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

BACKGROUND: Prior 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. METHODS: ALS 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). RESULTS: sALS 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. CONCLUSIONS: We 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.

ALSUntangled #60: light therapy.

ALSUntangled reviews alternative and off-label treatments for people with ALS. Here we review light therapy. We show that it has theoretically plausible mechanisms, three flawed pre-clinical data, studies, and one incompletely documented case report supporting its use. We explain why further studies are needed to determine whether any specific light therapy protocol can help people with ALS.

Radicava (edaravone) for amyotrophic lateral sclerosis: US experience at 1 year after launch.

Background: Radicava® (edaravone), approved for the treatment of amyotrophic lateral sclerosis (ALS) in 2017, may be administered intravenously at clinic sites, infusion centers or at home. Objective: To gain insights into the utilization of Radicava® at 1 year post-launch. Methods: Radicava® usage data were collected, and a survey was conducted among 75 physicians. Adverse events (AEs) were identified from a post-marketing safety database from 8 August 2017 through 3 August 2018 (cutoff date). Results: As of 6 August 2018, 3007 ALS patients were treated with Radicava®. Survey results indicated that 43% of patients received infusions at home, 32% in a clinician's office, and 26% at a referred site. Infusions were administered mainly via implanted port. The most commonly reported AEs were drug ineffective, death (not specified), therapeutic response unexpected, asthenia, fatigue, gait disturbance, disease progression, muscular weakness, fall, and dyspnea. Conclusions: The first year of Radicava® availability to ALS patients in the US provided many key learnings that will help shape strategies for improved patient care.

Exhaustively Characterizing a Patient Cohort by Prevalence of EMR Facts: a Generalized, Vendor-Agnostic Method for Quality Control and Research.

We present a method for rapidly ranking all distinct facts in an electronic medical record (EMR) system by howover-represented or under-represented they are in a patient cohort of interest relative to some larger referencepopulation of patients in the same EMR. We have implemented this method as a plugin for i2b2, the open sourcedata warehouse platform widely used in research health informatics. Our method is highly flexible in terms of whatmedical terminologies it supports and is vendor-independent thanks to leveraging the i2b2 star schema rather thanany one specific EMR. It can be applied to a wide range of informatics problems including finding healthdisparities, searching for variables to include in a risk calculator or computable phenotype, detection ofcomorbidities, discovery of adverse drug reactions. The case study we present here uses this software to findunlabeled flowsheets for patients suffering from amyotrophic lateral sclerosis.

Randomized double-blind study of botulinum toxin type B for sialorrhea in ALS patients.

Twenty ALS patients with sialorrhea refractory to medical therapy were enrolled in this double-blind, randomized study to receive either 2,500 U of botulinum toxin type B (BTxb) or placebo into the bilateral parotid and submandibular glands using electromyographic guidance. Patients who received BTxb reported a global impression of improvement of 82% at 2 weeks compared to 38% of those who received placebo (P < 0.05). This significant effect was sustained at 4 weeks. At 12 weeks, 50% of patients who received BTxb continued to report improvement compared to 14% of those who received placebo. There were no significant adverse events, including dysphagia, in the BTxb group, and there was no significant increase in the rate of decline of vital capacity.