Probable Amyotrophic Lateral Sclerosis Research Articles

Intermuscular coherence as an early biomarker for amyotrophic lateral sclerosis: The protocol for a prospective, multicenter study.

To describe the protocol of a prospective study to test the validity of intermuscular coherence (IMC) as a diagnostic tool and biomarker of upper motor neuron degeneration in amyotrophic lateral sclerosis (ALS). This is a multicenter, prospective study. IMC of muscle pairs in the upper and lower limbs is gathered in ∼650 subjects across three groups using surface electrodes and conventional electromyography (EMG) machines. The following subjects will be tested: 1) neurotypical controls; 2) patients with symptomatology suggestive for early ALS but not meeting probable or definite ALS by Awaji Criteria; 3) patients with a known ALS mimic. The recruitment period is between 3/31/2021 and 12/31/2025. Written consent will be sought from the subject or the subject's legally authorized representative during enrollment. The endpoints of this study include: 1) whether adding IMC to the Awaji ALS criteria improve its sensitivity in early ALS and can allow for diagnosis earlier; 2) constructing a database of IMC across different ages, genders, and ethnicities. This study may validate a new inexpensive, painless, and widely available tool for the diagnosis of ALS.

Diagnostic utility of Gold Coast criteria for amyotrophic lateral sclerosis in Asia

Objective: This study aimed to reveal the diagnostic utility of Gold Coast (GC) criteria in Japanese patients with amyotrophic lateral sclerosis (ALS) by comparing the sensitivity/specificity with revised El Escorial (R-EE) and Awaji criteria, because its utility has not been studied in Asian ALS. Methods: Consecutive 639 patients (529 with ALS and 110 with ALS mimics), who were suspected of ALS and referred to three Japanese ALS centers, were enrolled. Diagnostic accuracy and characteristics of false positive and negative in GC criteria were compared with those of the Awaji and R-EE criteria. Patients were categorized as definite, probable or possible ALS according to each criterion. Results: The sensitivity of GC criteria (96.8%, 95% confidence interval [CI]: 95.3–98.3%) was higher than that of Awaji (89.6%, 95% CI: 87.0–92.2%) and R-EEC (89.2, 95% CI: 86.6–91.8%) criteria (both, p < 0.001). The specificity was also higher with GC criteria (77.3%, 95% CI: 69.5–85.1%) than Awaji (65.5%, 95% CI: 56.6–74.4%) and R-EEC (66.4, 95% CI: 57.6–75.2%) criteria (both, p < 0.01). Using GC criteria, patients with cervical spondylosis and Parkinson’s syndrome tended to be diagnosed with ALS (i.e. “false positive”). Additionally, ALS patients diagnosed only by GC criteria less frequently had upper motor neuron (UMN) signs, compared with the other two criteria. Conclusion: Gold Coast criteria improve diagnostic accuracy for ALS in an Asian population, especially in patients with subtle UMN signs.

Genetics screening in an Italian cohort of patients with Amyotrophic Lateral Sclerosis: the importance of early testing and its implication.

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with an elusive etiology. While environmental factors have been considered, familial ALS cases have raised the possibility of genetic involvement. This genetic connection is increasingly evident, even in patients with sporadic ALS. We allowed access to the genetic test to all patients attending our clinic to identify the prevalence and the role of genetic variants in the development of the disease and to identify patients with potentially treatable forms of the disease. 194 patients with probable or definite ALS, were enrolled. A comprehensive genetic testing was performed, including sequencing all exons of the SOD1 gene and testing for hexanucleotide intronic repeat expansions (G4C2) in the C9orf72 gene using fluorescent repeat-primed PCR (RP-PCR). Whole Exome NGS Sequencing (WES) was performed, followed by an in silico multigene panel targeting neuromuscular diseases, spastic paraplegia, and motor distal neuropathies. We conducted statistical analyses to compare different patient groups. Clinically significant pathogenetic variants were detected in 14.43% of cases. The highest prevalence of pathogenetic variants was observed in fALS patients, but a substantial proportion of sALS patients also displayed at least one variant, either pathogenetic or of uncertain significance (VUS). The most observed pathogenetic variant was the expansion of the C9orf72 gene, which was associated with a shorter survival. SOD1 variants were found in 1.6% of fALS and 2.5% of sALS patients. The study reveals a significant number of ALS patients carrying pathogenic or likely pathogenic variants, with a higher prevalence in familial ALS cases. The expansion of the C9orf72 gene emerges as the most common genetic cause of ALS, affecting familial and sporadic cases. Additionally, SOD1 variants are detected at an unexpectedly higher rate, even in patients without a familial history of ALS, underscoring the crucial role of genetic testing in treatment decisions and potential participation in clinical trials. We also investigated variants in genes such as TARDBP, FUS, NEK1, TBK1, and DNAJC7, shedding light on their potential involvement in ALS. These findings underscore the complexity of interpreting variants of uncertain significance (VUS) and their ethical implications in patient communication and genetic counseling for patients' relatives. This study emphasizes the diverse genetic basis of ALS and advocates for integrating comprehensive genetic testing into diagnostic protocols. The evolving landscape of genetic therapies requires identifying all eligible patients transcending traditional familial boundaries. The presence of VUS highlights the multifaceted nature of ALS genetics, prompting further exploration of complex interactions among genetic variants, environmental factors, and disease development.

Incidence of amyotrophic lateral sclerosis-associated genetic variants: a clinic-based study.

This study is to determine the incidence of genetic forms of amyotrophic lateral sclerosis (ALS) in clinic-based population. Next-generation sequencing (NGS) of whole exome sequencing (WES) was conducted among a total of 374 patients with definite or probable ALS to identify ALS-associated genes based on ALSoD database ( https://alsod.ac.uk ) [2023-07-01]. Variants of ALS-associated genes were detected in 54.01% (202/374) ALS patients, among which 8.29% (31/374) were pathogenic/likely pathogenic (P/LP). The detection rates of P/LP variants were significantly higher in familial ALS than sporadic ALS (42.31% vs 5.75%, p < 0.001), while VUS mutations were more commonly detected in sporadic ALS (23.07% vs 47.13%, p = 0.018). There is no significant difference in detection rate between patients with and without early onset (8.93% vs 7.77%), rapid progression (9.30% vs 8.91%), cognitive decline (15.00% vs 7.93%), and cerebellar ataxia (20.00% vs 8.15%) (p > 0.05). Over half of our ALS patients carried variants of ALS-related genes, most of which were variants of uncertain significance (VUS). Family history of ALS could work as strong evidence for carrying P/LP variants regarding ALS. There was no additionally suggestive effect of indicators including early onset, progression rate, cognitive decline, or cerebellar ataxia on the recommendation of genetic testing in clinical practice.

Long-term follow-up of five families from Turkey with UBQLN2 variants (P10-8.008)

<h3>Objective:</h3> In this study, we aim to further define the phenotypic characteristics of the <i>UBQLN2</i> mutations in the ALS patients from Turkey. <h3>Background:</h3> Amyotrophic Lateral Sclerosis (ALS) is the most common motor neuron disease (MND), caused by degeneration of upper and lower motor neurons. <i>UBQLN2</i> gene, which encodes ubiquilin-2, a member of the ubiquitin-like protein family, has been associated with X-linked ALS. <h3>Design/Methods:</h3> Clinical and genetic findings of six patients and five asymptomatic carriers with <i>UBQLN2</i> variants from five unrelated families from Turkey diagnosed with possible, probable, or definite ALS by El Escorial criteria at the Department of Neurology, Istanbul Faculty of Medicine were evaluated. The samples were collected with the approval of the relevant institutional ethics boards, and informed written consent was obtained from each participant. <h3>Results:</h3> Two of the symptomatic and four of the asymptomatic patients were female. The mean age of onset was 20.7±7.84 (range 12–36) years. The mean age of asymptomatic patients was 48.2 (range 35–76) years. One of our patient had Madras MND. Three of them presented with weakness and muscle wasting of one hand, three with bulbar dysfunction symptoms, and one with foot drop. Four of our patients had prominent lower motor neuron signs at the onset of the disease. Five patients died during follow-up because of respiratory complications, mean time to death after the onset of disease was 8.4 years (range 4–14 years). Four distinct missense variants (P506S, P525S, M392I, S340I) were found in our families. <h3>Conclusions:</h3> This is the largest cohort from Turkey, indicating genotypic and phenotypic heterogeneity of UBQLN2 mutations. The S340I change was identified in 3 unrelated families from Turkey previously. M392I variant was found in two of our patients with distinct phenotype (Madras MND and juvenile onset slowly progressive MND). Further analyses are needed to clarify the pathogenicity of the M392I variant of UBQLN2. <b>Disclosure:</b> Dr. Durmus has nothing to disclose. Arman Cakar has nothing to disclose. Dr. Parman has nothing to disclose.

18F-FDG PET/CT as a molecular biomarker in the diagnosis of amyotrophic lateral sclerosis associated with prostate cancer and progressive supranuclear palsy: A case report

Introduction Amyotrophic lateral sclerosis (ALS) is a neurodegenerative, multisystem disorder. Its clinical presentation typically consists of progressive focal muscle atrophy and weakness. In addition to motor disorders, the association between ALS and cancer has been researched, such as frontotemporal dementia and progressive supranuclear palsy. The diagnosis is based primarily on the clinical history, physical examination, electrodiagnostic tests (with an EMG needle), and neuroimaging, such as MRI and 18 F-FDG PET/CT. Presentation of the case A 67-year-old male patient was diagnosed with prostate adenocarcinoma with a clinical picture of muscle weakness in the lower limbs that caused falls and was associated with fasciculations in the thighs and arms, alterations in the tone of voice, poor memory, and difficulty articulating words. In the neurological assessment, he described walking supported by a walker with decreased strength in both lower limbs and sensitivity without alterations. The diagnoses of upper and lower motor neuron disease and probable ALS were integrated. Furthermore, the probable coexistence of frontotemporal dementia/disorder (FDD) with ALS was considered. The main findings in the 18 F-FDG PET/CT study was hypometabolism in the cortex of the bilateral motor and premotor areas, the anterior cingulate, both caudate and putamen, a metabolic pattern compatible with ALS, and progressive supranuclear palsy. Conclusion Through the PET/CT studies, we demonstrated a case in which ALS, prostate cancer and progressive supranuclear palsy coexisted molecularly; it was clinically difficult to diagnose. Molecular imaging has potential in the diagnostic and prognostic evaluation of ALS. It is crucial to identify the disease early and reliably through metabolic patterns that allow us to confirm the disease or differentiate it from other pathologies.

A multicenter, randomized, double blind, placebo-controlled clinical trial of dl-3-butylphthalide in treatment of amyotrophic lateral sclerosis.

A multicenter, randomized, double blind, placebo-controlled clinical trial of dl-3-butylphthalide in treatment of amyotrophic lateral sclerosis.

M1/precuneus ratio as a surrogate marker of upper motor neuron sign in ALS

ObjectiveTo investigate whether primary motor cortex (M1) volume measured with an automated approach in MRI reflects upper motor neuron dysfunction and whether it can serve as a potential diagnostic and/or disease-tracking biomarker for amyotrophic lateral sclerosis (ALS). MethodsIn this retrospective study, we enrolled 95 subjects, including 33 possible or laboratory supported probable ALS, 26 probable or definite ALS (Prob/Def), 2 primary lateral sclerosis patients, 8 progressive muscular atrophy patients, 19 normal controls (NC) and 7 ALS patients having a second structural MRI scan. Some subjects also underwent functional MRI. We calculated M1, primary sensory cortex, precuneus volumes, and total gray matter volume (TGMV) with FreeSurfer. The sensorimotor network (SMN) was identified using independent component analysis. ResultsThe M1/precuneus ratio showed a significant difference between the NC and Prob/Def groups (p < 0.05). The diagnostic accuracy of the M1/precuneus ratio was moderate for distinguishing Prob/Def from NC (cutoff = 1.00, sensitivity = 0.42, specificity = 0.90). Two of eight cases without upper motor neuron dysfunction could be diagnosed with ALS using M1/precuneus ratio as a surrogate marker. A negative correlation between M1/precuneus ratio and functional activity was found in Brodmann area 6 in the SMN in all subjects. TGMV tended to decrease with disease progression (p = 0.04). InterpretationThe M1/precuneus volume ratio, associated with the SMN, may have potential as a surrogate biomarker of upper motor neuron dysfunction in ALS. Furthermore, TGMV may serve as an ALS disease-tracking biomarker.

КЛИНИЧЕСКИЙ СЛУЧАЙ КОМПЛЕКСНОЙ РЕАБИЛИТАЦИИ ПАЦИЕНТА С КОМОРБИДНЫМ НЕЙРОДЕГЕНЕРАТИВНЫМ И АУТОИММУННЫМ ЗАБОЛЕВАНИЯМИ

Motor neuron disease, in the vast majority of cases occurring in the form of amyotrophic lateral sclerosis is a rare neurodegenerative disease with a prevalence of 2–3 cases per 100 thousand people in the population. The paper presents the results of a clinical observation of a patient with probable amyotrophic lateral sclerosis which occurs comorbidly with autoimmune myositis since the diagnosis was made in January 2023, as well as the effect of a comprehensive 21-day rehabilitation on clinical characteristics in the rehabilitation department of PARUS medical resort &amp; SPA, LLC, near Novosibirsk. The individual rehabilitation course included physical rehabilitation, restorative training, apparatus physiotherapy and occupational therapy in addition to medication. By the end of the rehabilitation course, the indicators of the measured clinical scales improved: ALSFRS-R – by 3 times, MRC muscle strength – 2 times, Barthel – 2 times, Beck – 1.5 times, according to the walking scale of the Institute of Neurology – 1.3 times, paresis scale of the Institute of Neurology – 2 times, dysphagia – 4.5 times. The study allows expanding and supplementing the available data regarding the difficulty of verifying the diagnosis which directly affects the complexity of assessing the rehabilitation prognosis, setting rehabilitation goals and objectives in a patient with difficult to differentiate comorbid pathology.

Retinal nerve fiber layer thinning found in amyotrophic lateral sclerosis - Correlation with disease duration and severity.

The retinal involvement of amyotrophic lateral sclerosis (ALS) is a novel idea about a possible correlation between retinal nerve fiber layer (RNFL) thickness in different spectra of ALS patients. Finding the association of RNFL with disease duration and severity will help identify a novel noninvasive biomarker. The study was designed as a cross-sectional study and was conducted with a suitable proforma. We included the ALS cases based on the revised El Escorial criteria. Healthy controls were age and gender matched. We used the revised ALS functional rating scale (ALSFRS-R) to assess the operational status of the patients. We measured RNFL thickness in the four quadrants with spectral-domain optical coherence tomography (OCT) and analyzed it. We included 30 cases (60 eyes) and 10 healthy controls (20 eyes) having a mean (standard deviation [SD]) age of 49.5 (11.1) years with a median of 50 years, and a majority of them (65%) were middle aged (between 41 and 60 years). We found statistically significant differences in RNFL thicknesses between ALS patients and healthy controls. On segmental analysis, the right eye superior and nasal quadrants and the left eye superior, inferior, and nasal quadrants were significantly affected, along with a gross asymmetry found between the left and right eyes among ALS patients. There was a significant decrease in average RNFL thickness in definite ALS patients than probable ALS patients, with significantly reduced average RNFL thickness in moderate to severe ALS patients. On correlation analysis, disease duration showed a good negative correlation with bilateral average RNFL thickness, and the ALSFRS-R score demonstrated a good positive correlation with bilateral average RNFL thickness, which was statistically significant. Thus, a reduced bilateral RNFL thickness is associated with a decreased ALSFRS-R score. The retinal changes can serve as a marker for diagnosing and monitoring patients with ALS.

P.219 Novel clinical phenotype of early-onset amyotrophic lateral sclerosis and frontotemporal dementia with SNCB mutation

The continuum between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is well known spectrum of disease and genetic variability in this overlap has been previously reported. We report a novel clinical phenotype of early-onset ALS and FTD with a previously reported <i>SNCB</i> (β synuclein) mutation with Lewi body dementia. 45-year-old woman presented to our department complaining of progressive quadriparesis and dysphagia, which had started with right hemiparesis 4 months ago. She had a history of hypothyroidism but denied neurological family history. Neurologic examination revealed Hoffmann sign positive bilaterally and hyperreflexia of both knees. Nerve conduction study and electromyography showed low complex motor action potentials and widespread denervation in four limbs and thoracic paraspinal muscles without abnormal sensory nerve action potentials. CSF study was unremarkable. Diagnosis of probable ALS was established and riluzole 100mg daily was administered. Three months later, she reported a cognitive decline. In the neuropsychologic assessment battery, her language, memory, and frontal/executive function were below the first percentile for her age with relatively intact attention and visuospatial function. Brain MRI showed bilateral temporal atrophy, especially in the left anterior temporal area. SPECT revealed hypoperfusion in both frontal, temporal, and parietal cortices. Targeted next generation sequencing was conducted for ALS and FTD, and we found heterozygous c.208G>A mutation in <i>SNCB</i>. Despite tremendous research elucidating ALS-FTD, early onset case is rare. With this case, we report a new clinical phenotype of ALS-FTD with <i>SNCB</i> mutation, which has been only reported in few cases of Lewy body dementia and is being investigated recently. This case implies <i>SNCB,</i> which is assumed to contribute to neurodegeneration, can be a new candidate of ALS-FTD, especially in young age.

Characterization of the nigroestriatal system in a sample of patients with amyotrophic lateral sclerosis.

The coexistence of amyotrophic lateral sclerosis (ALS) with clinical forms of Parkinson disease (PD), although uncommon, is found to a greater degree than one would expect by chance. The pathological mechanisms of ALS and PD are still not fully understood, and the coexistence of these two diseases suggests that they could share mechanisms in common. Here we present a sample of patients with clinically definitive or probable ALS who were evaluated with single-photon emission computed tomography SPECT/TRODAT and compared with non-ALS controls. Patients with clinically definite or probable ALS were assessed with the amyotrophic lateral sclerosis functional rating scale (ALSFRS) to define severity and had their demographic data collected. The TRODAT results of patients with ALS were compared with those of patients with a diagnosis of PD with less than 10 years of duration, and with patients with a diagnosis of others movement disorders not associated with neurodegenerative diseases. A total of 75% of patients with ALS had TRODAT results below the levels considered normal; that was also true for 25% of the patients in the control group without neurodegenerative disease, and for 100% of the patients in the PD group. A statistically significant difference was found between patients with ALS and the control group without neurodegenerative disease in the TRODAT values < 0.05. Our study fits with the neuropathological and functional evidence that demonstrates the existence of nigrostriatal dysfunction in patients with ALS. Further research to better understand the role of these changes in the pathophysiological process of ALS needs to be performed.

Predictive parameters of early respiratory decline in amyotrophic lateral sclerosis.

Respiratory insufficiency is a common symptom during the course of amyotrophic lateral sclerosis (ALS). The diagnostic workup may be challenging and includes a wide array of diagnostic measures. In this study, the aim was to analyze the relationship between hypercapnia-associated symptoms, blood gas parameters and pulmonary function tests. In total, 109 patients (56 women, 53 men, 62.4 ± 11.9 years) with definite, possible or probable ALS according to El Escorial criteria were included. All patients received either arterial blood gas analysis, nocturnal capnometry or both. Pulmonary function was assessed by spirometry and peak cough flow. Clinical symptoms potentially indicating hypercapnia were assessed using 17 dichotomous (yes/no) items. Of 109 ALS patients, 40 had hypercapnia. The highest accuracy and specificity for predicting hypercapnia was observed for dyspnea at rest (Youden's index 17%, 95% confidence interval [CI] 2%-34%; sensitivity 23%, 95% CI 9%-38%; specificity 95%, 95% CI 88%-100%). Daytime fatigue yielded the highest sensitivity of 58% (95% CI 40%-76%). Logistic regression for all assessed symptoms combined yielded an area under the receiver operating charteristic curve of 0.8 (95% CI 0.7-0.9). Compared to the clinical symptoms, forced vital capacity and peak cough flow showed higher sensitivity (70% and 87%, respectively) but lacked specificity (33% and 20%). Evaluation of the presence of hypercapnic symptoms can be utilized to predict incipient respiratory insufficiency and should complement pulmonary function tests. Further studies are needed to validate specific questionnaires in this regard. No single hypercapnia-associated symptom or pulmonary function test on its own seems sufficient to safely predict hypercapnia.

Pain-Related Factors and Their Impact on Quality of Life in Chinese Patients With Amyotrophic Lateral Sclerosis.

ObjectivesPain is considered a common symptom in amyotrophic lateral sclerosis (ALS). However, the results of studies on pain in ALS are limited and inconsistent. The aim of our study was to comprehensively evaluate the potential factors of pain and effects on quality of life (QoL) in patients with ALS from China.Participants and MethodsPatients were eligible if they fulfilled the criteria of probable and definitive ALS according to the revised El Escorial criteria. Pain was assessed by the Brief Pain Inventory (BPI). Disease severity, sleep quality, fatigue, anxiety, depression, and quality of life (QoL) were evaluated in ALS patients by the ALS Functional Rating Scale-revised (ALSFRS-R) and ALS severity scale (ALSSS), Pittsburgh Sleep Quality Index (PSQI), Fatigue Severity Scale (FSS), Hamilton Anxiety Rating Scale (HARS), Hamilton Depression Rating Scale (HDRS) and McGill Quality of Life Questionnaire (MQOL). Then, the clinical characteristics of ALS patients with pain were compared with those without pain. Last, associated factors of pain, as well as impact on QoL in Chinese ALS patients, were assessed.ResultsA total of 86 ALS patients were included. ALS patients with pain tended to have higher FSS scores and poorer QoL. The FSS score and ALSSS [lower extremity (LE) + upper extremity (UE)] were associated with pain in ALS patients. The ALS Functional Rating Scale-revised (ALSFRS-R), Pain Severity Index (PSI), HARS and HDRS scores were significantly associated with both the physical and psychological domains of QoL.ConclusionOur study was the first to comprehensively evaluate factors associated with pain in Chinese ALS patients, finding that fatigue can be a risk factor for pain and ALSSS (LE + UE) score was related with pain intensity. Additionally, we identified the adverse effects of ALSSS (LE + UE), HARS and HDRS scores on QoL in Chinese ALS patients.

Fat-rich versus carbohydrate-rich nutrition in ALS: a randomised controlled study

ObjectiveThere is growing evidence that the course of amyotrophic lateral sclerosis (ALS) may be influenced beneficially by applying high-caloric food supplements (HCSs). However, it is unknown which composition of nutrients...

Safety and Effectiveness of Long-term Intravenous Administration of Edaravone for Treatment of Patients With Amyotrophic Lateral Sclerosis

Intravenous 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. To evaluate the long-term safety and effectiveness of intravenous edaravone therapy for patients with ALS in a real-world clinical setting. 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 ≥4 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). Intravenous edaravone plus riluzole vs riluzole only. 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. 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 patients did not differ within the EFAS and non-EFAS subgroups. This cohort study using propensity score matching found that, although long-term intravenous edaravone therapy for patients with ALS was feasible and mainly well tolerated, it was not associated with any disease-modifying benefit. Intravenous edaravone may not provide a clinically relevant additional benefit compared with standard therapy alone.

Assessment of Therapeutic Response of Edaravone and Riluzole Combination Therapy in Amyotrophic Lateral Sclerosis Patients.

Background:Amyotrophic lateral sclerosis (ALS) is a progressive disease characterized by chronic degeneration of upper and lower motor neurons and finally death within 3–5 years usually because of respiratory failure. Riluzole and edaravone are presently available treatments. It may be better to try combination therapy rather than taking individual medications.Objectives:To compare the effectiveness of (edaravone + riluzole) combination therapy versus riluzole therapy alone in slowing down the progression of ALS and to evaluate the role of serum creatinine as a marker of disease progression.Materials and Methods:Observational, randomized, parallel assignment, open label study. Thirty patients with definite and probable ALS were randomly assigned to two treatment groups. The case group received (riluzole + edaravone) for the initial 6 months, followed by riluzole for the next 6 months. The control group received riluzole for 12 months. After 6 and 12 months, changes in ALS functional rating scale (ALSFRS-R), mRS, and Japanese ALS scores were determined. P value <.05 was considered significant.Results:An increase in mRS at 6 months in the case group versus control group was 0.07 versus 0.20, respectively (p =0.02). At 12 months, it was 0.47 versus 0.53, respectively (p =0.17). A decrease in serum creatinine at 6 months in case group versus control group was 0.08 versus 0.09, respectively (p =.82). There was no change in ALS FRS for bulbar symptoms (salivation), 3.46 versus 3.46 in the case group (p =.018) for the first 6 months.Conclusions:Combined with riluzole, edaravone slows disease progression and is safe, but the effect is short-term. Bulbar symptoms respond better to combination therapy. The serum creatinine is helpful in monitoring disease progression.

Could We Predict Respiratory Failure in Amyotrophic Lateral Sclerosis?

Introduction: Respiratory complications are important in the prognosis of amyotrophic lateral sclerosis (ALS). The aim of this study was to determine the electrophysiological findings that may predict respiratory failure. Methods: According to the Awaji electrodiagnostic criteria, 30 patients with ALS who were diagnosed with definite or probable ALS without respiratory failure were included in the study. Nerve conduction studies, needle electromyography (EMG), and single-breath count tests were performed in all patients. In addition, the pulmonary function tests, swallowing EMG, and arterial blood gas analysis of the patients were recorded and evaluated. The patients were followed until respiratory failure developed. Results: As a result of 18 months of follow-up, 26 of 30 patients developed respiratory failure. When the contribution of the accessory respiratory muscles to the respiratory effort before the development of respiratory failure was evaluated clinically and electrophysiologically, it was observed that the most common muscles involved in the respiratory effort were sternocleidomastoid (SCM), trapezius, and rectus abdominis. Before the development of respiratory failure, the latest neurogenic EMG findings were seen in the SCM (50% cases), trapezius (20% cases), and thoracic paraspinal muscles (17% of cases), respectively. It was thought that this finding could be an important early electrophysiologic marker in predicting the development of respiratory failure in ALS cases. Conclusions: To sum up, the presence of neurogenic changes in certain muscles in needle EMG and demonstration of the contribution of certain accessory respiratory muscles in respiration can be used as an electrophysiological marker to predict the development of respiratory failure.

Longitudinal Quantitative MRI Evaluation of Muscle Involvement in Amyotrophic Lateral Sclerosis.

Background: Biomarkers of disease progression and outcome measures are still lacking for patients with amyotrophic lateral sclerosis (ALS). Muscle MRI can be a promising candidate to track longitudinal changes and to predict response to the therapy in clinical trials.Objective: Our aim is to apply quantitative muscle MRI in the evaluation of disease progression, focusing on thigh and leg muscles of patients with ALS, and to explore the correlation between radiological and clinical scores.Methods: We enrolled newly diagnosed patients with ALS, longitudinally scored using the ALS Functional Rating Scale-Revised (ALSFRS-R), who underwent a 3T muscle MRI protocol including a 6-point Dixon gradient-echo sequence and multi-echo turbo spin echo (TSE) T2-weighted sequence for quantification of fat fraction (FF), cross-sectional area (CSA), and water T2 (wT2). A total of 12 muscles of the thigh and six muscles of the leg were assessed by the manual drawing of 18 regions of interest (ROIs), for each side. A group of 11 age-matched healthy controls (HCs) was enrolled for comparison.Results: 15 patients (M/F 8/7; mean age 62.2 years old, range 29–79) diagnosed with possible (n = 2), probable (n = 12), or definite (n = 1) ALS were enrolled. Eleven patients presented spinal onset, whereas four of them had initial bulbar involvement. All patients performed MRI at T0, nine of them at T1, and seven of them at T2. At baseline, wT2 was significantly elevated in ALS subjects compared to HCs for several muscles of the thigh and mainly for leg muscles. By contrast, FF was elevated in few muscles, and mainly at the level of the thigh. The applied mixed effects model showed that FF increased significantly in the leg muscles over time (mainly in the triceps surae) and that wT2 decreased significantly in line with worsening in the leg subscore of ALSFRS-R, mainly at the leg level and in the anterior and medial compartment of the thigh.Conclusions: Quantitative MRI represents a non-invasive tool that is able to outline the trajectory of pathogenic modifications at the muscle level in ALS. In particular, wT2 was found to be increased early in the clinical history of ALS and also tended to decrease over time, also showing a positive correlation with leg subscore of ALSFRS-R.

Muscle ultrasonography in detecting fasciculations: A noninvasive diagnostic tool for amyotrophic lateral sclerosis.

Muscle ultrasound (MUS) is an emerging noninvasive tool to identify fasciculations in amyotrophic lateral sclerosis (ALS). We assessed the utility of MUS in detecting fasciculations in suspected ALS patients. Thirty-three patients (25 men) with possible (n=7), probable (n=12), or definite ALS according to Awaji criteria were studied. Electromyography was done in biceps brachii, quadriceps, and thoracic paraspinal muscles and MUS in biceps, triceps, deltoid, abductor-digiti-minimi, quadriceps, hamstrings, tibialis anterior, thoracic paraspinal, and tongue muscles. The age at onset and illness duration was 49.73 ± 12.7 years and 13.57 ± 9.7months, respectively. Limb-onset=24 patients (72.7%) and bulbar-onset=9 (27.3%). Totally 561 muscles were examined by MUS. Fasciculations were detected in 84.3% of muscles, 98.4% with and 73% without clinical fasciculations (p < 0.001). Fasciculation detection rate (FDR) by MUS was significantly higher in muscles with wasting (95.6%) than without wasting (77.6%, p < 0.001). Compared with EMG, FDR was significantly higher with MUS in quadriceps (81.8% vs. 51.5%, p=0.002) and thoracic paraspinal muscles (75.8% vs. 42.4%, p=0.013). The proportion of patients with definite ALS increased from 42% by clinical examination to 70% after combining EMG and MUS findings. MUS is more sensitive in detecting fasciculations than electromyography (EMG) and provides a safer, faster, painless, and noninvasive alternative to EMG in detecting fasciculations in ALS.