Bulbar-onset Amyotrophic Lateral Sclerosis Research Articles

Outcomes after intervention for enteral nutrition in patients with amyotrophic lateral sclerosisin multidisciplinary clinics.

Patients with amyotrophic lateral sclerosis (ALS) are susceptible to malnutrition, with appropriate management of nutritional interventions an active area of investigation. We sought to determine the impact of gastrostomy tube placement in ALS patients, exploring the correlation between forced vital capacity (FVC), malnutrition, and perioperative complications. A retrospective review was performed of clinically diagnosed ALS patients treated at two multidisciplinary clinics (University of Kansas, University of Nebraska) from January 2009 to September 2020 who were referred for gastrostomy. Data collected included demographics, disease characteristics, and key gastrostomy related dates/outcomes. Two hundred thirty-nine patients were included with a median age of 65 years and median of 589 days from symptom onset to gastrostomy (interquartile range, 404-943). The population was predominantly Non-Hispanic White with bulbar-onset ALS. 30-day mortality was 4% and 30-day morbidity was 13%. Weight loss, body mass index, and predicted FVC at placement showed no increased 30-day morbidity or mortality association. Bulbar-onset ALS patients exhibited higher overall mortality postplacement than limb onset (odds ratio: 1.85, 95% confidence interval: 1.03-3.33). There was a 5% incidence of symptoms suggestive of refeeding syndrome. Rates of major/minor complications and 30-day mortality related to gastrostomy placement in our population were similar compared with prior studies in ALS. The lack of difference in outcomes based on FVC at procedure may suggest this is not predictive of outcome, or perhaps, high-quality perioperative respiratory management. Alternative reasons may account for the increased morbidity and mortality of gastrostomy placement in the ALS population.

Bulbar-onset amyotrophic lateral sclerosis in a patient with genetically confirmed Huntington’s disease: a case study

BackgroundThe rationale for this paper is a description of a patient from Southeast Europe with genetically confirmed Huntington’s disease (HD), coexisting with sporadic, bulbar-onset amyotrophic lateral sclerosis (ALS). To the best of our knowledge, the total number of reported cases with confirmed coexistence of HD and ALS is less than 20. Thus, it is an extremely rare condition speculated to be in a range from 2 to 6 per billion, and data from this part of the World are completely missing.Case presentationHere we report a 72-year-old female with a family history of HD who had generalized chorea and hyperreflexia. Using the PCR-based test for the detection of the CAG triplet repeat expansion, the presence of HD was confirmed. After several months, our patient had progressively developed dysarthria and dysphagia, followed by spastic quadriparesis, generalized muscle wasting, spontaneous fasciculations and sialorrhea. The diagnosis of definite ALS was established based on the patient’s neurological status, electromyography findings and current El Escorial criteria.ConclusionsOur study emphasizes the need for the recognition of the co-occurrence of clinically distinct and rare genetic disorders, such as HD and ALS. New insights from the studies dealing with these rare topics could significantly contribute to the contest of new gene therapy trials.

33 Amyotrophic Lateral Sclerosis with and without Bulbar Onset: Cognitive and Behavioral Findings from an Outpatient Sample

Objective:The relationship between frontotemporal dementias (FTDs) and amyotrophic lateral sclerosis (ALS) is well established and is believed to be more pronounced in those with bulbar onset ALS (B-ALS). This study compared cognitive and behavioral symptoms among persons with B-ALS to those of individuals with nonbulbar phenotypes (NB-ALS).Participants and Methods:Outpatient clinic data collected during an initial neuropsychology consultation at an ALS interdisciplinary clinic in an academic medical center was retroactively analyzed. All individuals were diagnosed with ALS by neurologists specializing in movement and neuromuscular disorders based on results of neurological/motor examination, electromyographies, and (when available) genotypic data. Total scores on the short form of the Montreal Cognitive Assessment (MoCA-SF) and scores on the ALS Cognitive Behavioral Screen (ALS-CBS) and ALS CBS Caregiver questionnaire were of focus. 22 B-ALS and 44 NB-ALS individuals were compared on said measures using univariate analyses while controlling for ALS symptoms duration.Results:B-ALS individuals scored significantly lower on the MoCA-SF (F(2)=3.15, p=0.05, n2=0.13) and the tracking subscale of the ALS-CBS (F(2)=3.50, p=0.04, n2=0.17). The groups were not significantly different on other ALS-CBS measures, including caregiver-rated behavior questionnaire.Conclusions:Consistent with previous research, this study found lower total scores on a brief screener of global cognition and tasks of tracking requiring cognitive control in those with B-ALS relative to NB-ALS individuals. Interestingly, despite behavioral variant being the most prevalent FTD phenotype, the groups did not differ significantly in terms of caregiver-rated behavioral changes. It is hypothesized that the absence of these differences could reflect effects of gradual loss of speech and functionality that secondarily limit caregivers' abilities to observe behavioral changes concerning for possible behavioral variant FTD. That said this could reflect limitations of the sample and/or study design, and further exploration is therefore needed. Recommendations for future studies of neuropsychological/behavioral variables in B-ALS as well as development of more targeted instruments for use in this population are discussed.

Trigeminal Nerve Involvement in Bulbar-Onset Anti-IgLON5 Disease.

Anti-IgLON5 disease (IgLON5-D) may present with a bulbar-onset motor neuron disease-like phenotype, mimicking bulbar-onset amyotrophic lateral sclerosis. Recognition of their distinctive clinical and paraclinical features may help for differential diagnosis. We report 2 cases of atypical trigeminal neuropathy in bulbar-onset IgLON5-D. Trigeminal nerve involvement was assessed using comprehensive clinical, laboratory, electrophysiologic, and MRI workup. Both patients were referred for progressive dysphagia, sialorrhea, and hoarseness. They were treated with bilevel positive airway pressure for nocturnal hypoventilation. Patient 1 complained of continuous facial burning pain with allodynia, exacerbated by mastication and prolonged speech. Patient 2 reported no facial pain. Anti-IgLON5 autoantibodies (IgLON5-Abs) were positive in serum for both patients and CSF for patient 1. Cerebral MRI revealed bilateral T2 fluid-attenuated inversion recovery (FLAIR) hyperintensity and enlargement of trigeminal nerves without gadolinium enhancement in both patients. Needle myography showed fasciculations in masseter muscles. Blink-reflex study confirmed bilateral trigeminal neuropathy only in patient 2. Cortical laser-evoked potentials showed a bilateral small-fiber dysfunction in the trigeminal nerve ophthalmic branch in patient 1. In case of progressive atypical bulbar symptoms, the presence of a trigeminal neuropathy or trigeminal nerve abnormalities on MRI should encourage the testing of IgLON5-Abs in serum and CSF.

A deep learning-based telemonitoring application to automatically assess oral diadochokinesis in patients with bulbar amyotrophic lateral sclerosis

Background and objectivesTimely identification of dysarthria progression in patients with bulbar-onset amyotrophic lateral sclerosis (ALS) is relevant to have a comprehensive assessment of the disease evolution. To this goal literature recognized the utmost importance of the assessment of the number of syllables uttered by a subject during the oral diadochokinesis (DDK) test. MethodsTo support clinicians, this work proposes a remote deep learning-based system, which consists (i) of a web application to acquire audio tracks of bulbar-onset ALS patients and healthy control subjects while performing the oral DDK test (i.e., repeating the /pa/, /pa-ta-ka/ and /oo-ee/ syllables) and (ii) a DDK-AID network designed to process the acquired audio signals which have different duration and to output the number of per-task syllables repeated by the subject. ResultsThe DDK-AID network overcomes the comparative method achieving a mean Accuracy of 90.23 in counting syllables repeated by the eleven bulbar-onset ALS-patients while performing the oral DDK test. ConclusionsThe proposed remote monitoring system, in the light of the achieved performance, represents an important step towards the implementation of self-service telemedicine systems which may ensure customised care plans.

A store-and-forward cloud-based telemonitoring system for automatic assessing dysarthria evolution in neurological diseases from video-recording analysis

Background and objectives:Patients suffering from neurological diseases may develop dysarthria, a motor speech disorder affecting the execution of speech. Close and quantitative monitoring of dysarthria evolution is crucial for enabling clinicians to promptly implement patients’ management strategies and maximizing effectiveness and efficiency of communication functions in term of restoring, compensating or adjusting. In the clinical assessment of orofacial structures and functions, at rest condition or during speech and non-speech movements, a qualitative evaluation is usually performed, throughout visual observation. Methods:To overcome limitations posed by qualitative assessments, this work presents a store-and-forward self-service telemonitoring system that integrates, within its cloud architecture, a convolutional neural network (CNN) for analyzing video recordings acquired by individuals with dysarthria. This architecture – called facial landmark Mask RCNN – aims at locating facial landmarks as a prior for assessing the orofacial functions related to speech and examining dysarthria evolution in neurological diseases. Results:When tested on the Toronto NeuroFace dataset, a publicly available annotated dataset of video recordings from patients with amyotrophic lateral sclerosis (ALS) and stroke, the proposed CNN achieved a normalized mean error equal to 1.79 on localizing the facial landmarks. We also tested our system in a real-life scenario on 11 bulbar-onset ALS subjects, obtaining promising outcomes in terms of facial landmark position estimation. Discussion and conclusions:This preliminary study represents a relevant step towards the use of remote tools to support clinicians in monitoring the evolution of dysarthria.

Biomarkers in cerebrospinal fluid for amyotrophic lateral sclerosis phenotypes.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving both upper and lower motor neurons. The motor phenotypes of ALS are highly clinically heterogeneous, and the underlying mechanisms are poorly understood. A comparative proteomic analysis was performed in the cerebrospinal fluid (CSF) of bulbar-onset (BO) and spinal-onset (SO) ALS patients and controls (n = 14). Five biomarker candidates were selected from a differentially regulated protein pool, and further validation was performed in a larger independent cohort (n = 92) using enzyme-linked immunosorbent assay (ELISA). A total of 1732 CSF proteins were identified, and 78 differentially expressed proteins were found among BO-ALS patients, SO-ALS patients, and controls. Five promising biomarker candidates were selected for further validation, and lipopolysaccharide-binding protein (LBP) and HLA class II histocompatibility antigen, DR alpha chain (HLA-DRA) were validated. CSF LBP levels were increased in ALS patients compared with controls and higher in BO-ALS versus SO-ALS. The increased CSF LBP levels were correlated with the revised ALS Functional Scale (ALSFRS-R) score. CSF HLA-DRA levels were specifically elevated in BO-ALS patients, and there was no significant difference between SO-ALS patients and controls. Increased HLA-DRA expression was correlated with decreased survival. Our data shows that elevated CSF LBP is a good biomarker for ALS and correlates with clinical severity, and increased HLA-DRA is a specific biomarker for BO-ALS and may predict short survival. It also suggests that the microglial pathway and HLA-II-related adaptive immunity may be differentially involved in ALS phenotypes and may be new therapeutic targets for ALS.

MicroRNA-23a-3p Is Upregulated in Plasma Exosomes of Bulbar-onset ALS Patients and Targets ERBB4

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease related to the progressive death of motor neurons. Understanding the pathogenesis of ALS continues to provide considerable challenges. Bulbar-onset ALS involves faster functional loss and shorter survival time than spinal cord-onset ALS. However, debate is ongoing regarding typical plasma miRNA changes in ALS patients with bulbar onset. Exosomal miRNAs have not yet been described as a tool for bulbar-onset ALS diagnosis or prognosis prediction. In this study, candidate exosomal miRNAs were identified by small RNA sequencing using samples from patients with bulbar-onset ALS and healthy controls. Potential pathogenic mechanisms were identified through enrichment analysis of target genes for differential miRNAs. Expression of miR-16-5p, miR-23a-3p, miR-22-3p, and miR-93-5p was significantly up-regulated in plasma exosomes from bulbar-onset ALS patients compared with healthy control subjects. Among them, miR-16-5p and miR-23a-3p were significantly lower in spinal-onset ALS patients than those with bulbar-onset. Furthermore, up-regulation of miR-23a-3p in motor neuron-like NSC-34 cells promoted apoptosis and inhibited cell viability. This miRNA was found to directly target ERBB4 and regulate the AKT/GSK3β pathway. Collectively, the above miRNAs and their targets are related to the development of bulbar-onset ALS. Our research indicates that miR-23a-3p might have an effect on motor neuron loss observed in bulbar-onset ALS and may be a novel target for the therapy of ALS in the future.

Myofiber Type Shift in Extraocular Muscles in Amyotrophic Lateral Sclerosis.

To investigate changes in myofiber composition in the global layer (GL) and orbital layer (OL) of extraocular muscles (EOMs) from terminal amyotrophic lateral sclerosis (ALS) donors. Medial recti muscles collected postmortem from spinal-onset ALS, bulbar-onset ALS, and healthy control donors were processed for immunofluorescence with antibodies against myosin heavy chain (MyHC) IIa, MyHCI, MyHCeom, laminin, neurofilaments, synaptophysin, acetylcholine receptor γ-subunit, and α-bungarotoxin. The proportion of myofibers containing MyHCIIa was significantly smaller and MyHCeom was significantly larger in the GL of spinal-onset ALS and bulbar-onset ALS donors compared to control donors. Changes in the GL were more prominent in the bulbar-onset ALS donors, with a significantly larger proportion of myofibers containing MyHCeom being present compared to spinal-onset ALS donors. There were no significant differences in the myofiber composition in the OL. In the spinal-onset ALS donors, the proportions of myofibers containing MyHCIIa in the GL and MyHCeom in the OL were significantly correlated with the disease duration. Neurofilament and synaptophysin were present at motor endplates of myofibers containing MyHCeom in ALS donors. The EOMs of terminal ALS donors displayed changes in the fast-type myofiber composition in the GL, with a more pronounced alteration in bulbar-onset ALS donors. Our results align with the worse prognosis and subclinical changes in eye movement function previously observed in bulbar-onset ALS patients and suggest that the myofibers in the OL might be more resistant to the pathological process in ALS.

Teaching Video NeuroImage: Disabling Jaw Clonus in a Patient With Bulbar-Onset Amyotrophic Lateral Sclerosis Successfully Treated With Botulinum Toxin.

Jaw clonus is a rare neurologic finding associated with supranuclear lesions of the trigeminal nerve. It is rare in amyotrophic lateral sclerosis (ALS).1 We describe a 63-year-old patient with ALS who presented with a disabling and sustained jaw clonus, reduced by mouth resting and elicited by mouth opening (Video 1). Association of baclofen (25 mg/3id), tizanidine (2 mg/id), and benzodiazepine treatments were ineffective. Onabotulinum toxin A injections were administered into the temporal (13 units) and masseter (25 units) muscles bilaterally. She experienced a complete relief of her symptom up to 4–5 months, with no side effects (Video 1). She confirmed improvement in quality of life.

ALS patients in otorhinolaryngology: A retrospective study.

ObjectivesGiven its rarity and the lack of clear clinical markers, amyotrophic lateral sclerosis (ALS) remains a diagnostic challenge. Because bulbar‐onset ALS (buALS) presents with impaired speech or swallowing, patients are often primarily referred to an otolaryngologist (ORL) or phoniatrician. The objectives of this retrospective cohort study were to analyze the role of ORLs and phoniatricians in ALS diagnostics and treatment and the potential diagnostic delay related to initial visit to aforementioned specialists.MethodsWe reviewed data for all 327 patients treated for ALS through the Hospital District of Helsinki and Uusimaa (HUS) between 2010 and 2014, focusing specifically on 110 (34%) patients presenting with bulbar nerve onset (buALS). Their presenting symptoms, referral to specialized care, and delay in referral to a neurology clinic were assessed. Indications and findings from swallowing studies were reviewed as well as the incidence of percutaneous endoscopic gastrostomy (PEG) and tracheostomy.ResultsAmong the 110 patients with buALS, 64 (58%) were primarily referred to a neurologist, 28 (25%) to an ORL, and five (5%) to a phoniatrician. The most common presenting symptom was dysarthria in 89 patients, (81%), followed by dysphagia in 26 (24%). In most cases, an ORL or phoniatrician suspected a neuromuscular disease; however, in eight (24%) cases, the neurological etiology of symptoms was missed. Overall, 49 (45%) patients underwent a swallowing study and 86 (78%) patients underwent PEG placement.ConclusionsAmong buALS patients, 30% initially consulted an ORL or phoniatrician and 45% underwent a swallowing study. Based on our results, swallowing studies rarely lead to immediate PEG placement. An initial visit to other specialists had no impact on diagnostic delays or survival.

Detection of changes in synaptic density in amyotrophic lateral sclerosis patients using 18 F-SynVesT-1 positron emission tomography.

Synaptic loss is well established as the major correlate of characteristic and consistent pathology in amyotrophic lateral sclerosis (ALS). We aimed to assess the possible discriminant diagnostic value of 18 F-SynVesT-1 positron emission tomography (PET) as a marker of ALS pathology and investigate whether specific synaptic density signatures are present in ALS with different subtypes. Twenty-one patients with ALS and 25 healthy controls (HCs) were recruited. All participants underwent 18 F-SynVesT-1-PET. Synaptic density between ALS and HCs and between different ALS subgroups were compared. Correlation between synaptic density and clinical features in ALS was also analyzed. Low uptake distribution was found in the group comprising 21 ALS patients as compared with HCs in the right temporal lobe and the bilateral inferior frontal gyrus, anterior cingulate, and hippocampus-insula region. We also found low uptake in the bilateral superior temporal gyrus, hippocampus-insula, anterior cingulate, and left inferior frontal gyrus in ALS patients with cognitive impairment compared to HCs. Furthermore, compared to spinal onset ALS, bulbar onset ALS showed low uptake in the bilateral cingulate gyrus and high uptake in the bilateral superior temporal gyrus and left occipital lobe. No significant result was found in correlation analysis. This approach may provide a direct measure of synaptic density, and it therefore might represent a potentially useful biomarker for ALS diagnosis, as well as for estimating the cognitive decline and site of onset in ALS. 18 F-SynVesT-1-PET is presently not justified as a routine investigation to detect evidence of brain dysfunction leading to progression in ALS.

Comparison of Slow and Forced Vital Capacity on Ability to Evaluate Respiratory Function in Bulbar-Involved Amyotrophic Lateral Sclerosis.

Background and ObjectiveThe percent-predicted forced vital capacity (FVC%) in the pulmonary function test (PFT) is generally used to evaluate the respiratory function in amyotrophic lateral sclerosis (ALS). The slow vital capacity (SVC) is another method to evaluate the respiratory function. Some neurologists found that the FVC% was not reflective of respiratory symptoms and the percent-predicted SVC (SVC%) was found to be higher in some patients with bulbar-onset ALS. We aimed to compare the percent predicted SVC (SVC%) with FVC% in evaluating the respiratory function and investigate the associations between the associations between clinical characteristics and the difference between the SVC% and the FVC% (SVC%-FVC%) in bulbar-involved ALS patients.MethodThis prospective study included patients with bulbar-involved ALS who visited the Peking University Third Hospital between October 2020 and November 2021. They underwent comprehensive clinical assessments, including bulbar symptom assessments, revised ALS functional rating scale (ALSFRS-R), Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (Roads), and PFTs. The group differences were analyzed using parametric and non-parametric tests.ResultsA total of 59 participants were initially enrolled, and 51 of them were included in the final analysis. In patients with bulbar-involved ALS, the SVC% (73.82 ± 21.95%) was significantly higher (p = 0.013) than the FVC% (71.42 ± 23.15%). After controlling for other relevant variables, a partial correlation analysis showed a significant correlation (r = −0.352, p = 0.041) between ALSFRS-R1 score and SVC%-FVC%.ConclusionOur prospective study found that the SVC% was significantly higher and more reflective of actual respiratory function than the FVC% in patients with bulbar-involved ALS. Furthermore, the severity of dysarthria was found to be positively correlated with SVC%-FVC%, providing a clinical marker for predicting SVC%-FVC%.

Chronic respiratory failure negatively affects speech function in patients with bulbar and spinal onset amyotrophic lateral sclerosis: retrospective data from a tertiary referral center

Background: Although dysarthria and respiratory failure are widely described in literature as part of the natural history of Amyotrophic lateral sclerosis (ALS), the specific interaction between them has been little explored. Aim: To investigate the relationship between chronic respiratory failure and the speech of ALS patients. Materials and methods: In this cross-sectional retrospective study we reviewed the medical records of all patients diagnosed with ALS that were accompanied by a tertiary referral center. In order to determine the presence and degree of speech impairment, the Amyotrophic Lateral Sclerosis Functional Rating Scale-revised (ALSFRS-R) speech sub-scale was used. Respiratory function was assessed through spirometry and through venous blood gasometry obtained from a morning peripheral venous sample. To determine whether differences among groups classified by speech function were significant, maximum and mean spirometry values of participants were compared using multivariate analysis of variance (MANOVA) with Tukey’s post hoc test. Results: Seventy-five cases were selected, of which 73.3% presented speech impairment and 70.7% respiratory impairment. Respiratory and speech functions were moderately correlated (seated FVC r = 0.64; supine FVC r = 0.60; seated FEV1 r = 0.59 and supine FEV1 r = 0.54, p < .001). Multivariable logistic regression revealed that the following variables were significantly associated with the presence of speech impairment after adjusting for other risk factors: seated FVC (odds ratio [OR] = 0.862) and seated FEV1 (OR = 1.106). The final model was 81.1% predictive of speech impairment. The presence of daytime hypercapnia was not correlated to increasing speech impairment. Conclusion: The restrictive pattern developed by ALS patients negatively influences speech function. Speech is a complex and multifactorial process, and lung volume presents a pivotal role in its function. Thus, we were able to find that lung volumes presented a significant correlation to speech function, especially in those with bulbar onset and respiratory impairment. Neurobiological and physiological aspects of this relationship should be explored in further studies with the ALS population.

Comparative Performance of Different Respiratory Test Parameters for Detection of Early Respiratory Insufficiency in Patients With ALS.

To compare the performance of different respiratory function testing parameters in a multidisciplinary amyotrophic lateral sclerosis (ALS) clinic. Demographics, clinical data, and respiratory testing parameters were abstracted from the medical records of patients who attended a multidisciplinary ALS clinic from 2008 to 2016. We compared the performance of the 3 primary respiratory test parameters used by Medicare for the initiation of noninvasive ventilation (NIV) (forced vital capacity [FVC] < 50% predicted, maximum inspiratory pressure [MIP] < 60 cm H2O, and abnormal overnight pulse oximetry [OvOx]) on how they related to several clinically relevant attributes. Four hundred seventy-six patients were identified who underwent at least 1 respiratory test. Abnormalities of OvOx, MIP, and FVC occurred at a median of 1.6, 1.5, and 3.8 years from disease onset, respectively (p < 0.00001). Patients with bulbar-onset ALS exhibited earlier abnormalities in MIP and FVC than in spinal-onset ALS (p < 0.005). The median survival after an abnormal OvOx, MIP, or FVC test was 1.4, 1.4, and 0.9 years, respectively (p < 0.0001). Using the ALS Functional Rating Score respiratory subscales, at the time of reported respiratory symptoms there were abnormalities in OvOx (60%), MIP (69%), and FVC (19%). Conversely, when respiratory parameter abnormalities preceded reported respiratory symptoms, this occurred with frequencies in OvOx (79%), MIP (42%), or FVC (24%). Four hundred forty-three patients (93.1%) developed at least 1 abnormal respiratory measure meeting Medicare criteria for NIV consideration, but fewer than 50% in our cohort demonstrated NIV use. Improved survival in subjects using NIV was statistically significant in patients with bulbar-onset ALS. Abnormalities in OvOx and MIP perform better than FVC at early detection of neuromuscular respiratory weakness in ALS. Initiation of NIV in patients with respiratory insufficiency may improve the overall survival in ALS. In the setting of the COVID-19 pandemic, FVC and MIP have not been routinely performed because of infectious aerosol generation. OvOx, which we now routinely mail to patients' homes, has been used exclusively during the COVID-19 pandemic and allows for continued remote monitoring of the respiratory status of patients with ALS. This cohort study provides Class III evidence that in people with ALS, OvOx and MIP are valuable respiratory parameters for the detection of early respiratory insufficiency.

Clinical and electrophysiological characteristics of respiratory onset amyotrophic lateral sclerosis: a single-centre study.

We compared the clinical characteristics of patients with respiratory, bulbar and limb onset amyotrophic lateral sclerosis (ALS) who visited a single tertiary centre for 8years. Total of 115 ALS patients with respiratory, bulbar and limb onset ALS, including sex, body mass index (BMI), presence of lung disease, age at diagnosis, disease duration after initial symptoms, ALS Functional Rating Scale (ALSFRS-R) and progression rate (Delta-FS), pulmonary function, amplitude and distal latency (DL) of the phrenic nerves and blood creatine kinase (CK) and uric acid levels were collected. The prevalence of respiratory, bulbar and limb onset ALS were 5.2%, 28.7% and 66.1%, respectively. The mean age at diagnosis and ALSFRS-R were 67.8 ± 5.5, 63.8 ± 10.1 and 59.2 ± 11.7 in the descending order. The mean amplitude (0.18 ± 0.10mV) and DL (9.5 ± 1.7ms) of the phrenic nerves were significantly decreased and prolonged in respiratory onset ALS compared with other types of ALS patients. Patients with respiratory onset ALS had normal creatine kinase (CK) levels, whereas patients with other types of ALS had increased CK levels. Although rare, respiratory onset ALS may occur and should be considered during the initial differential diagnosis. In this study, patients with respiratory onset ALS were characterised by male predominance, with a higher baseline ALSFRS-R, lower BMI and phrenic nerve study well discriminated respiratory onset ALS from bulbar or limb onset ALS patients.

Characteristics of Dysphagia Based on the Type of ALS in Korean Patients Evaluated Using Videofluoroscopic Study: A Retrospective Analysis.

Dysphagia is one of the main serious issues for amyotrophic lateral sclerosis (ALS) patients because of causing malnutrition and aspiration pneumonia. Early detection and management of dysphagia are essential for the long-term survival. In this study, videofluoroscopic swallowing study (VFSS) results of bulbar and spinal onset ALS patients were compared. VFSS results and revised ALS Functional Rating Scale (ALSFRS-R) score were also analyzed to assess the correlation between dysphagia and functional status of patients. ALS patients with swallowing difficulties who underwent VFSS were recruited retrospectively. Two oral, seven pharyngeal, and two esophageal components of VFSS were evaluated. An ALSRFRS-R bulbar subtype score < 9 was used to divide the groups with severe bulbar symptoms. Total 109 Korean ALS patients (39 bulbar vs 70 spinal) were included. Bulbar ALS patients exhibited a significantly longer oral transit time (OTT) then spinal ALS patients, especially in severe bulbar patients with low ALSRFRS-R bulbar subscale. In bulbar ALS patients, penetration (thick liquid), aspiration, OTT, and Penetration-Aspiration Scale (PAS) were significantly correlated with ALSFRS-R bulbar subscale score. However, in spinal ALS patients, only OTT (thin liquid) and aspiration (thick liquid) were significantly correlated with ALSFRS-R bulbar subscale score. Bulbar ALS patients demonstrated significantly longer OTT than spinal ALS patients, and ALSFRS-R bulbar subscale score also correlated well with bulbar ALS patients. Therefore, high vigilance and aggressive treatment for dysphagia especially in bulbar ALS patients rather than spinal ALS patients are mandatory.

Alveolar Ventilation-Targeted Versus Spontaneous/Timed Mode for Home Noninvasive Ventilation in Amyotrophic Lateral Sclerosis.

Home noninvasive ventilation (NIV) is increasingly used in amyotrophic lateral sclerosis (ALS) to improve symptoms and survival. Our primary objective was to compare intelligent volume-assured pressure support (iVAPS) versus spontaneous/timed (S/T) modes regarding time to first change in ventilator parameters and the number of interventions over 6 months in subjects with ALS in a respiratory therapist (RT)-led program. In this study, 30 subjects with ALS meeting criteria for NIV initiation were randomized to iVAPS or S/T. NIV was initiated using standardized protocols targeting optimal tidal volume and comfort in a daytime session. Download data were recorded at 1 week and 1 and 6 months. Any changes in ventilator parameters were recorded. Of the 30 subjects, 56.7% had bulbar onset ALS, 8 died, and 11 in each group completed the study. Median time to first parameter change was 33.5 (interquartile range [IQR] 7.7-96.0) d versus 41.0 (IQR 12.5-216.5) d for iVAPS versus S/T groups, respectively, (P = .48). The average number of RT interventions was similar between groups (1.1 ± 1.1 vs 0.9 ± 0.9 at 1 month, P = .72; 2.4 ± 2.1 vs 2.4 ± 2.3 at 6 months, P = .95, for iVAPS vs S/T, respectively). Adherence was significantly lower with iVAPS than S/T at 1 week but not at 1 or 6 months. Download parameters were similar between groups at 1 week and 6 months except for higher residual apnea-hypopnea index (AHI) and less spontaneously triggered breaths with iVAPS at 6 months. The time to first change of parameters and the number of interventions at 6 months from NIV initiation were similar for the iVAPS and S/T modes in subjects with ALS. With iVAPS, adherence was lower transiently at NIV initiation, and the residual AHI was higher at 6 months. Alveolar ventilation-targeted NIV may require a longer adaptation period and result in greater upper-airway instability predominantly in patients with bulbar ALS.

Lack of an association between SCFD1 rs10139154 polymorphism and amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. Through a genome-wide association study (GWAS), the Sec1 family domain-containing protein 1 (SCFD1) rs10139154 variant at 14q12 has emerged as a risk factor gene for ALS. Moreover, it has been reported to influence the age at onset (AAO) of patients with ALS. The aim of the present study was to assess the association of the SCFD1 rs10139154 polymorphism with the risk of developing ALS. For this purpose, 155 patients with sporadic ALS and 155 healthy controls were genotyped for the SCFD1 rs10139154. The effect of the SCFD1 rs10139154 polymorphism was then examined on the following parameters: i) The risk of developing ALS; ii) the AAO of ALS; iii) the site of ALS onset (patients with bulbar onset ALS vs. healthy controls; and patients with limb onset ALS vs. healthy controls); and iv) the AAO of ALS onset with subgroup analyses based on the site of onset (bulbar and limb, crude and adjusted for sex). The analysis of all the outcomes was performed assuming five genetic models. Crude and adjusted analyses were applied. The threshold for statistical significance was set at 0.05. The results revealed no association between SCFD1 rs10139154 and any of the examined phenotypes in any of the models examined. On the whole, based on the findings of the present study, SCFD1 rs10139154 does not appear to play a determining role in the risk of developing ALS.

Gut- and oral-dysbiosis differentially impact spinal- and bulbar-onset ALS, predicting ALS severity and potentially determining the location of disease onset

BackgroundPrior studies on the role of gut-microbiome in Amyotrophic Lateral Sclerosis (ALS) pathogenesis have yielded conflicting results. We hypothesized that gut- and oral-microbiome may differentially impact two clinically-distinct ALS subtypes (spinal-onset ALS (sALS) vs. bulbar-onset ALS (bALS), driving disagreement in the field.MethodsALS patients diagnosed within 12 months and their spouses as healthy controls (n = 150 couples) were screened. For eligible sALS and bALS patients (n = 36) and healthy controls (n = 20), 16S rRNA next-generation sequencing was done in fecal and saliva samples after DNA extractions to examine gut- and oral-microbiome differences. Microbial translocation to blood was measured by blood lipopolysaccharide-binding protein (LBP) and 16S rDNA levels. ALS severity was assessed by Revised ALS Functional Rating Scale (ALSFRS-R).ResultssALS patients manifested significant gut-dysbiosis, primarily driven by increased fecal Firmicutes/Bacteroidetes-ratio (F/B-ratio). In contrast, bALS patients displayed significant oral-dysbiosis, primarily driven by decreased oral F/B-ratio. For sALS patients, gut-dysbiosis (a shift in fecal F/B-ratio), but not oral-dysbiosis, was strongly associated with greater microbial translocation to blood (r = 0.8006, P < 0.0001) and more severe symptoms (r = 0.9470, P < 0.0001). In contrast, for bALS patients, oral-dysbiosis (a shift in oral F/B-ratio), but not gut-dysbiosis, was strongly associated with greater microbial translocation to blood (r = 0.9860, P < 0.0001) and greater disease severity (r = 0.9842, P < 0.0001). For both ALS subtypes, greater microbial translocation was associated with more severe symptoms (sALS: r = 0.7924, P < 0.0001; bALS: r = 0.7496, P = 0.0067). Importantly, both sALS and bALS patients displayed comparable oral-motor deficits with associations between oral-dysbiosis and severity of oral-motor deficits in bALS but not sALS. This suggests that oral-dysbiosis is not simply caused by oral/bulbar/respiratory symptoms but represents a pathological driver of bALS.ConclusionsWe found increasing gut-dysbiosis with worsening symptoms in sALS patients and increasing oral-dysbiosis with worsening symptoms in bALS patients. Our findings support distinct microbial mechanisms underlying two ALS subtypes, which have been previously grouped together as a single disease. Our study suggests correcting gut-dysbiosis as a therapeutic strategy for sALS patients and correcting oral-dysbiosis as a therapeutic strategy for bALS patients.