The future of ALS diagnosis and staging: where do we go from here?

Amyotrophic lateral sclerosis (ALS) is a rare, progressive multi-system neurodegenerative disorder. Its clinical presentation varies considerably leading to delays in diagnosis, which has dire consequences in a disease where early intervention is key to optimize outcomes and limit care giver burden. There are a range of diagnostic criteria available to aid ALS diagnosis, as well staging methods to assess disease progression. However, they all suffer from inter-rater variability, complexity, and confusion in use. Such difficulties, when medical appointment times are limited and becoming more virtually based, have the potential to amplify uncertainty and errors in ALS diagnosis and prognosis. This review provides a clinical overview of the best way to balance the needs of evidence-based medicine and the patient. We focus on ALS diagnostic criteria and staging systems currently in use in clinical practice and explore factors that could enhance diagnostic efficiency and assessment of disease progression.

Saliva and Saliva Extracellular Vesicles for Biomarker Candidate Identification-Assay Development and Pilot Study in Amyotrophic Lateral Sclerosis.

Saliva is gaining increasing attention as a source of biomarkers due to non-invasive and undemanding collection access. Extracellular vesicles (EVs) are nano-sized, cell-released particles that contain molecular information about their parent cells. In this study, we developed methods for saliva biomarker candidate identification using EV-isolation and proteomic evaluation. We used pooled saliva samples for assay development. EVs were isolated using membrane affinity-based methods followed by their characterization using nanoparticle tracking analysis and transmission electron microscopy. Subsequently, both saliva and saliva-EVs were successfully analyzed using proximity extension assay and label-free quantitative proteomics. Saliva-EVs had a higher purity than plasma-EVs, based on the expression of EV-proteins and albumin. The developed methods could be used for the analysis of individual saliva samples from amyotrophic lateral sclerosis (ALS) patients and controls (n = 10 each). The starting volume ranged from 2.1 to 4.9 mL and the amount of total isolated EV-proteins ranged from 5.1 to 42.6 µg. Although no proteins were significantly differentially expressed between the two groups, there was a trend for a downregulation of ZNF428 in ALS-saliva-EVs and an upregulation of IGLL1 in ALS saliva. In conclusion, we have developed a robust workflow for saliva and saliva-EV analysis and demonstrated its technical feasibility for biomarker discovery.

Primary lateral sclerosis natural history study - planning, designing, and early enrollment.

Introduction/Aims. Primary lateral sclerosis (PLS) is exceedingly rare and has been an enigmatic disease. Recent progress has drastically changed this perception, with early biomarkers being investigated and potential medications for PLS emerging at the preclinical stage. The aim of this paper is to describe a study of PLS natural history and discuss the limitations and proposed solutions to the study of a rare and slowly progressive disease. Methods. The PLS Natural History Study is a 30-site, 24-month, prospective study that is supported by multiple funding sources. The study aims to enroll 50 early PLS (disease duration ≤4 years) and 50 definite PLS (disease duration 4 to 15 years) participants using modified PLS Diagnostic Criteria. Smartphone-based assessments including semi-quantitative and quantitative measures and patient-reported outcomes are utilized. In-person quantitative measures are also completed during site visits. The change in the PLS Functional Rating Scale score is the primary outcome. The study utilizes the NeuroBANK® patient-centric data capture and management platform. The biostatistical analysis plan has been developed. Results. In one year, 28 participants have been recruited. Enrollment has been much slower than anticipated due to the COVID-19 pandemic, the rarity of PLS, and potential study competition for internal resources from ALS clinical trials. Discussion. We discuss the need for more innovative methods to enroll and study individuals with such rare diseases and propose a number of mechanisms by which more efficient enrollment could be facilitated.

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

BACKGROUND AND OBJECTIVES: To compare the performance of different respiratory function testing parameters in a multidisciplinary amyotrophic lateral sclerosis (ALS) clinic. METHODS: 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. RESULTS: 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. DISCUSSION: 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. CLASSIFICATION OF EVIDENCE: 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.

SIMpLE: A Mobile Cloud-Based System for Health Monitoring of People with ALS.

Adopting telemonitoring services during the pandemic for people affected by chronic disease is fundamental to ensure access to health care services avoiding the risk of COVID-19 infection. Among chronic diseases, Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's disease, is a progressive neurodegenerative disease of adulthood, caused by the loss of spinal, bulbar and cortical motor neurons, which leads to paralysis of the voluntary muscles and, also, involves respiratory ones. Therefore, remote monitoring and teleconsulting are essential services for ALS patients with limited mobility, as the disease progresses, and for those living far from ALS centres and hospitals. In addition, the COVID 19 pandemic has increased the need to remotely provide the best care to patients, avoiding infection during ALS centre visits. The paper illustrates an innovative, secure medical monitoring and teleconsultation mobile cloud-based system for disabled people, such as those with ALS (Amyotrophic Lateral Sclerosis). The design aims to remotely monitor biosignals, such as ECG (electrocardiographic) and EMG (electromyographic) signals of ALS patients in order to prevent complications related to the pathology.

Single breath counting is an effective screening tool for forced vital capacity in ALS.

Objective: To measure the correlation between single breath counting (SBC) and forced vital capacity (liters, FVCL) in amyotrophic lateral sclerosis (ALS) patients and to define the utility of SBC for determining when patients meet the threshold for initiation of noninvasive positive pressure ventilation (FVC < 50% predicted [FVCpred]). Methods: Both patient paced (SBCpp) or externally paced (SBCep) counting along with FVCL+pred and standard clinical data were collected. Linear regression was used to examine SBCpp and SBCep as a predictor of FVCL. Receiver operating characteristic curve analysis evaluated the sensitivity and specificity of SBC categorically predicting FVCpred of ≤50%. Results: In 30 ALS patients, SBC explained a moderate proportion of the variance in FVCL (SBCpp: R2= 0.431, p < 0.001; SBCep: R2 = 0.511, p < 0.01); this proportion improved when including covariates (SBCpp: R2= 0.635, p < 0.01; SBCep: R2= 0.657, p < 0.01). Patients with minimal speech involvement performed similarly in unadjusted (SBCpp: R2 = 0.511, p < 0.01; SBCep: R2= 0.595, p < 0.01) and adjusted (SBCpp: R2 = 0.634, p < 0.01; SBCep: R2= 0.650, p < 0.01) models. SBCpp had 100% sensitivity and 60% specificity (area under curve (AUC) = 0.696) for predicting FVCpred <50%. SBCep had 100% sensitivity and 56% specificity (AUC = 0.696). With minimal speech involvement SBCpp and SBCep both had 100% sensitivity and 76.1% specificity (SPCpp: AUC = 0.845; SBCep: AUC = 0.857). Conclusions: SBC explains a moderate proportion of variance in FVC and is an extremely sensitive marker of poor FVC. When FVC cannot be obtained, such as during the current COVID-19 pandemic, SBC is helpful in directing patient care.

The patient's perspective of remote respiratory assessments during the COVID-19 pandemic.

Forced vital capacity (FVC) is an essential respiratory measurement for assessment and monitoring of patients with Amyotrophic Lateral Sclerosis (ALS). Our clinic rapidly implemented remote assessment of FVC after COVID-19 related restrictions on respiratory testing were imposed, using mini-spirometers and video consultation. We sought to evaluate the patient's experiences of performing remote respiratory assessments to guide future development and optimisation of the service. Twenty-five patients completed surveys. The mean age was 65.2 years and average time from diagnosis was 17.04 (2-99) months. Seventy-two percent (n = 18) required help from a caregiver to perform the tests. Ninety-two percent (n = 23) of patients reported that overall, they were satisfied and were happy to continue with remote respiratory assessment. Reducing the number of clinic visits for review and assessment was valued by 92% (n = 23) and reducing the risk associated with COVID-19 was valued by 96% (n = 24). The highest frequency reported as acceptable for performing the remote breathing assessments was monthly (60%, n = 15), followed by every second month (28%, n = 7). Remote respiratory testing is viewed positively by patients. These technologies used in combination with video-consultations and other novel forms of remote monitoring implemented in response to the COVID-19 crisis will continue to be valuable tools for clinical care in future. However, further evaluation of the validity of remote respiratory assessment is required.

Cortical excitability threshold can be increased by the AMPA blocker Perampanel in amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Cortical hyperexcitability is a feature of amyotrophic lateral sclerosis (ALS) and cortical excitability can be measured using transcranial magnetic stimulation (TMS). Resting motor threshold (MT) is a measure of cortical excitability, largely driven by glutamate. Perampanel, a glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor blocker, is predicted to increase the cortical excitability threshold. This study aimed to evaluate TMS to functionally assess target engagement in a study of perampanel in ALS. METHOD: We studied the MT of ALS patients randomized to a single dose of perampanel or placebo 5:1 hourly for 4 h. Twelve patients participated at 4 mg and 7 returned for dosing and retesting at 8 mg. The study was terminated in April 2020 due to coronavirus disease 2019-related restrictions, after 7 out of 12 planned patients had received the 8 mg dose. Serum concentrations were also measured. RESULTS: Ten patients received the 4 mg dose (2 received placebo) and 5 received the 8 mg dose (2 received placebo). Motor Threshold increased at 2 h after dosing in the combined treatment group +7% of maximal stimulator output (P < .01). Change could be detected in the larger 4 mg group (P = .02), but not in the smaller 8 mg dose group (P = .1). No side effects were reported after single dose exposure. DISCUSSION: This study shows that perampanel effects the physiology of upper motor neurons. Studies aiming at gauging the effect of perampanel on ALS disease progression are already ongoing. Motor threshold may serve as a marker of biological target engagement.

Telemedicine for management of patients with amyotrophic lateral sclerosis through COVID-19 tail.

Over the last months, due to coronavirus disease (COVID-19) pandemic, containment measures have led to important social restriction. Healthcare systems have faced a complete rearrangement of resources and spaces, with the creation of wards devoted to COVID-19 patients. In this context, patients affected by chronic neurological diseases, such as amyotrophic lateral sclerosis (ALS), are at risk to be lost at follow-up, leading to a higher risk of morbidity and mortality. Telemedicine may allow meet the needs of these patients. In this commentary, we briefly discuss the digital tools to remotely monitor and manage ALS patients. Focusing on detecting disease progression and preventing life-threatening conditions, we propose a toolset able to improve ALS management during this unprecedented situation.

Amyotrophic lateral sclerosis: update on clinical management.

PURPOSE OF REVIEW: The current review will provide recent updates in the clinical management of amyotrophic lateral sclerosis (ALS). RECENT FINDINGS: Although there is no cure for ALS, there are new treatments, growing knowledge of genetics, development of clinical staging systems, and the recent coronavirus disease 2019 pandemic that have recently impacted the clinical management of ALS. Increased understanding of genetics has helped provide insights into pathophysiology, the staging systems and clinical measures help to provide tools for monitoring disease clinically, and the recent coronavirus disease 2019 pandemic has provided opportunities to develop telemedicine and remote monitoring of disease thereby increasing accessibility to care and reducing burden of travel to centers for people living with the disease and their caregivers. SUMMARY: ALS is a progressive neurodegenerative disease that causes degeneration of the motor neurons which leads to paralysis and respiratory failure. Despite the lack of a cure, multidisciplinary care, proactive respiratory management, nutritional care and management of symptoms as well as pharmacological interventions that can improve quality of life and survival.

Validation of the Italian version of self-administered ALSFRS-R scale.

OBJECTIVES: To validate and assess the reliability of the Italian version of self-administered ALSFRS-R, considering patients' clinical and cognitive features and caregiver's help. Methods: During the COVID-19 pandemic, by analyzing the results of 70 paired self-administered vs standard telephone-administered ALSFRS-R, we calculated overall score, single item scores, ALSFRS-R domain scores, King's and MiToS stage inter-rater agreement and reliability using different validated methods. We created the Italian version of self-administered ALSFRS-R following ENCALS recommendation. Results: Correlation between the two scales was 0.94 and no systematic directional bias was found. The intraclass correlation coefficient (ICC) was very high (>0.90) for the vast majority of the considered classification criteria, especially King's total score (0.96) and MiToS score (0.94). A higher ICC was found when the patients answered the questionnaire with the caregiver's help (0.95). Conclusions: Online self-administered ALSFRS-R scale is a valid tool to stratify ALS patients into clinical stages and to implement telemedicine monitoring.

Amyotrophic lateral sclerosis care and research in the United States during the COVID-19 pandemic: Challenges and opportunities.

Coronavirus disease 2019 has created unprecedented challenges for amyotrophic lateral sclerosis (ALS) clinical care and research in the United States. Traditional evaluations for making an ALS diagnosis, measuring progression, and planning interventions rely on in-person visits that may now be unsafe or impossible. Evidence- and experience-based treatment options, such as multidisciplinary team care, feeding tubes, wheelchairs, home health, and hospice, have become more difficult to obtain and in some places are unavailable. In addition, the pandemic has impacted ALS clinical trials by impairing the ability to obtain measurements for trial eligibility, to monitor safety and efficacy outcomes, and to dispense study drug, as these also often rely on in-person visits. We review opportunities for overcoming some of these challenges through telemedicine and novel measurements. These can reoptimize ALS care and research in the current setting and during future events that may limit travel and face-to-face interactions.