conducted serial assessments at ∼three to four-month intervals. Results: Loss of appetite is more prevalent in patients with ALS than NND controls (29 vs. 11.1%, odds ratio = 3.27 (1.1–9.6); p < 0.01). In patients with ALS, loss of appetite is associated with greater weight loss and greater loss of fat mass. Appetite scores in patients with ALS worsens as disease progresses and are correlated with worsening ALS Functional Rating Scale-Revised scores. Conclusion: We confirm that loss of appetite is prevalent in patients with ALS and is significantly associated with weight loss and loss of fat mass. Appetite worsens with disease progression. Identification and early interventions to address loss of appetite in patients with ALS may prevent or slow weight loss; this could improve disease outcome.

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.

Is the evidence strong enough for acupuncture ameliorates clinical symptoms in patients with amyotrophic lateral sclerosis: A protocol for a systematic review and meta-analysis.

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.

Variation in assistive technology use in Motor Neuron Disease according to clinical phenotypes and ALS Functional Rating Scale - Revised Score: A prospective observational study.

Assistive devices enhance independence and quality of life for people living with motor neuron disease (MND), but prescription can be challenging. Improved prescription of assistive devices, through improved understanding of the relationship between clinical phenotypes, Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R) functional domain sub-scores and assistive technology required by people living with MND. Prospective, observational consecutive-sample study of 269 patients with MND diagnosis. MND phenotype, ALSFRS-R scores and assistive technology devices in use. A statistically significant difference in total concurrent assistive technology item use was found between phenotypes (p = 0.001), with those with ALS Bulbar onset using the least. There was also a statistically significant difference in assistive technology usage in five of seven assistive technology categories across the clinical phenotypes, namely orthoses (p < 0.000), mobility devices (p < 0.000), transfer devices (p < 0.000), communication devices (p < 0.000), and activities of daily living devices (p = 0.016). Correlations between ALSFRS-R sub-score items and assistive technology count confirmed the utility of this outcome measure for equipment prescription. Clinicians need to consider MND phenotype and/or ALSFRS-R domain sub-score in clinical decision-making regarding assistive technology, as this will determine the pattern of disease and its progression, and hence assistive technology required.

Recumbent stepping aerobic exercise in amyotrophic lateral sclerosis: a pilot study

Aerobic exercise can promote neuroplastic responses in the healthy and injured brain. Although the role of exercise in amyotrophic lateral sclerosis (ALS) is debated, new evidence suggests that exercise may reduce disease progression. While common exercise modalities such as the treadmill and cycle ergometer have been explored in ALS, the safety and feasibility of a total body recumbent stepper have not been investigated. Additionally, the functional and neurophysiological effects of recumbent stepping in ALS are still unknown. Here, we investigated the safety and feasibility of a 4-week recumbent stepping program to slow disease progression in ALS and possibly facilitate neuroplasticity. Nine individuals with ALS performed moderate intensity recumbent stepping for four weeks. Outcomes included participation satisfaction questionnaire, ALS Functional Rating Scale Revised (ALSFRS-R), clinical tests of walking and endurance, fatigue severity scale, Beck depression inventory, SF-12, and transcranial magnetic stimulation-induced motor evoked potentials (MEPs). All measurements were collected at baseline, post-intervention, and at the 1-month follow-up. Eight participants completed the study without any adverse events. The ALSFRS-R scores were similar at the end of the study and at follow-up. No significant differences were noted for any of the clinical outcomes. MEPs were present only in two participants and changes in corticomotor excitability after exercise were minimal. Results from this preliminary study support the safety and feasibility of 12 sessions of total body recumbent stepping in individuals with ALS.

Case study: improvement in amyotrophic lateral sclerosis symptoms in a patient receiving edaravone infusions

Background: HB is a 52-year-old female who was diagnosed with amyotrophic lateral sclerosis (ALS) in February 2017. Her symptoms began in September 2016 with right-hand weakness, and they rapidly declined as demonstrated in decreased ALS Functional Rating Scale-Revised (ALSFRS-R) assessment score results from 27/48 in April 2017 to 18/48 in August 2017. HB was prescribed riluzole at the time of diagnosis and began receiving edaravone infusions in November 2017. During the initial visit for the edaravone infusions, the visiting nurse evaluated the patient to be bedbound with no movement of any extremities. She was unable to facially express any emotions except for crying, and she was nonverbal but able to communicate using a speech-generating device. Edaravone has been proven to slow the progression of ALS symptoms. However, after receiving several cycles of edaravone infusions, HB has demonstrated an improvement in specific categories of her ALS symptoms.Objectives: The purpose of this case study is to describe the potential improvement of ALS symptoms in a patient receiving edaravone infusions.Methods: A retrospective review of the patient’s medical documentation from July 2017 to December 2017 was performed, which comprised of the prescriber’s office visit notes, the home infusion company’s multi-disciplinary assessments, and interviews with the patient’s family members.Results: HB received a total of three infusion cycles with edaravone. Her ALSFRS-R scores improved from 16/48 to 21/48. Improvements were noted in the following categories: ability to turn in bed, dyspnea, orthopnea, and respiratory insufficiency. After completion of the first cycle, the patient’s family members reported that she had more energy and was no longer napping throughout the day. While being transferred from the bed to a wheelchair, the patient was able to assist by using her upper and lower extremities. Most notable, however, were the observations made by the visiting nurse. When returning for the second cycle of edaravone infusions, the patient was sitting up in a chair and greeted the nurse with a smile and said “Hi.” This was the first clear verbal communication the patient had since becoming nonverbal in August 2017.Conclusions: Though edaravone has only been clinically proven to slow the progression of ALS symptoms, HB has demonstrated symptom reversal in several categories, including respiratory function and mobility of her extremities. Data will continue to be collected and evaluated with each edaravone cycle.

Effects of early introduction of non-invasive positive pressure ventilation based on forced vital capacity rate of change: Variation across amyotrophic lateral sclerosis clinical phenotypes.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease associated with high morbidity and mortality. We evaluated the ability of pulmonary function tests to predict disease progression by ALS clinical phenotypes, and the timing of the introduction of non-invasive positive pressure ventilation (NIPPV). A cohort study was performed in all adult patients who fulfilled El Escorial criteria at a tertiary-care academic medical centre for veterans in the USA from 1 January 2010 to 31 December 2014. Eligible patients underwent sitting and supine forced vital capacity (FVC) and the FVC rate of change (RoC) per month was calculated. ALS Functional Rating Scale-Revised (ALSFRS-R) scores were collected. A total of 137 patients were included in our analysis. The average survival from ALS onset was 31.40 (±40.04) months. The general cohort median (IQR) RoC was -0.87 (-2.55 to 0.34)/-0.65 (-2.55 to 0.70) % per month (P=0.81) of the sitting/supine FVC, respectively. However, mean monthly RoC varied among the ALS phenotypes, with higher variation among global ALS, where greater decline in RoC was noted. The average time from ALS onset to tracheostomy was 27.88 (±22.21) months. The average sitting/supine FVC RoC for subjects requiring tracheostomy was -2.86 (±3.77)/-3.63 (±3.75) at the time of tracheostomy, compared to -1.190 (±2.38)/-1.07 (±3.78) for those who did not require the procedure. Although NIPPV use did not result in statistically significant improvements in either the sitting or supine FVC %, it did slow the RoC decline of patients with global ALS phenotypes. Initiation of NIPPV based on decline in RoC rather than the absolute value of either sitting or supine FVC may result in early stabilisation of ALS patients' pulmonary deterioration for the global clinical phenotype, and thus may have the potential for prolonging survival until tracheostomy or death.

Serum ferritin is a candidate biomarker of disease aggravation in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease. The mechanism that defines the loss of neurons in ALS is still not clearly understood, and there is no effective therapy to block its progression. Previous studies indicate that a disorder of iron homeostasis exists in ALS and based on this, the change of serum iron and ferritin and the association between iron metabolism and clinical features in Chinese Han patients with ALS was further investigated in the present study, in order to define its pathogenesis. Two cohorts were established: An ALS group consisting of 24 patients and a control group consisting of 38 healthy volunteers. Venous blood samples were collected for serum iron and ferritin analysis. The results indicated that the levels of serum iron were significantly decreased in patients with ALS (P<0.05), while there was no significant difference in serum ferritin between the ALS and control groups. However, the levels of serum ferritin were increased significantly in ALS patients with bulbar-onset (vs. limb-onset in females), dysphagia (vs. without dysphagia), longer disease duration (>12 months vs. ≤12 months in males) and lower ALS Functional Rating Scale-Revised score (<33 vs. ≥33; P<0.05). These results suggested that there was dysregulation of iron metabolism in Chinese Han patients with ALS and that serum ferritin may be a candidate biomarker of aggravation in these patients.

Neuronal apoptosis inhibitory protein is implicated in amyotrophic lateral sclerosis symptoms

The delineation of the molecular pathology underlying amyotrophic lateral sclerosis (ALS) is being hampered by the lack of suitable biomarkers. We have previously reported that bromocriptine upregulates the endogenous antioxidative factor, neuronal apoptosis inhibitory protein (NAIP), sustains motor function and slows disease progression in ALS patients, implying the NAIP’s implication in ALS. Here, we aimed to verify a correlation of NAIP level with disease progression in ALS patients. The amount of NAIP in mononuclear cells (MNC) from peripheral blood from ALS patients (n = 18) and the age matched healthy controls (n = 12) was validated by NAIP-Dot blotting. Notably, the MNC-NAIP level in ALS patients (0.62 ± 0.29 ng) was nearly half of that in the healthy controls (1.34 ± 0.61 ng, P = 0.0019). Furthermore, the MNC-NAIP level in ALS patients and their ALS Functional Rating Scale-Revised (ALSFRS-R) score were evaluated through 1 year. Regression analysis of the MNC-NAIP vs ALSFRS-R indicated that a higher amount of MNC-NAIP was associated with a smaller change in ALSFRS-R at 12 months (R2 = 0.799; P = 0.016), suggesting that a progressive increment of the MNC-NAIP led to slower ALS progression. Our present report implies that NAIP will have broad implications for ALS symptoms as a risk factor and a promising prognostic biomarker.

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

Baseline Predictors of Noninvasive Ventilation Use in Amyotrophic Lateral Sclerosis

SESSION TITLE: Pulmonary Manifestations of Systemic Diseases SESSION TYPE: Original Investigation Slide PRESENTED ON: Wednesday, November 1, 2017 at 07:30 AM - 08:30 AM PURPOSE: Respiratory failure due to neuromuscular weakness is the most common cause of death for patients with Amyotrophic Lateral Sclerosis (ALS). Non-invasive ventilation (NIV) can improve quality of life and potentially improve survival. However, due to variable progression of ALS, the timing of onset of respiratory weakness remains uncertain. The ability to predict non-invasive ventilation use may help guide patient-physician communication, specialist referral, monitoring decisions, and clinical trial design. In this study, we sought to determine the baseline risk factors for eventual initiation of NIV. METHODS: We performed a retrospective cohort study of 572 patients who met El Escorial criteria for Suspected, Possible, Probable, or Definite ALS. All patients were seen in a multidisciplinary Neurology outpatient clinic at the University of Pennsylvania. Outpatient visits occurred approximately every three months between May 2010 and October 2016. Study variables included demographics, ALS Functional Rating Scale-Revised (ALSFRS-R) score, height, weight, comorbid conditions, smoking history, symptom onset date, symptom onset site, El Escorial criteria, forced vital capacity (FVC) in seated position, NIV initiation date, and date of death. We used univariate and multivariate Cox proportional hazard models, censoring at date of death or last visit date. The final multivariate model used backward elimination. RESULTS: The median age of diagnosis was 65.2 (interquartile range, 57.3 to 72.7) years and 58.4% were male. There were 812 person-years of follow-up time, and 45.5% (n=260) were initiated on NIV during the study period. The median time to NIV initiation was 184 days (interquartile range, 37 to 386 days). In a multivariate analysis, factors significantly associated with risk of NIV included older age at diagnosis (per 10 years, HR 1.27, 95% CI 1.13 - 1.44, p<0.001), fewer years between symptoms and diagnosis (HR 0.73, 95% CI 0.64-0.83, p<0.001), being underweight (HR 2.18, 95% CI 1.24-3.82, p=0.007), African-American race (HR 1.83, 95% CI 1.19-2.81, p=0.006), lower decile of percent predicted FVC (HR 1.15, 95% CI 1.09-1.22, p<0.001), history of hypertension (HR 1.34, 95% CI 1.01-1.78, p=0.040), lumbosacral symptom onset (reference: bulbar onset, HR 1.67, 95% CI 1.17-2.38, p=0.005), and El Escorial criteria of Suspected ALS (HR 0.62, 95% CI 0.41-0.95, p=0.027) or Possible ALS (HR 0.67, 95% CI 0.44-1.00, p=0.050) with a reference of Definite ALS. CONCLUSIONS: We identified baseline risk factors that were significantly associated with initiation of NIV in ALS patients. To our knowledge, this is the largest cohort study of ALS patients to identify risk factors for respiratory insufficiency. These factors may reveal important mechanisms of respiratory failure in ALS, which could be targeted with novel therapies. CLINICAL IMPLICATIONS: While many of the risk factors were not modifiable (e.g., older diagnosis age), such predictors could be used to develop a risk prediction score, inform communication with patients, guide clinical trial design, as well as facilitate early referral to pulmonologists. DISCLOSURE: The following authors have nothing to disclose: Jason Ackrivo, E. Wileyto, Lauren Elman, John Hansen-Flaschen, Steven Kawut No Product/Research Disclosure Information

Behavioral and affective features of amyotrophic lateral sclerosis patients

Evaluating the cognitive and behavioral features in amyotrophic lateral sclerosis (ALS) patients is important for therapy and care. Fifty-seven ALS, 5 ALS with the behavioral variant of frontotemporal dementia (FTD) (ALS-FTD), 12 FTD patients, and 35 control subjects were evaluated by 10 different tests for cognitive and behavioral (mini-mental state examination (MMSE), Hasegawa dementia rating scale – revised (HDS-R), frontal assessment battery (FAB), Montreal cognitive assessment (MoCA), ALS-frontotemporal dementia-Questionnaire (ALS-FTD-Q), and anosognosia scale), affective (depression, apathy, and behavioral and psychological symptoms of dementia (BPSD)), and activities of daily living (ADL) assessments. The motor functions of ALS patients were evaluated by ALS functional rating scale – revised (ALSFRS-R) and modified Norris scale.ALS-FTD-Q scores showed intermediate behavioral disturbances of ALS patients between ALS-FTD and FTD patients and control subjects, but FAB, MoCA, and anosognosia scales did not. Both FAB and MoCA scores were significantly correlated with MMSE and HDS-R in ALS patients, but ALS-FTD-Q was not. ALS-FTD-Q score was significantly correlated with ALSFRS-R, apathy, BPSD, and ADL scores in ALS patients.Thus, in ALS patients, both FAB and MoCA tests were useful to assess frontal cognitive impairments, while ALS-FTD-Q was useful to detect mild behavioral and affective disturbances.

Structural MRI correlates of amyotrophic lateral sclerosis progression

PurposeAmyotrophic lateral sclerosis (ALS) presents with varying degrees of brain degeneration that can extend beyond the corticospinal tract (CST). Furthermore, the clinical course and progression of ALS varies widely. Brain...

Elevated levels of ferritin in the cerebrospinal fluid of amyotrophic lateral sclerosis patients.

The aim of the study was to detect changes in the levels of ferritin heavy chain (FHC), ferritin light chain (FLC), and transferrin in the cerebrospinal fluid (CSF) and serum of amyotrophic lateral sclerosis (ALS) patients and to analyze the correlations between the levels of these proteins and various clinical parameters. Cerebrospinal fluid and serum samples were obtained from 54 ALS patients and 46 non-inflammatory neurological disease control (non-INDC) patients. CSF and serum FHC, FLC, and transferring levels were measured via the enzyme-linked immunosorbent method using a commercial ELISA kit, and the times from onset (durations), ALS functional rating scale-revised (ALSFRS-r) scores, and disease progression rates (DPRs) were analyzed by registered neurologists. Statistical analysis was performed via Prism software. Compared with controls, ALS patients exhibited significantly increased FHC and FLC levels in CSF, which were positively correlated with DPR and negatively correlated with duration. Serum transferrin levels were significantly increased in ALS patients but were not correlated with disease progression. FHC and FLC in CSF rapidly increased as the disease worsened. This study demonstrated that the clinical measurement of FHC and FLC in CSF may be beneficial for disease differentiation and evaluating progression in patients with ALS. Compared with levels in serum, the levels of FHC and FLC in CSF might be more reliable for diagnosing and assessing the progression of ALS.

Association Between Dietary Intake and Function in Amyotrophic Lateral Sclerosis

ImportanceThere is growing interest in the role of nutrition in the pathogenesis and progression of amyotrophic lateral sclerosis (ALS).ObjectiveTo evaluate the associations between nutrients, individually and in groups, and ALS function and respiratory function at diagnosis.Design, Setting, and ParticipantsA cross-sectional baseline analysis of the Amyotrophic Lateral Sclerosis Multicenter Cohort Study of Oxidative Stress study was conducted from March 14, 2008, to February 27, 2013, at 16 ALS clinics throughout the United States among 302 patients with ALS symptom duration of 18 months or less. ExposuresNutrient intake, measured using a modified Block Food Frequency Questionnaire (FFQ).Main Outcomes and MeasuresAmyotrophic lateral sclerosis function, measured using the ALS Functional Rating Scale–Revised (ALSFRS-R), and respiratory function, measured using percentage of predicted forced vital capacity (FVC). ResultsBaseline data were available on 302 patients with ALS (median age, 63.2 years [interquartile range, 55.5-68.0 years]; 178 men and 124 women). Regression analysis of nutrients found that higher intakes of antioxidants and carotenes from vegetables were associated with higher ALSFRS-R scores or percentage FVC. Empirically weighted indices using the weighted quantile sum regression method of “good” micronutrients and “good” food groups were positively associated with ALSFRS-R scores (β [SE], 2.7 [0.69] and 2.9 [0.9], respectively) and percentage FVC (β [SE], 12.1 [2.8] and 11.5 [3.4], respectively) (all P < .001). Positive and significant associations with ALSFRS-R scores (β [SE], 1.5 [0.61]; P = .02) and percentage FVC (β [SE], 5.2 [2.2]; P = .02) for selected vitamins were found in exploratory analyses.Conclusions and RelevanceAntioxidants, carotenes, fruits, and vegetables were associated with higher ALS function at baseline by regression of nutrient indices and weighted quantile sum regression analysis. We also demonstrated the usefulness of the weighted quantile sum regression method in the evaluation of diet. Those responsible for nutritional care of the patient with ALS should consider promoting fruit and vegetable intake since they are high in antioxidants and carotenes.

Increased ratio of circulating neutrophils to monocytes in amyotrophic lateral sclerosis.

Objective:To elucidate amyotrophic lateral sclerosis (ALS) biomarkers and potential mechanisms of disease, we measured immune cell populations in whole blood from a large cohort of patients with ALS.Methods:Leukocytes were isolated from the blood of 44 control patients and 90 patients with ALS. The percentages and total numbers of each cell population were analyzed using flow cytometry and matched with patient ALS Functional Rating Scale–Revised (ALSFRS-R) score to correlate leukocyte metrics with disease progression.Results:We show a significant increase in the percentage of neutrophils and a significant decrease in the percentage of CD4 T cells and CD16− monocytes in the blood of patients with ALS compared to controls; however, only CD16− monocyte levels correlated with disease progression. We also examined the monocyte surface expression of CCRL2 and CCR3; CD16− monocytes displayed decreased percentages and total numbers expressing CCR3, but these numbers did not correlate with ALSFRS-R score. We found that combining multiple disease metrics yielded the most accurate predictor of disease progression: the ratio of neutrophils to CD16− monocytes (N:M ratio) is significantly increased in patients with ALS and better correlates with disease progression than any other single metric.Conclusions:These observations implicate neutrophils and monocytes as important factors in late disease progression.

Association between depression and survival in Chinese amyotrophic lateral sclerosis patients.

To determine the prevalence of depression, to identify correlated factors for depression, and to explore the impact on the progression or survival of amyotrophic lateral sclerosis (ALS) by depression in a Chinese population. A total of 166 ALS patients were recruited. Diagnosis of depression disorders and the severity of depression were established by using the fourth diagnostic and statistical manual of mental disorders, Hamilton Depression Rating Scale-24 items (HDRS-24) and Beck Depression Inventory (BDI). Major depression was found in 15 patients (9.6%). The multiple regression analysis showed that a lower ALS Functional Rating Scale-Revised (ALSFRS-R) score was correlated with increasing HDRS scores and BDI scores (P=0.018 and P=0.012). No significant difference in the median survival time between ALS patients with and without depression was revealed by Kaplan-Meier analysis (log-rank P=0.282). Cox hazard model showed that the presence of depression in ALS was unrelated to the survival, while the severity of depression in ALS was correlated with the survival. The presence and severity of depression in ALS did not correlate with the progression of ALS. Major depression in ALS is uncommon. Depression evaluation should be given to ALS patients, especially those with lower ALSFRS-R score. The severity of depression may be associated with the survival; however, depression does not worse the progression of ALS.

Amyotrophic lateral sclerosis: promising therapeutic outcome-not far away?

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.

Reference Range of Respiratory Muscle Strength and Its Clinical Application in Amyotrophic Lateral Sclerosis: A Single-Center Study.

Background and PurposeEvaluating respiratory function is important in neuromuscular diseases. This study explored the reference ranges of the maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), and sniff nasal inspiratory pressure (SNIP) in healthy adults, and applied them to amyotrophic lateral sclerosis (ALS) patients.MethodsMIP, MEP, and SNIP were measured in 67 healthy volunteers aged from 21 to 82 years. Reference ranges were evaluated by multivariate regression analysis using the generalized additive modeling of location, scale, and shape method. Thirty-six ALS patients were reviewed retrospectively, and abnormal values of MIP, MEP, and SNIP were determined according to the reference ranges.ResultsMIP, MEP, and SNIP were abnormal in 57.1%, 51.4%, and 25.7% of the ALS patients, respectively. MIP and SNIP were significantly correlated with the degree of restrictive pattern and respiratory symptoms. The ALS Functional Rating Scale-Revised score was correlated with SNIP.ConclusionsThis study has provided the reference range of respiratory muscle strength in healthy adults. This range is suitable for evaluating respiratory function in ALS patients.

Phase I Trial of Repeated Intrathecal Autologous Bone Marrow-Derived Mesenchymal Stromal Cells in Amyotrophic Lateral Sclerosis

Stem cell therapy is an emerging alternative therapeutic or disease-modifying strategy for amyotrophic lateral sclerosis (ALS). The aim of this open-label phase I clinical trial was to evaluate the safety of two repeated intrathecal injections of autologous bone marrow (BM)-derived mesenchymal stromal cells (MSCs) in ALS patients. Eight patients with definite or probable ALS were enrolled. After a 3-month lead-in period, autologous MSCs were isolated two times from the BM at an interval of 26 days and were then expanded in vitro for 28 days and suspended in autologous cerebrospinal fluid. Of the 8 patients, 7 received 2 intrathecal injections of autologous MSCs (1 × 10(6) cells per kg) 26 days apart. Clinical or laboratory measurements were recorded to evaluate the safety 12 months after the first MSC injection. The ALS Functional Rating Scale-Revised (ALSFRS-R), the Appel ALS score, and forced vital capacity were used to evaluate the patients' disease status. One patient died before treatment and was withdrawn from the study. With the exception of that patient, no serious adverse events were observed during the 12-month follow-up period. Most of the adverse events were self-limited or subsided after supportive treatment within 4 days. Decline in the ALSFRS-R score was not accelerated during the 6-month follow-up period. Two repeated intrathecal injections of autologous MSCs were safe and feasible throughout the duration of the 12-month follow-up period. Stem cell therapy is an emerging alternative therapeutic or disease-modifying strategy for amyotrophic lateral sclerosis (ALS). To the authors' best knowledge, there are no clinical trials to evaluate the safety of repeated intrathecal injections of autologous bone marrow mesenchymal stromal cells in ALS. After the clinical trial (phase I/II) was conducted, the stem cell (HYNR-CS, NEURONATA-R) was included in the revision of the regulations on orphan drug designation (number 160; December 31, 2013) and approved as a New Drug Application (Department of Cell and Gene Therapy 233; July 30, 2014) by the Korean Food and Drug Administration. The phase II trial is expected to be reported later.