Acute central nervous system inflammation following COVID-19 vaccination: An observational cohort study.

BACKGROUND: Reports suggest a potential association between coronavirus disease 2019 (COVID-19) vaccines and acute central nervous system (CNS) inflammation. OBJECTIVE: The main objective of this study is to describe features of acute CNS inflammation following COVID-19 vaccination. METHODS: A retrospective observational cohort study was performed at the BARLO MS Centre in Toronto, Canada. Clinicians reported acute CNS inflammatory events within 60 days after a COVID-19 vaccine from March 2021 to August 2022. Clinical characteristics were evaluated. RESULTS: Thirty-eight patients (median age 39 (range: 20-82) years; 60.5% female) presented within 0-55 (median 15) days of a receiving a COVID-19 vaccine and were diagnosed with relapsing remitting multiple sclerosis (MS) (n = 16), post-vaccine transverse myelitis (n = 7), clinically isolated syndrome (n = 5), MS relapse (n = 4), tumefactive demyelination (n = 2), myelin oligodendrocyte glycoprotein antibody disease (n = 1), neuromyelitis optica spectrum disorder (n = 1), chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (n = 1) and primary autoimmune cerebellar ataxia (n = 1). Twenty-two received acute treatment and 21 started disease-modifying therapy. Sixteen received subsequent COVID-19 vaccination, of which 87.5% had no new or worsening neurological symptoms. CONCLUSION: To our knowledge, this is the largest study describing acute CNS inflammation after COVID-19 vaccination. We could not determine whether the number of inflammatory events was higher than expected.

Complement Inhibition in Myasthenia Gravis and Neuromyelitis Optica Spectrum Disorder.

The complement system is a tightly controlled signaling network that plays a role in innate immune surveillance. However, abnormal signaling through this pathway contributes to tissue damage in several inflammatory, autoimmune, and degenerative diseases. Myasthenia gravis (MG) and neuromyelitis optica spectrum disorders (NMOSD) have complement dysfunction at the core of pathogenesis, providing a strong rationale for therapeutic targeting of complement components. The purpose of this paper is to briefly review the role of complement activation in the pathogenesis of MG and NMOSD, to discuss the rationale and evidence for complement inhibition as a method to manage these diseases, and to provide a Canadian perspective on the use of complement inhibition therapy through real-world cases of MG and NMOSD.

Expert opinion on the use of cladribine tablets in clinical practice.

BACKGROUND: Gaps in current product labels and a lack of detailed clinical guidelines leaves clinicians' questions on the practical management of patients receiving cladribine tablets for the treatment of relapsing multiple sclerosis (MS) unanswered. We describe a consensus-based programme led by international MS experts with the aim of providing recommendations to support the use of cladribine tablets in clinical practice. METHODS: A steering committee (SC) of nine international MS experts led the programme and developed 11 clinical questions concerning the practical use of cladribine tablets. Statements to address each question were drafted using available evidence, expert experiences and perspectives from the SC and an extended faculty of 33 MS experts, representing 19 countries. Consensus on recommendations was achieved when ⩾75% of respondents expressed an agreement score of 7-9, on a 9-point scale. RESULTS: Consensus was achieved on 46 out of 47 recommendations. Expert-agreed practical recommendations are provided on topics including: the definition of highly active disease; patterns of treatment response and suboptimal response with cladribine tablets; management of pregnancy planning and malignancy risk, infection risk and immune function, and switching to and from cladribine tablets. CONCLUSION: These expert recommendations provide up-to-date relevant guidance on the use of cladribine tablets in clinical practice.

Prevalence of Fabry Disease and Outcomes in Young Canadian Patients With Cryptogenic Ischemic Cerebrovascular Events.

BACKGROUND AND PURPOSE: Previous studies reported Fabry disease in 0% to 4% of young patients with cryptogenic ischemic stroke (IS). We sought to determine the prevalence of Fabry and outcomes among young Canadians with cryptogenic IS or transient ischemic attack (TIA). METHODS: We prospectively enrolled individuals aged 18 to 55 with IS or speech or motor TIA, and no cause identified despite predetermined investigation. α-galactosidase-A gene was sequenced for Fabry diagnosis. National Institutes of Health Stroke Scale score was measured at presentation to quantify stroke severity. Modified Rankin Scale determined functional outcomes ≤7 days after presentation and 6 months later. RESULTS: We enrolled 365 patients with IS and 32 with TIA. α-galactosidase-A sequencing identified a single carrier of a genetic variant of unknown significance (p.R118C) and no well-recognized pathogenic variants. Mean National Institutes of Health Stroke Scale score was 3.1. Proportion of patients with modified Rankin Scale of 0 to 2 was 70.7% at ≤7 days and 87.4% at 6 months. National Institutes of Health Stroke Scale score at presentation and diabetes mellitus predicted 6-month modified Rankin Scale. Thirteen patients experienced 5 recurrent IS and 9 TIA during follow-up. No patient died. Most patients (98.7%) returned home. Among previous workers, 43% had residual working limitations. CONCLUSIONS: In this Canadian cohort of patients with cryptogenic IS or TIA, the prevalence of Fabry was 0.3% if p.R118C variant is considered as pathogenic. This suggests that more cost-effective methods should be applied for diagnosis of Fabry rather than systematic genetic screening in this population. Overall, cryptogenic IS in young adults is associated with favorable outcomes.

Anti-JC Virus Antibody Prevalence in Canadian MS Patients.

BACKGROUND: Anti-John Cunningham (JCV) antibodies have been detected in approximately 50% to 60% of multiple sclerosis (MS) patients. Age, sex, and geographic location have been associated with seroprevalence differences. We describe anti-JCV antibody prevalence in the Canadian cohort of patients enrolled in the JCV Epidemiology in MS study. METHODS: This cross-sectional multicenter study evaluated the effects of demographic and disease characteristics on anti-JCV antibody seroprevalence in MS patients irrespective of disease type and treatment. A single blood sample was collected for analysis of anti-JCV antibodies using a two-step enzyme-linked immunosorbent assay (ELISA). Chi-square and logistic regression tests were used to determine significance. RESULTS: A total of 4198 Canadian MS patients participated in the study; the overall anti-JCV antibody prevalence was 56.3% (95% confidence interval: 54.8% to 57.8%). Seroprevalence was significantly associated with age (increasing from 45% in young to 61% in those >60 years), sex, and region (p<0.0001 for age and sex; p=0.005 for region). No significant differences in anti-JCV antibody prevalence were associated with race, MS disease type and duration, or number and duration of treatments. Immunosuppressant use was associated with a higher seroprevalence rate (63.4%) compared with no immunosuppressant use (55.9%; p=0.040). CONCLUSIONS: Canadian MS patients had an overall anti-JCV antibody seroprevalence that was consistent with previous studies using the two-step ELISA. Significant associations of anti-JCV antibody positivity were found with age, sex, region, and immunosuppressant therapy, whereas seroprevalence was not associated with race, MS type, MS duration, or number or duration of MS treatments.

Prevalence of Fabry disease in young patients with cryptogenic ischemic stroke.

BACKGROUND: A German study diagnosed 4% of young cryptogenic ischemic stroke patients with Fabry disease, an X-linked lysosomal storage disease caused by mutations in the alpha-galactosidase A (α-GAL-A) gene resulting in an accumulation of glycosphingolipids. A lower prevalence was found in other geographic regions. AIM: To determine the prevalence of Fabry disease in a Canadian population of young cryptogenic ischemic stroke patients. MATERIALS AND METHODS: Patients with cryptogenic ischemic stroke at age 16-55 were retrospectively identified in our institutional stroke database and underwent a focused clinical evaluation. We sequenced the α-GAL-A gene and measured the levels of blood globotriaosylsphingosine in subjects with mutations of undetermined pathogenicity. Fabry disease was diagnosed in patients with pathogenic mutations or increased levels of blood globotriaosylsphingosine. RESULTS: Ninety-three of 100 study subjects had normal α-GAL-A gene polymorphisms. Seven had mutations of undetermined pathogenicity, including one with increased globotriaosylsphingosine (prevalence, 1%; 95% confidence interval, <.01%-6%). No subjects had angiokeratomas or other clinical manifestations of Fabry disease. Investigation results suggestive of Fabry disease (idiopathic hypertrophic cardiomyopathy, proteinuria, vertebrobasilar dolichoectasia, and the pulvinar sign) were found only in subjects with normal α-GAL-A genes. Apart from the 100 study subjects, our database included another patient with a family history of Fabry disease and a pathogenic mutation identified before her ischemic stroke presentation as the first clinical manifestation of Fabry disease. Both Fabry patients experienced recurrent ischemic stroke. CONCLUSIONS: Fabry disease accounts for a small proportion of young Canadians with cryptogenic ischemic stroke. Identification of Fabry biomarkers remains a research priority to delineate stroke patients disserving routine screening.

Fabry's disease: a prospective multicenter cohort study in young adults with cryptogenic stroke.

BACKGROUND: Stroke in young adults is etiologically diverse and may represent a diagnostic challenge remaining cryptogenic in one-fourth of cases. Limited information is available on the prevalence of Fabry's disease, a treatable multisystem inherited lysosomal storage disorder, and disability in young patients with cryptogenic stroke. DESIGN AND METHODS: The Canadian Fabry Stroke Screening Initiative (CFSSI) is a prospective multicenter cohort study of young adults (age 18-55) presenting with an ischemic stroke, transient ischemic attack, or intracerebral haemorrhage of unknown etiology to stroke centres across Canada. Diagnosis of Fabry's disease is made by direct DNA analysis of blood samples for α-galactosidase gene mutations or polymorphisms. Demographics, clinical information, and investigations including brain Magnetic Resonance Imaging (MRI) are collected. Functional neurological assessment includes neurological examination, the National Institutes of Health (NIH) stroke scale, modified Rankin scale, and the Barthel index. A follow-up interview is conducted by telephone or in person approximately six-months after the index stroke/transient ischemic attack/intracerebral haemorrhage to determine patient outcomes, quality of life, and patient use of medications. MAIN OUTCOME: Prevalence of positive DNA mutation or single nucleotide polymorphism screens for Fabry's disease as a proportion of total cryptogenic stroke. Secondary outcomes include incident risk of new or recurrent vascular event at six-months, discharge disposition, disability at six-months as measured by the modified Rankin scale, mean time from symptoms onset to the definite etiological diagnosis, and length of hospital stay. CONCLUSION: This study constitutes the first initiative to determine the prevalence of a positive screen for Fabry's disease in young adults with stroke in Canada. Moreover, the Canadian Fabry Stroke Screening Initiative will provide information on recurrent vascular events, disability at six-months (modified Rankin scale), and disposition in this understudied population.

Stroke unit care: does ischemic stroke subtype matter?

BACKGROUND: Stroke unit care improves outcomes following ischemic stroke. However, it is not known whether all ischemic stroke subtypes benefit equally from stroke unit admission. OBJECTIVE: To determine whether the benefit of stroke unit admission is similar among all ischemic stroke subtypes. Design, setting and patients Prospective cohort study including patients admitted with an acute ischemic stroke between July 2003 and September 2007 to stroke centers participating institutions in the Registry of the Canadian Stroke Network. Ischemic stroke subtype information was determined according to the modified Trial of Org 10 172 in Acute Stroke Treatment criteria and categorized as small vessel disease (lacunar), large artery atherosclerotic disease, cardioembolic, or other (including both other determined and undetermined causes). Main outcome measures The primary outcome measure was all-cause mortality at 30 days after stroke. Secondary outcomes were seven-day mortality and death or institutionalization at discharge. RESULTS: Among 6223 eligible patients with ischemic stroke admitted to regional stroke centers in Ontario, the mean age was 72 years and 52·4% were male. Overall 30-day mortality was 12·2%. The 30-day risk-adjusted mortality was lower for stroke unit care across all stroke subtypes (for lacunar stroke 3·0% vs. 5·3%; for large artery disease 7·5% vs. 14·5%; for cardioembolic 15·3% vs. 23·3%; and for other causes 8·9% vs. 15·9%). In multivariable analysis, after controlling for age, gender, medical comorbidities, and stroke severity, there was a significant reduction in stroke mortality associated with stroke unit admission in all stroke subtypes (odds ratio (95% confidence interval) for lacunar stroke 0·48 (0·27-0·88), for large artery atherosclerotic disease 0·39 (0·27-0·56), for cardioembolic 0·46 (0·36-0·59), and for other causes 0·45 (0·29-0·70)). The results remained similar after a sensitivity analysis excluding patients receiving palliative care, and a secondary analysis including 3215 patients with missing Trial of Org 10 172 in Acute Stroke Treatment classification. CONCLUSION: This study provides 'real-world' evidence that all ischemic stroke subtypes do benefit from a stroke unit admission regardless of the etiology. There is no justification for withholding access to stroke unit care based on stroke subtype.