ABSTRACTIntroduction/AimsSpirometry is the conventional means to measure lung function in amyotrophic lateral sclerosis (ALS), but is dependent on patient effort and bulbar strength. We aimed to use electric impedance tomography (EIT), an emerging non‐invasive imaging modality, to measure dynamic lung volume changes.MethodsTwenty‐one patients with ALS underwent sitting and supine spirometry for forced vital capacity (FVC), and sitting and supine EIT. There were 13 patients in the high FVC group (FVC ≥ 80% predicted) and 8 in the low FVC group (FVC < 80% predicted). Additional demographic and clinical data were collected from clinical records.ResultsOnly the low FVC group had significant loss of lung volumes in the supine position (R2 = 0.89 and p < 0.001). The supine volume loss measurement at 10 min correlated with sitting (r2 = 0.47) and supine FVC (r2 = 0.36), maximum inspiratory (r2 = −0.44) and expiratory pressures (r2 = 0.36) (MIP and MEP), and the ALS Functional Rating Scale‐Revised (ALSFRS‐R) dyspnea subscore (r2 = 0.36).DiscussionEIT is an emerging alternative to existing measures of lung function in ALS, but without need for patient effort or bulbar strength. Significant losses in lung volume are seen on supine compared to upright position in patients with respiratory dysfunction. Further study is needed to determine relationships to existing clinical measures.

Background: LC-FAOD may be missed in neuromuscular (NM) clinics due to its rarity and absence from common NM genetic panels. The Canadian Neuromuscular Disease Registry (CNDR) collects real-world patient data and includes a network of clinician-investigators. Our objective was to inform future registry work by evaluating diagnosis pathways for LC-FAOD patients and estimating the number followed at Canadian NM clinics. Methods: A questionnaire was developed with an expert committee and circulated to 111 CNDR-affiliated NM neurologists. Results: 12 neurologists in 5 provinces, primarily adult-treating (n=8) completed the survey (10.8% response rate). Eleven (91.7%) practiced for >10 years. Agreement trends existed between definition of, and tests to evaluate, rhabdomyolysis. Four clinics routinely follow LC-FAOD patients. In the last 1-2 years, respondents diagnosed approximately 91 patients with LC-FAOD (mean=7.5 per clinic). 83.3% never received continuing education on LC-FAOD, though 75% indicated interest in expert-led webinars. Further data will be presented. Conclusions: Low sample size limits conclusions about LC-FAOD clinical trends. Results suggest LC-FAOD may be under-diagnosed or not routinely followed by NM specialists, limiting viability of an LC-FAOD registry. Practitioners may be interested in LC-FAOD-specific education. Future work could include collaboration with metabolic geneticists on education initiatives to raise awareness and improve care for these patients.

Background: ALS is a progressive neurodegenerative disease without a cure and limited treatment options. Edaravone, a free radical scavenger, was shown to slow disease progression in a select group of patients with ALS over 6 months; however, the effect on survival was not investigated in randomized trials. The objective of this study is to describe real-world survival effectiveness over a longer timeframe. Methods: This retrospective cohort study included patients with ALS across Canada with symptom onset up to three years. Those with a minimum 6-month edaravone exposure between 2017 and 2022 were enrolled in the interventional arm, and those without formed the control arm. The primary outcome of tracheostomy-free survival was compared between the two groups, accounting for age, sex, ALS-disease progression rate, disease duration, pulmonary vital capacity, bulbar ALS-onset, and presence of frontotemporal dementia or C9ORF72 mutation using inverse propensity treatment weights. Results: 182 patients with mean ± SD age 60±11 years were enrolled in the edaravone arm and 860 in the control arm (mean ± SD age 63±12 years). Mean ± SD time from onset to edaravone initiation was 18±10 months. Tracheostomy-free survival will be calculated. Conclusions: This study will provide evidence for edaravone effectiveness on tracheostomy-free survival in patients with ALS.

BACKGROUND:Interest in health care provider (HCP) wellness and burnout is increasing; however, minimal literature explores HCP wellness in the context of Amyotrophic Lateral Sclerosis (ALS) care. OBJECTIVES:We sought to determine rates of burnout and resiliency, as well as challenges and rewards in the provision of ALS care. METHODS:A survey link was sent to physicians at all Canadian ALS centers for distribution to ALS HCPs in their network. The survey included demographics questions, and validated measures for resiliency and burnout; the Brief Resilient Coping Scale (BRCS) and the Single Item Burnout Score (SIBS). Participants were asked to describe challenges and rewards of ALS care, impact of COVID-19 pandemic, and how their workplace could better support them. RESULTS:There were 85 respondents across multiple disciplines. The rate of burnout was 47%. Burnout for female respondents was significantly higher (p = 0.007), but not for age, role, or years in ALS clinic. Most participants were medium resilient copers n = 48 (56.5%), but resiliency was not related to burnout. Challenges included feeling helpless while patients relentlessly progressed to death, and emotionally charged interactions. Participants found fulfillment in providing care, and through relationships with patients and colleagues. There was a strongly expressed desire for increased resources, team building/debriefing, and formal training in emotional exhaustion and burnout. CONCLUSIONS:The high rate of burnout and challenges of ALS care highlight the need for additional resources, team-building, and formal education around wellness.

Nutrition concerns are prevalent in individuals with Amyotrophic Lateral Sclerosis (ALS). Despite the prevalence of nutrition concerns, few data are available on perceptions and experiences of nutrition interventions in individuals with ALS and their caregivers; this study aimed to collect this information. An online survey was developed and hosted on Survey Monkey®. Individuals with ALS and their caregivers from Saskatchewan, Canada, were invited to complete the survey through email to attendees of the ALS Clinic (Saskatoon, Canada), and via the ALS Society of Saskatchewan Facebook page in February-March, 2021. Quantitative data were analyzed using descriptive statistics. Twelve eligible respondents completed the survey (n = 10 individuals with ALS; n = 2 caregivers). The present study found nutrition was important to respondents and there was interest in trying diets and supplements for ALS management; of note, many respondents were interested in exploring the ketogenic diet. Six (50%) respondents had weight loss concerns. All respondents would recommend consulting with a dietitian upon being diagnosed with ALS. Many respondents reported a predefined negative perception of tube feeding. The results of this study suggest that increasing the accessibility of dietitians could positively impact ALS-related care. The findings also provide guidance for dietitians to enhance nutrition care for individuals with ALS.

In this article we review complications to the peripheral nervous system that occur as a consequence of viral infections, with a special focus on complications of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). We discuss neuromuscular complications in three broad categories; the direct consequences of viral infection, autoimmune neuromuscular disorders provoked by viral infections, and chronic neurodegenerative conditions which have been associated with viral infections. We also include discussion of neuromuscular disorders that are treated by immunomodulatory therapies, and how this affects patient susceptibility in the current context of the coronavirus disease 2019 (COVID-19) pandemic. COVID-19 is associated with direct consequences to the peripheral nervous system via presumed direct viral injury (dysgeusia/anosmia, myalgias/rhabdomyolysis, and potentially mononeuritis multiplex) and autoimmunity (Guillain Barré syndrome and variants). It has important implications for people receiving immunomodulatory therapies who may be at greater risk of severe outcomes from COVID-19. Thus far, chronic post-COVID syndromes (a.k.a: long COVID) also include possible involvement of the neuromuscular system. Whether we may observe neuromuscular degenerative conditions in the longer term will be an important question to monitor in future studies.

Botulism was first described in victims of food poisoning who developed a rapidly progressive descending paralysis, and has since been developed into a therapeutic agent. The mechanism of action stems from an anaerobic bacterium, Clostridium botulinum, that secretes various serotypes of botulinum neurotoxin. Botulinum Toxin A (BoNT-A) has many clinical indications including movement disorders, spasticity, migraines, pain syndromes, hyperhidrosis, and cosmetics. BoNT-A is considered to be generally safe with reported side effects including injection site focal weakness, cough, fever, malaise, headache, and injection site reactions. A review of the literature reveals rare reports of generalized weakness and iatrogenic botulism following therapeutic use of BoNT-A for dystonia, hyperhidrosis, spasticity, and movement disorders. We present a case of probable iatrogenic botulism following administration of BoNT-A for hyperhidrosis that is uniquely confounded by recent fluoroquinolone antibiotic use (ciprofloxacin), which also has documented action on the neuromuscular junction. A 31-year-old female was referred for assessment of hand weakness after her second trial of BoNT-A intradermal injection for hyperhidrosis. Her only comorbidities were a remote lumbar spine fusion and a recently treated urinary tract infection with ciprofloxacin. She did not have any personal or family history of neuromuscular disease. She first had a Botulinum A (Onabotulinum) injection 2 months prior to presentation, where she received 50U in each axilla (total of 100U). Two weeks prior to presentation, she had a second treatment that involved 100U of Onabotulinum A into each of her palms (2:1 dilution) and 50U into each axilla (1:1 dilution). The injections were administered in a grid pattern by a physician with extensive experience and skill using BoNT-A. She noticed symptoms 5 days following her second round of injections, which included fatigue, dry mouth, blurred vision, mild headache, and bilateral hand weakness. Her initial exam was significant for mild neck flexion weakness, fatigable deltoid weakness, and bilateral hand weakness (finger extensors 4+/5, first dorsal interossei (FDI) 4/5, abductor pollicis brevis (APB) 4−/5). Her electrophysiologic studies demonstrated decreased amplitude of the right median and ulnar nerves on motor studies (Table 1). Repetitive nerve stimulation at 2Hz (right median to APB) showed maximal decrement following maximal voluntary contraction (MVC), with maximal decrement 4 min post-MVC. Her repetitive nerve stimulation at 50Hz (right median to APB) showed facilitation of 181% (Figure 1). Electromyography (EMG) demonstrated small motor (MUAPs) suggestive of myopathic units in FDI, APB, and the deltoid. These studies are suggestive of a presynaptic neuromuscular junction localization and given her medical history, iatrogenic botulism was considered. At her 3-month follow-up, her exam had improved as she now had only mild FDI and APB weakness. Her electrophysiologic studies improved as well, with only a mildly low ulnar motor amplitude, no facilitation on rapid RNS, less decrement on slow RNS, and improved appearance of myopathic units on EMG in the hand intrinsic muscles. By 9 months, her physical exam and electrophysiology were completely normal. No other adverse events were reported among other patients who used this particular batch of Onabotulinum A. Botulism is clinically characterized by symmetric descending paralysis that is often associated with dilated pupils, dry mouth, diplopia, ptosis, dysphagia, dysarthria, and respiratory failure. Our patient demonstrated symptoms consistent with this syndrome, including visual disturbances, weakness, and dry mouth. Electrophysiology in botulism classically shows a reduced compound muscle action potential (CMAP) amplitude that increases with high-frequency repetitive nerve stimulation demonstrating facilitation, and decrement at low-frequency repetitive nerve stimulation, which was seen in our case. Botulinum neurotoxin binds to the SV2 receptor on the presynaptic membrane of the neuromuscular junction, and then interferes with exocytosis of acetylcholine, which results in reduced acetylcholine released into the junction and therefore reduced muscle activation. Fluoroquinolone antibiotics also act on the neuromuscular junction by chelating ionized calcium, and therefore inhibiting acetylcholine release presynaptically and may also act directly on acetylcholine receptors as well. To our knowledge, this combination of drugs has not been previously reported to cause neuromuscular junction issues, however, it is likely that both contributed to our patient’s presentation. The mechanism for the involvement of sites distant from the injection of BoNT-A is controversial, with main theories including hematogenous spread, retrograde axonal transport of the toxin, or an immune-mediated phenomenon. Singlefiber EMG done at sites distant from the injection site have been shown to have jitter and blocking, demonstrating a presynaptic process, even in the absence of clinical weakness or abnormal routine electrophysiologic testing. It seems that higher doses of BoNT-A and repeated use may be risk factors for the dissemination of BoNT-A after local injection. It is important for clinicians to be aware of the neuromuscular complications of commonly used medications including antibiotics and botulinum toxin. LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES

Objective: To understand current genetic testing practices at Canadian ALS clinics. Methods: An online survey and phone interviews, with clinicians practicing in 27 ALS clinics in Canada, were employed to collect data. Quantitative and qualitative analyses were conducted. Results: Ninety-three percent (25/27) of ALS clinics in Canada are routinely ordering genetic testing for familial ALS, while 33% (9/27) of clinics are routinely ordering genetic testing for sporadic ALS. Barriers to genetic testing include a perceived lack of an impact on treatment plan, difficulty in obtaining approvals, primarily from provincial Ministries of Health, and limited access to genetic counseling. Predictive testing practices were found to be the most variable across the country. The average wait time for a symptomatic patient living with ALS to see a genetic counselor in Canada is 10 months (range 0-36 months). Conclusions: Access to genetic testing, and testing practices, vary greatly across Canadian ALS clinics. There may be patients with a monogenetic etiology to their ALS who are not being identified given that genetic testing for patients diagnosed with ALS is not routinely performed at all clinics. This study highlights potential inequities for patients with ALS that can arise from variability in health care delivery across jurisdictions, in a federally-funded, but provincially-regulated, health care system. Clinical trials for both symptomatic ALS patients and pre-symptomatic ALS gene carriers are ongoing, and ALS clinicians in Canada are motivated to improve access to genetic testing for ALS.

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BACKGROUND:Photovoice is a qualitative research tool increasingly utilized in the healthcare field to understand the illness experience from the patient and caregiver perspective. This is the first study to evaluate photovoice in the context of amyotrophic lateral sclerosis (ALS).OBJECTIVE:A patient and caregiver centered research tool was utilized to gain a greater understanding of challenges faced when living with ALS.METHODS:Eight patients and three corresponding caregivers participating by taking photographs, writing descriptive text, and participating in individual and group interviews. Inductive thematic analysis was employed to uncover recurring themes.RESULTS:Five main themes were identified; 1) facing the diagnosis, 2) loss of function, 3) isolation, 4) health system challenges, and 5) hope. Despite the devasting impact of ALS, the majority of participants reported a surprising amount of positivity in the face of receiving this difficult diagnosis, and demonstrated incredible creativity and adaptability to meet the ensuing loss of function. However, patients and caregivers discussed feelings of isolation and health care system challenges. The importance of hope was a strong and recurring theme.CONCLUSIONS:The photovoice research tool demonstrates the profound resilience of these participants, and challenges the medical community to find ways of fostering positivity and hope throughout the ALS disease course. Further clinic and community resources, education, and supports are needed to combat the sense of isolation and health care system challenges experienced by patients and their caregivers.

Background: Spinal Muscular Atrophy (SMA) is a rare disease that affects 1 in 11 000 live births. Recent developments in SMA treatments have included new disease-modifying therapies that require high quality data to inform decisions around initiation and continuation of therapy. In Canada, there are no nationally agreed upon outcome measures (OM) used in adult SMA. Standardization of OM is essential to obtain high quality data that is comparable among neuromuscular clinics. Objective: To develop a recommended toolkit and timing of OM for assessment of adults with SMA. Methods: A modified delphi method consisting of 2 virtual voting rounds followed by a virtual conference was utilized with a panel of expert clinicians treating adult SMA across Canada. Results: A consensus-derived toolkit of 8 OMwas developed across three domains of function, with an additional 3 optional measures. Optimal assessment frequency is 12 months for most patients regardless of therapeutic access, while patients in their first year of receiving disease-modifying therapy should be assessed more frequently. Conclusions: The implementation of the consensus-derived OM toolkit will improve monitoring and assessment of adult SMA patients, and enrich the quality of real-world evidence. Regular updates to the toolkit must be considered as new evidence becomes available.

We report the recruitment activities and outcomes of a multi-disease neuromuscular patient registry in Canada. The Canadian Neuromuscular Disease Registry (CNDR) registers individuals across Canada with a confirmed diagnosis of a neuromuscular disease. Diagnosis and contact information are collected across all diseases and detailed prospective data is collected for 5 specific diseases: Amyotrophic Lateral Sclerosis (ALS), Duchenne Muscular Dystrophy (DMD), Myotonic Dystrophy (DM), Limb Girdle Muscular Dystrophy (LGMD), and Spinal Muscular Atrophy (SMA). Since 2010, the CNDR has registered 4306 patients (1154 pediatric and 3148 adult) with 91 different neuromuscular diagnoses and has facilitated 125 projects (73 academic, 3 not-for-profit, 3 government, and 46 commercial) using registry data. In conclusion, the CNDR is an effective and productive pan-neuromuscular registry that has successfully facilitated a substantial number of studies over the past 10 years.

Objective Spinobulbar muscular atrophy (SBMA) is an X-linked adult-onset neuromuscular disorder that causes progressive weakness and androgen insensitivity in hemizygous males. This condition is reported to be extremely rare, but has higher prevalence in certain populations due to multiple founder effects. Anecdotal observations of a higher prevalence of SBMA in patients of Indigenous descent in Saskatchewan led us to perform this study, to estimate the disease prevalence, and to attempt to identify a founder effect. Methods For our prevalence estimation, we identified patients with confirmed SBMA diagnosis from the Saskatoon neuromuscular clinic database for comparison with population data available from Statistics Canada. For our haplotype analysis, participants with SBMA were recruited from 2 neuromuscular clinics, as well as 5 control participants. Clinical data were collected, as well as a DNA sample using saliva kits. We performed targeted quantification of DXS1194, DXS1111, DXS135, and DXS1125 microsatellite repeats and the AR GGC repeat to attempt to identify a disease haplotype and compare it with prior studies. Results We estimate the prevalence of SBMA among persons of Indigenous descent in Saskatchewan as 14.7 per 100,000 population. Although we believe that this is an underestimate, this still appears to be the highest population prevalence for SBMA in the world. A total of 21 participants were recruited for the haplotype study, and we identified a unique haplotype that was shared among 13 participants with Indigenous ancestry. A second shared haplotype was identified in 2 participants, which may represent a second founder haplotype, but this would need to be confirmed with future studies. Conclusions We describe a very high prevalence of SBMA in western Canadians of Indigenous descent, which appears to predominantly be due to a founder effect. This necessitates further studies of SBMA in these populations to comprehensively ascertain the disease prevalence and allow appropriate allocation of resources to support individuals living with this chronic disease.

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Monday, April 27April 14, 2020Free AccessCanadian ALS Best Practice Recommendations (2749)Christen Shoesmith, Agessandro Abrahao, Timothy Benstead, Marvin Chum, Nicolas Dupre, Aaron Izenberg, Wendy Johnston, … Show All … , Sanjay Kalra, Desmond Leddin, Colleen O’Connell, Kerri Schellenberg, Anu Tandon, and Lorne Zinman Show FewerAuthors Info & AffiliationsApril 14, 2020 issue94 (15_supplement)https://doi.org/10.1212/WNL.94.15_supplement.2749 Letters to the Editor

ABSTRACT:Background:Diagnostic delay in amyotrophic lateral sclerosis (ALS) is common. In a recent Canadian study evaluating provincial differences in care, Saskatchewan had the longest delay at 27 months. Since Saskatchewan has a large rural population, this study sought to determine whether geographically determined access to a neurologist at tertiary centers could be contributing to this lengthy delay.Methods:A retrospective chart review of 171 patients seen in the ALS clinic in Saskatoon, Saskatchewan was performed. Urban or rural location, distance from nearest tertiary center, and clinically relevant data were collected.Results:There was no difference between urban and rural populations for delay in symptom onset to diagnosis. For rural patients, linear regression modeling did not uncover a significant relationship between distance from tertiary center and time to diagnosis. Additionally, there were no differences between urban and rural dwellers either for referral or utilization of feeding tube, noninvasive ventilation, riluzole, or communication devices. Contrary to the previous data showing a 27-month diagnostic delay in Saskatchewan, our study which included a larger provincial population found the mean diagnostic delay was 16.6 months.Conclusions:This study did not uncover differences in diagnostic delay or ALS care between urban and rural dwellers. Further study is required to determine reproducibility of results.

Objective To evaluate safety, dose response, and preliminary efficacy ofreldesemtivover 12 weeks in patients with amyotrophic lateral sclerosis (ALS).Methods:Patients (<= 2 years since diagnosis) with slow upright vital capacity (SVC) of >= 60% were randomized 1:1:1:1 toreldesemtiv150, 300, or 450 mg twice daily (bid) or placebo; active treatment was 12 weeks with 4-week follow-up. Primary endpoint was change in percent predicted SVC at 12 weeks; secondary measures included ALS Functional Rating Scale-Revised (ALSFRS-R) and muscle strength mega-score.Results:Patients (N = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance (p = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R,p = 0.09; muscle strength mega-score,p = 0.31). Post hoc analyses pooling all activereldesemtiv-treated patients compared against placebo showed trends toward benefit in all endpoints (progression rate for SVC, ALSFRS-R, and muscle strength mega-score (nominal p values of 0.10, 0.01 and 0.20 respectively)).Reldesemtivwas well tolerated, with nausea and fatigue being the most common side effects. A dose-dependent decrease in estimated glomerular filtration rate was noted, and transaminase elevations were seen in approximately 5% of patients. Both hepatic and renal abnormalities trended toward resolution after study drug discontinuation.Conclusions:Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoringreldesemtivfor all three endpoints, with effect sizes generally regarded as clinically important. Tolerability was good; modest hepatic and renal abnormalities were reversible. The impact ofreldesemtivon patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898)

POINTS CLES La sclerose laterale amyotrophique (SLA) est une maladie progressive invalidante due a une degenerescence des motoneurones dans le cerveau et la moelle epiniere; elle provoque faiblesse, atrophie musculaire, fasciculations et spasticite[1][1]. La forme la plus frequente est