Background: We evaluated the utility of the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) in predicting risk of gastrostomy tube (G-tube) insertion in patients with ALS. Methods: We conducted a retrospective study using the Pooled Resource Open-Access ALS Clinical Trials Database. People with ALS, at least two ALSFRS scores, and baseline swallowing subscore >1 were included. G-tube outcome was defined as reaching a swallowing subscore ≤1. Predictors were ALSFRS bulbar subscores (swallowing, speech, salivation). Survival analyses estimated median time to outcome and cumulative probability of outcome within 91 days. Individuals were censored at last ALSFRS score. Results: We included 6,943 participants. Median [95% CI] time to G-tube insertion was 245 [228, 285], 562 [547, 621], and 1,268 [980, 1,926] for baseline swallowing subscores of 2, 3, and 4, respectively. Probability of G-tube insertion was associated with baseline swallowing, speech, and salivation subscores (log-rank test p < 0.0001). For patients who transitioned to a swallowing subscore of 2 or 3, 18.1% [95% CI 16.1, 20.3] and 1.9% [95% CI 1.3, 2.7] required G-tube insertion within 91 days of score transition. Conclusions: ALSFRS bulbar subscores may identify patients at risk of G-tube insertion. Probability of G-tube insertion within 91 days is low if swallowing subscore ≥3.

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: The presence of intraluminal thrombi (ILT) in acutely symptomatic carotid stenosis (“hot carotid”) represents a therapeutic dilemma for physicians. With little evidence to guide treatment, current ILT management approaches rely on individual or institutional preferences. Methods: This mixed methods study analyzed themes from semi-structured interviews with 22 stroke physicians from 16 centers, paired with a worldwide case-based survey of 628 stroke physicians conducted through the “Practice Current” section of Neurology: Clinical Practice. Results: In the thematic analysis of the interviews and quantitative analysis of the survey, participants favoured using anticoagulation with or without antiplatelet agents in patients with ILT (463/628, 74%). Despite a preference for anticoagulation, uncertainty regarding optimal antithrombotic management was noted in the thematic analysis. Additional themes identified included a preference for re-imaging patients in 3-5 days after initiating treatment to look for complete or partial clot resolution, at which point most experts would then be comfortable proceeding with revascularization if indicated, though uncertainty regarding the optimal timing of revascularization was noted. Conclusions: In cases of ILT in the “hot carotid” practice patterns of global experts show a preference for using anticoagulation and reimaging patients in 3-5 days, though there is considerable equipoise regarding the most appropriate management of these patients.

Background: Females with generalized myasthenia gravis (gMG) report lower quality of life (QoL) compared to males. Our objective was to determine whether sex differences in treatment and time to treatment initiation may contribute to this difference. Methods: We performed a single centre retrospective study of people diagnosed with gMG. We used multivariable logistic and Cox regression models to assess the association between sex and study outcomes, adjusting for duration from onset to diagnosis, age at diagnosis, thymoma, and antibody status. Results: 179 people with gMG were included. Mean age at diagnosis was 58.4 years, mean follow-up was 4.8 years, and 58.1% were male. There was no association between sex and odds of starting prednisone (adjusted odds ratio [aOR]=0.58, 95% confidence interval [95%CI]=0.28-1.19, p=0.14) or steroid sparing agents (aOR=0.72, 95%CI=0.39-1.35, p=0.31). Similarly, sex was not associated with time to starting prednisone (adjusted hazard ratio [aHR]=0.74, 95% confidence interval [95%CI]=0.52-1.06, p=0.10) or steroid sparing agents (aHR=0.82, 95%CI=0.55-1.22, p=0.33). Females were more likely to start plasmapheresis (aOR=3.15, 95%CI=1.09-9.07, p=0.03). Conclusions: We found no sex differences in first and second line immunotherapy for gMG that might explain differences in QoL. Females were more likely to initiate plasmapheresis, which may reflect greater disease severity.

Background: The Canadian Registry for Amyloidosis Research (CRAR) is a nationwide disease registry of transthyretin (ATTR) and light-chain (AL) amyloidosis. Recent advances in disease-modifying therapy have improved prognosis, however there is a critical need for real-world evidence to address knowledge gaps, particularly longer-term therapeutic outcomes and surveillance strategies. Methods: A multi-stakeholder process was undertaken to develop a consensus dataset for ATTR- and AL-amyloidosis. This process included surveys to rank the importance of potential data items, and a consensus meeting of the CRAR steering committee, (comprised of multidisciplinary clinical experts, and patient organization representatives). Patients and patient organizations supported the development and implementation of a patient-reported dataset. Results: Consensus data items include disease onset, progression, severity, treatments, and outcomes, as well as patient-reported outcomes. Both prospective and retrospective (including deceased) patient cohorts are included. Further baseline data will be presented on an initial cohort of patients. Conclusions: CRAR has been established to collect a longitudinal, multidisciplinary dataset that will evaluate amyloidosis care and outcomes. CRAR has launched at multiple specialty amyloidosis centers nationally and is continually expanding. The growth of this program will promote opportunities to assess real-world safety and efficacy and inform the cost-effectiveness of therapies while supporting patient recruitment for research.

Background: Little evidence exists to guide the management of symptomatic non-stenotic carotid disease (SyNC). SyNC, which refers to carotid lesions with less than 50% artery stenosis, has been increasingly implicated as a cause of stroke and TIA. Methods: Semi-structured interviews with 22 stroke physicians from 16 centers were conducted as part of the Hot Carotid Qualitative Study. This study explored decision-making approaches, opinions and attitudes regarding the management of symptomatic carotid disease. Presented here are a subset of results related to the decision to revascularize patients with SyNC. Results: Thematic analysis revealed equipoise in the decision to revascularize patients with SyNC. Participants discussed a desire to use imaging features (e.g plaque rupture and plaque morphology) to inform the decision to revascularize, though significant uncertainty remains in appraising the risk conferred by certain features. Experts support further study to better understand the use of these features in risk appraisal for patients with SyNC. Conclusions: The decision to revascularize patients with SyNC is an area with significant equipoise. Experts identify the use of imaging features as an important tool in informing the decision to pursue revascularization in patients with SyNC though more study is required in this area to better inform practice.

Background: There are uncertainties regarding the optimal management of acutely symptomatic carotid stenosis (“hot carotids”). We sought to explore the approaches of stroke physicians to anti-thrombotic management, imaging, and revascularization in patients with “hot carotids”. Methods: We used a qualitative descriptive methodology to examine decision-making approaches of physicians regarding the management of hot carotids. We conducted semi-structured interviews with 22 stroke physicians from various specialties in 16 centers across 4 continents. Results: Important themes regarding anti-thrombotic included limitations of existing clinical trial evidence, competing physician preferences, antiplatelet therapy while awaiting revascularization and various regional differences. Timely imaging availability, breadth of information gained, and surgeon/interventionalist preferences were important themes influencing the choice of imaging modality. The choice of revascularization intervention was influenced by healthcare system factors such as use of multidisciplinary review and operating room/angiography suite availability, and patient factors like age and infarct size. Many themes related to uncertainties in the management of hot carotids were also discussed. Conclusions: Our study revealed themes that are important to international stroke experts. We highlight common and divergent practices while underscoring important areas of clinical equipoise and uncertainty. Teams designing international carotid trials may wish to accommodate identified variations in practice patterns and areas of uncertainty.

Background: Mutations in GDP-Mannose Pyrophosphorylase B (GMPPB) cause a spectrum of disease ranging from muscular dystrophy to congenital myasthenic syndrome (CMS). Recognition of neuromuscular junction dysfunction has important treatment implications. Methods: We describe a person with GMPPB mutation causing an overlapping limb girdle muscular dystrophy - myasthenic syndrome with robust response to acetylcholinesterase inhibitors. We review the literature on the muscular dystrophy - CMS and explore the phenotypic features that aid in recognizing neuromuscular junction dysfunction. Results: A 35-year-old woman presented with a 10-year history of debilitating myalgias, symmetrical limb girdle and neck weakness, and chronic CK elevation. Electromyography showed a non-irritable myopathy. Biopsies were consistent with muscular dystrophy. Whole genome sequencing revealed two heterozygous pathogenic mutations in the GMPPB gene, giving a diagnosis of genetically confirmed limb girdle muscular dystrophy. Subsequently, repetitive nerve stimulation revealed decrement in the trapezius muscle suggestive of an overlap myasthenic syndrome. She was started on pyridostigmine resulting in recovery of full motor power with significant functional improvement. Conclusions: Identification and treatment of neuromuscular junction dysfunction caused by GMPPB mutations can significantly improve motor power and function. Early onset of progressive fatigable proximal weakness, spared ocular and facial muscles, and pyridostigmine responsiveness are important features of GMPPB-related CMS.

Background: Criteria to formalize the diagnosis of amyotrophic lateral sclerosis (ALS) and refine clinical trial populations have evolved. The recently proposed Gold Coast criteria (GCC) are intended to simplify use and increase sensitivity. We evaluated sensitivity of GCC and potential impacts on therapeutic trial enrollment. Methods: We performed a single center retrospective study including patients diagnosed with ALS between 2016 – 2021. We determined criteria met at diagnosis according to revised El Escorial (rEEC), Awaji (AC) and GCC. We compared sensitivity and examined impacts GCC would have on enrollment in landmark ALS trials. Results: We included 203 people with ALS. Sensitivity of GCC (96.1%, 95% confidence interval [CI] = 92.2-98.2%) was significantly higher than rEEC (89.8%, 95% CI 84.6-93.4%, χ2 = 5.3, p = 0.01) and AC (89.3%, 95% CI 84.1-93.0%, χ2 = 6.1, p = 0.006). GCC was more sensitive than clinically definite or probable rEEC (47.6%, 95% CI 40.6-54.6%, χ2 = 117.6, p = < 0.001) and use would result in increased eligibility in landmark therapeutic trials. Conclusions: GCC are more sensitive than rEEC and AC at time of diagnosis in ALS. Use of GCC in our population would expand clinical trial participation and make results more widely generalizable.

Background: Light chain (AL) amyloidosis is a plasma cell disorder characterized by abnormal fibrillary light chain deposition causing cardiac, renal, hepatic, gastrointestinal and peripheral nervous system dysfunction. Muscle disease occurs in 1.5% of individuals causing progressive proximal weakness thus far considered untreatable. Methods: We reviewed two cases of AL amyloidosis associated myopathy at our institution who had robust response to plasmapheresis. Both were at stringent clinical response following CyBorME therapy during peak severity of their myopathy. Results: In case 1, a 70-year-old male with recently diagnosed kappa light chain multiple myeloma and cardiac/renal amyloidosis developed severe subacute proximal weakness preventing ambulation. CK was normal and electromyography was consistent with irritable myopathy. Deltoid biopsy showed perimysial and endomysial amyloidosis. A trial of plasmapheresis in a tapering schedule resulted in robust recovery of strength. In case 2, a 67-year-old female with recently diagnosed kappa light chain multiple myeloma with amyloidosis on fat pad aspirate developed severe subacute proximal weakness requiring prolonged hospital admission. CK was normal and electromyography demonstrated non-irritable myopathy. Bicep biopsy showed perivascular amyloidosis. A trial of plasmapheresis in a tapering schedule resulted in robust recovery of strength. Conclusions: Plasmapheresis is a novel and potentially effective treatment for patients with AL amyloidosis associated myopathy.

Background: Neuromuscular junction transmission impairment has been described in amyotrophic lateral sclerosis (ALS). The degree of repetitive nerve stimulation (RNS) decrement may correlate with disease activity if measurement is repeatable. We determined test-retest correlation of decremental response in patients with ALS. Methods: RNS (3 Hz) was assessed by blinded technician and clinician on median - abductor pollicis brevis (median-APB), ulnar - adductor digiti minimi (ulnar-ADM), and/or accessory - trapezius (accessory-TRAP) nerve-muscle pairs during two evaluations. Repeatability was assessed by measuring the strength of test-retest correlation using the Pearson correlation coefficient (r). Results: 24 patients were included. Decrement was measured for 16 patients on median-APB, 22 on ulnar-ADM, and 24 on accessory-TRAP. Repeated measures of decrement demonstrated strong test-retest correlation for median-APB (r = 0.82, p < 0.001) and accessory-TRAP (r = 0.87, p < 0.001). Correlation was poor in ulnar-ADM (r = −0.01, p = 0.949). Correlation was superior in median-APB muscles with higher Medical Research Council (MRC) grade strength (MRC ≥ 4, r = 0.89, p = 0.001 vs MRC < 4, r = 0.73, p = 0.062). Conclusions: Decremental response in patients with ALS has strong test-retest correlation in median-APB and accessory-TRAP, but not in ulnar-ADM.

Background: Whereas the beneficial effect of antiplatelet therapy for recurrent stroke prevention is well-established, uncertainties remain regarding the optimal anti-thrombotic regimen for acutely symptomatic carotid stenosis (“hot carotid”), particularly as patients await revascularization. We sought to explore the approaches of stroke physicians to peri-procedural anti-thrombotic management of patients with “hot carotids”. Methods: We conducted semi-structured interviews regarding “hot carotid” management with purposive sampling of 20 stroke physicians from 14 centres in North America, Europe, Asia, and Australia. We identified key themes using conventional qualitative content analysis. Results: Important themes revealed from our discussion included limitations of existing clinical trial evidence, competing surgeon versus neurologist/internist preferences, and single vs dual antiplatelet therapy (DAPT) while awaiting revascularization. Areas of uncertainty included the management of stroke while on aspirin, implications of non-stenotic features of carotid disease (intraluminal thrombus, plaque morphology), the role of newer anti-platelet agents or anticoagulants, platelet aggregation testing, and how soon to start DAPT. Conclusions: Our qualitative analysis revealed themes that were important to stakeholders in stroke care. Teams designing international trials will have to accommodate identified variations in anti-thrombotic practice patterns and take into consideration areas of uncertainty, such as newer anti-thrombotic agents, and the implication of non-stenotic features of carotid disease.

Background: Evidence informing the choice between endarterectomy and stenting for acutely symptomatic carotid stenosis (“hot carotid”) is dated, and uncertainties remain regarding the optimal imaging modality. We sought to explore the thoughts of stroke physicians regarding the perioperative management of patients with acute symptomatic carotid stenosis. Methods: We conducted semi-structured interviews regarding “hot carotid” management with purposive sampling of 20 stroke physicians from 14 centres in North America, Europe, Asia, and Australia. We identified key themes using conventional qualitative content analysis. Results: Timely imaging availability, breadth of information gained, and surgeon/interventionalist preference emerged as important themes informing the choice of imaging modality. Multidisciplinary decision making, operating room/angiography suite availability, and implications of patient age and infarct size were important themes related to the choice of revascularization. Areas of uncertainty included utility of carotid plaque imaging, timing of revascularization, and the role of intervention with borderline stenosis or intraluminal thrombus. Conclusions: Our qualitative analysis revealed themes that were important to stroke experts. Teams designing international trials will have to accommodate identified variations in practice patterns and take into consideration areas of uncertainty, such as timing of revascularization, imaging of carotid plaque and non-stenotic features of carotid disease (intraluminal thrombus, plaque morphology).

Background: Patients with acutely symptomatic carotid stenosis (“hot carotid”) have high up-front risk of recurrent strokes. Uncertainties remain regarding optimal anti-thrombotic management, particularly while awaiting revascularization with endarterectomy or stenting (CEA/CAS). Methods: We administered a worldwide electronic survey through Neurology: Clinical Practice. Respondents chose their preferred antithrombotic regimen (1) in a general case of acutely symptomatic carotid stenosis, (2) if the patient was already on aspirin, or (3) had associated intraluminal thrombus(ILT). Responses among different groups were compared using multivariable logistic regression. Results: We received 668 responses from 71 countries. Most respondents favoured CEA(69.1%) over CAS, an aspirin-containing regimen(88.5%), and a clopidogrel-containing regimen(64.4%) if already on aspirin. Monotherapy was favoured by 54.4-70.6% across scenarios. The preferred dual therapy was low-dose aspirin(75-100mg) plus clopidogrel(22.2%), or high-dose aspirin(160-325mg) plus clopidogrel if already on aspirin(12.2%). Respondents favouring CAS more often chose ≥2 agents (adjusted odds-ratio[aOR] vs CEA: 2.00, 95%CI 1.36-2.95,p=0.001) or clopidogrel-containing regimens (aOR:1.77,1.16-2.70,p=0.008). Respondents from Europe less commonly chose multiple agents (aOR vs United States/Canada: 0.57,0.35–0.93,p=0.023) while those from Asia more often favored multi-agent regimens (aOR:1.95,1.11–3.43,p=0.020). Conclusions: Our results highlight the heterogeneous anti-thrombotic management of hot carotids. Future trials should likely include high-dose aspirin monotherapy or low-dose aspirin/clopidogrel dual-therapy as a comparator arm to stimulate enrolment.

Background: Unplanned hospital readmission is inconvenient for patients, puts them at risk of harm, and is a resource strain. We reviewed available literature on risk factors for readmission following discharge specifically from neurology inpatient services with a focus on factors unique to non-stroke neurology admissions. Methods: We conducted a systematic search using PRISMA methodology of MEDLINE, EMBASE, and CENTRAL databases up to January 1, 2018. Two independent reviewers screened articles for inclusion. English-language articles were included that identified factors related to hospital readmission after discharge from a neurology service. Admissions with stroke as the primary focus were excluded. Results: Of 9508 unique abstracts, 25 met inclusion criteria and were included for review. Multiple factors impacting probability of readmission were identified including age, living alone, history of nonepileptic seizure, length of stay, services consulted during hospital stay, hospital volume, and severity of illness. Conclusions: There are identifiable risk factors that influence likelihood of readmission to hospital following discharge from neurology inpatient services, although the non-stroke literature is sparse. There is a need for future prospective work to investigate modifiable risk factors and opportunities to reduce readmission rates and improve patient safety.

Case Description: A 64 year-old male presented with left-sided weakness and altered level of consciousness after a suspected seizure. MR Brain demonstrated right mesial temporal lobe diffusion restriction. Empiric antiviral and antibiotic treatments were initiated despite CSF negative for HSV/VZV and enteroviruses. Lumbar puncture on admission day five was unchanged and empiric treatments were discontinued. On day 13 he deteriorated into status epilepticus necessitating ICU transfer. A third lumbar puncture demonstrated elevated protein and HSV-1 positive PCR. Acyclovir was restarted with guarded prognosis. Discussion: Detection of HSV-1 in CSF is considered the diagnostic gold standard for HSV-1 encephalitis. The validated multiplex assay used in Alberta, Canada has a 95% level of detection significantly better than the recommended threshold for HSV laboratory diagnosis. Previous reports have indicated that CSF PCR may be negative early in the disease course. Others have suggested that initially negative/follow up positive HSV PCR cases may represent secondary reactivation or release from underlying tissue damage. Consideration of the full clinical picture is crucial in patients with HSV negative PCR. Continuation of antiviral therapy may be appropriate in select HSV PCR negative patients.

Background: Despite the ease of intraoperative injection, intrathecal morphine (ITM) is rarely provided in lumbar spine surgery. We therefore sought to demonstrate the safety and efficacy of ITM following lumbar fusion. Methods: In this double-blind trial, 150 patients undergoing elective instrumented lumbar fusion were randomly assigned to receive a single injection of ITM (0.2 mg) or placebo (saline) prior to wound closure. Primary outcomes were postoperative pain on the visual-analog scale during the inital 24 hours after surgery and respiratory depression. Secondary outcomes included related adverse events, opioid requirements, and length of stay. Outcome curves were estimated in an intention-to-treat, repeated-measures analysis. Results: Age, disability, operative times, and pre-operative pain were similar in both groups. ITM was associated with less pain both at rest (p<0.002) and with movement (p<0.02) during the initial 24 hours following surgery. ITM did not increase the cumulative incidence of respiratory depression (hazard ratio 0.86, p=0.66). While ITM reduced postoperative opioid requirements (p<0.03), there was no significant difference in length of stay (p=0.67). Adverse events did not significantly differ between groups. The early benefits of ITM on postoperative pain were no longer apparent after 48 hours. Conclusions: A single ITM injection safety reduces postoperative pain following lumbar fusion. (ClinicalTrials.gov NCT01053039)