Canadian Consensus Guidelines for the Diagnosis and Treatment of Autoimmune Encephalitis in Adults.

Autoimmune encephalitis is increasingly recognized as a neurologic cause of acute mental status changes with similar prevalence to infectious encephalitis. Despite rising awareness, approaches to diagnosis remain inconsistent and evidence for optimal treatment is limited. The following Canadian guidelines represent a consensus and evidence (where available) based approach to both the diagnosis and treatment of adult patients with autoimmune encephalitis. The guidelines were developed using a modified RAND process and included input from specialists in autoimmune neurology, neuropsychiatry and infectious diseases. These guidelines are targeted at front line clinicians and were created to provide a pragmatic and practical approach to managing such patients in the acute setting.

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.

Low-Field (64mT) Portable MRI for Rapid Point-of-Care Diagnosis of DIS in Patients Presenting with Optic Neuritis.

BACKGROUND AND PURPOSE: Low-field 64mT portable brain MRI (pMRI) has recently shown diagnostic promise for MS. This study aimed to evaluate the utility of pMRI in assessing dissemination in space (DIS) in patients presenting with optic neuritis and determine whether deploying pMRI in the MS clinic can shorten the time from symptom onset to MRI. MATERIALS AND METHODS: Newly diagnosed optic neuritis patients referred to a tertiary academic MS center from July 2022 to January 2024 underwent both point-of-care pMRI and subsequent conventional 3T MRI (cMRI). Images were evaluated for periventricular (PV), juxtacortical (JC) and infratentorial (IT) lesions. DIS was determined on brain MRI per 2017 McDonald criteria. Test characteristics were computed using cMRI as the reference. Interrater and intermodality agreement between pMRI and cMRI were evaluated using Cohen's kappa. Time from symptom onset to pMRI and cMRI during the study period was compared to the preceding 1.5 years before pMRI implementation using Kruskal-Wallis with post-hoc Dunn's tests. RESULTS: Twenty patients (median age: 32.5 [IQR, 28-40]; 80% females) were included, of whom 9 (45%) and 5 (25%) had DIS on cMRI and pMRI, respectively. Median time interval between pMRI and cMRI was 7 days (IQR, 3.5-12.5). Interrater agreement was very good for PV (95%, κ=0.89), and good for JC and IT lesions (90%, κ=0.69 for both). Intermodality agreement was good for PV (90%, κ=0.80) and JC (85%, κ=0.63), and moderate for IT lesions (75%, κ=0.42) and DIS (80%, κ=0.58). pMRI had a sensitivity of 56% and specificity of 100% for DIS.The median time from symptom onset to pMRI was significantly shorter (8.5 days [IQR 7-12]) compared to the interval to cMRI before pMRI deployment (21 days [IQR 8-49], n=50) and after pMRI deployment (15 days [IQR 12-29], n=30) (both p<0.01). Time from symptom onset to cMRI in those periods was not significantly different (p=0.29). CONCLUSIONS: In optic neuritis patients, pMRI exhibited moderate concordance, moderate sensitivity and high specificity for DIS compared to cMRI. Its integration into the MS clinic reduced the time from symptom onset to MRI. Further studies are warranted to evaluate the role of pMRI in expediting early MS diagnosis and as an imaging tool in resource-limited settings. ABBREVIATIONS: pMRI = portable MRI; cMRI = conventional MRI; pwMS = patients with MS; PV = periventricular; JC= juxtacortical; IT = infratentorial; DIS = dissemination in space.

Diagnosis and Management of Central Nervous System Demyelinating Disorders.

The spectrum of demyelinating diseases affecting the central nervous system is broad. Although many have a chronic course, neuroinflammatory conditions often present with acute to subacute onset symptoms requiring hospitalization when severe. This article reviews the acute phase assessment and management of these disorders, with a particular focus on multiple sclerosis, neuromyelitis optica spectrum disorder, myelin oligodendrocyte glycoprotein antibody disorder, and several atypical demyelinating diseases.

Autoimmune Encephalitis and Autoantibodies: A Review of Clinical Implications.

BACKGROUND: Autoimmune encephalitis (AE) is a common cause of encephalitis. We review the most recent evidence on this neuroimmune condition and autoantibody testing currently available. CONTENT: Clinical criteria, neuroimaging and electroencephalography can facilitate the diagnosis of AE prior to obtaining autoantibody testing results, and lead to a diagnosis of AE even in the absence of a recognized antibody. Early treatment of AE has been found to correlate with improved long-term functional and cognitive outcomes. We suggest a clinical approach to diagnosis based on the predominant area of nervous system involvement and the results of ancillary testing that are widely available. We also propose a 2-tiered approach to the acute management of probable or definite AE. We, finally, provide guidance on the long-term management of AE-a challenging and understudied area. SUMMARY: Much work remains to be done to improve the care of patients with AE. As understanding of the pathophysiology and predisposing factors underlying this condition steadily increases, a more evidence-based, targeted approach to the treatment of AE is still desired. Nonetheless, looking at the progress made over the past 2 decades, since the discovery of the first autoantibodies associated with AE, one cannot help but feel optimistic about the road ahead.

Association of No Evidence of Disease Activity With No Long-term Disability Progression in Multiple Sclerosis: A Systematic Review and Meta-analysis.

OBJECTIVE: We conducted a systematic review and meta-analysis to evaluate the relationship between No Evidence of Disease Activity (NEDA) and no long-term disability progression on low and high efficacy therapy in relapsing-remitting multiple sclerosis (RRMS). METHODS: MEDLINE, Embase, and the Cochrane Database were searched from January 1, 2006 to January 26, 2021. We selected studies which evaluated NEDA-3 (no relapse, new MRI lesion, or confirmed disability progression) at one or two years and had a minimum of four years' follow-up for determination of disability progression. Data were extracted by two independent reviewers and were meta-analyzed using a random effects model. Primary outcome of no disability progression was defined as no confirmed progression on the Expanded Disability Status Scale (EDSS) during follow-up. We assessed the odds ratio for no disability progression with NEDA vs. Evidence of Disease Activity (EDA). Positive predictive value of NEDA for no disability progression was summarized for studies with prevalence of no progression >80% vs. <80% separately. RESULTS: We included 29 studies in our qualitative synthesis of which 27 (16 low efficacy, 11 high efficacy) were included in the meta-analysis (n=10,935 participants). Median follow-up was 5.6 years (IQR: 4.3, 8.0 years). The pooled odds ratios for no progression with NEDA-3 vs. EDA were 2.32 (95% CI: 1.58-3.42; I2=73%) for low efficacy therapy and 3.19 (1.86-5.47; I2=86%) for high efficacy therapy. Among studies with prevalence of no progression at follow-up >80%, the pooled positive predictive value for low efficacy therapy was 91% (95% CI: 89-93%) and for high efficacy therapy was 92% (95% CI: 88-94%). Among studies with prevalence of no progression <80%, the pooled positive predictive value for low efficacy therapy was 81% (95% CI: 75-86%) and for high efficacy therapy was 86% (95% CI: 80-90%). CONCLUSIONS: NEDA-3 is associated with no long-term disability progression in RRMS on both low and high efficacy therapies. Further studies of early composite outcome measures incorporating easily measurable biomarkers, and longer follow-up, may help to improve on prognostic value of NEDA-3 in RRMS.

Association of NEDA-4 With No Long-term Disability Progression in Multiple Sclerosis and Comparison With NEDA-3: A Systematic Review and Meta-analysis.

BACKGROUND AND OBJECTIVES: No evidence of disease activity (NEDA)-4 has been suggested as a treatment target for disease-modifying therapy (DMT) in relapsing-remitting multiple sclerosis (RRMS). However, the ability of NEDA-4 to discriminate long-term outcomes in MS and how its performance compares with NEDA-3 remain uncertain. We conducted a systematic review and meta-analysis to evaluate (1) the association between NEDA-4 and no long-term disability progression in MS and (2) the comparative performance of NEDA-3 and NEDA-4 in predicting no long-term disability progression. METHODS: English-language abstracts and manuscripts were systematically searched in MEDLINE, Embase, and the Cochrane databases from January 2006 to November 2021 and reviewed independently by 2 investigators. We selected studies that assessed NEDA-4 at 1 or 2 years after DMT start and had at least 4 years of follow-up for determination of no confirmed disability progression. We conducted a meta-analysis using random-effects model to determine the pooled odds ratio (OR) for no disability progression with NEDA-4 vs EDA-4. For the comparative analysis, we selected studies that evaluated both NEDA-3 and NEDA-4 with at least 4 years of follow-up and examined the difference in the association of NEDA-3 and NEDA-4 with no disability progression. RESULTS: Five studies of 1,000 patients (3 interferon beta and 2 fingolimod) met inclusion criteria for both objectives. The median duration of follow-up was 6 years (interquartile range: 4-6 years). The prevalence of NEDA-4 ranged from 4.2% to 13.9% on interferon beta therapy and 24.9% to 25.1% on fingolimod therapy. The pooled OR for no long-term confirmed disability progression with NEDA-4 vs EDA-4 was 2.14 (95% confidence interval: 1.36-3.37; I2 = 0). We did not observe any significant difference between NEDA-4 and NEDA-3 in the comparative analyses. DISCUSSION: In patients with RRMS, NEDA-4 at 1-2 years was associated with 2 times higher odds of no long-term disability progression, at 6 years compared with EDA-4, but offered no advantage over NEDA-3.

Clinical characteristics and outcomes of multiple sclerosis patients with COVID-19 in Toronto, Canada.

OBJECTIVE: To report clinical characteristics and outcomes of people with multiple sclerosis (PwMS) who developed COVID-19 infection in Toronto, Canada. METHODS: Descriptive, retrospective, single-center study that included all known PwMS at the St. Michael's Hospital MS Clinic who had PCR-confirmed COVID-19 infection between March 2020 and May 2021. RESULTS: Of 7000 PwMS in our clinic, 80 (1.1%) tested positive for SARS-CoV-2. Fifty-four (67.5%) were on disease-modifying therapy (DMT) without over-representation of any single treatment. Seventy-one patients (88.8%) had mild symptoms, but nine (11.3%) were hospitalized and one 70-year-old male patient not on treatment died. Of those hospitalized, one-third were treated with ocrelizumab. CONCLUSION: In Toronto, PwMS did not appear to have higher prevalence of COVID-19 infection compared to the general population, but disease severity may be affected by DMT use. Our findings add to the accumulating global data regarding COVID-19 infection in PwMS.

Ovarian resection in anti-N-methyl-D-aspartate receptor encephalitis: A comparison of surgical approaches.

Background: For patients with anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) and ovarian teratoma, "conservative" surgical approaches (complete or partial unilateral oophorectomy or bilateral partial oophorectomies) are associated with clinical improvement. "Aggressive" ovarian resections (complete bilateral oophorectomy or "blind" ovarian resections without pre-operative evidence of teratoma) are also reported, although the evidence supporting these approaches is unclear. Objective: To compare the one-year functional outcomes of patients with NMDARE who underwent conservative vs. aggressive ovarian resections. Methods: Patients with NMDARE undergoing ovarian resection between January 1st, 2012 and December 31st, 2021 were retrospectively identified from three North American tertiary care centers. Primary outcome was a modified Rankin Scale score of 0-2 one year after ovarian resection. Fisher exact and Wilcoxon rank sum tests were used to compare demographic features, disease characteristics, and functional outcomes between the two surgical groups. A fixed-effects meta-analysis of studies reporting functional outcomes based on surgical approach was also performed. Results: Twenty-three patients were included. Eight underwent aggressive surgical management. There was a non-significant trend toward an association between aggressive surgical management and younger age-at-onset, higher baseline disease severity, and longer delays to treatment. There was no difference between "aggressive" (3/8, 38%) and "conservative" (11/15, 73%) management groups in achieving the primary outcome (OR95% = <0.1-1.9; p = 0.18). Findings were similar when considering data from 52 patients in two published studies (RR = 0.74; CI95% = 0.48-1.13; p = 0.16). Conclusions: Aggressive ovarian resection was not associated with improved outcomes in patients with NMDARE in this series. Group differences may have contributed, recognizing that patients who underwent aggressive resection tended to be sicker, with procedures performed later in the disease course. Based on available evidence, we advocate for function-sparing resection in patients with imaging-confirmed/suspected teratoma, and repeated multi-modal imaging in at-risk patients with NMDARE refractory to conventional treatment.

Dural venous sinus thrombosis after lumbar puncture in a patient with idiopathic intracranial hypertension.

INTRODUCTION: Idiopathic intracranial hypertension (IIH) is one of the most common causes of papilloedema seen by ophthalmologists and neurologists. Patients with IIH routinely undergo lumbar puncture (LP) for diagnosis. Dural venous sinus thrombosis (DVST) is a rare complication of cerebrospinal fluid pressure (CSF)-lowering procedures such as lumbar puncture and epidural and may be an intracranial complication of IIH. CASE DESCRIPTION: A 29-year-old obese woman was diagnosed with severe idiopathic intracranial hypertension (IIH) after she presented with new-onset headache, pulsatile tinnitus and blurred vision. Magnetic resonance imaging (MRI) and venography (MRV) were normal apart from signs of intracranial hypertension. Lumbar puncture (LP) revealed an opening pressure of 40 cm of water. Due to the severity of the papilloedema and vision loss, she was referred for a ventriculoperitoneal shunt and found to have venous sinus thrombosis involving the superior sagittal sinus on the pre-operative computed tomography (CT) head 5 days after the LP. CT venography (CTV) one day later and MRV 3 days later showed significant worsening as the thrombosis extended into the deep venous system. She was started on therapeutic heparin and her symptoms and vision improved and she did not develop any neurological complications. CONCLUSIONS: DVST should be considered in IIH patients who have worsening papilloedema or symptoms of intracranial hypertension. Repeat venous imaging can prevent devastating consequences such as venous infarcts of haemorrhage in these patients.

Spinal Cord MRI in Multiple Sclerosis.

Spinal cord (SC) MRI in multiple sclerosis (MS) has significant usefulness in clinical and investigational settings. Conventional MRI of the SC is used in clinical practice, because it has both diagnostic and prognostic value. A number of advanced, quantitative SC MRI measures that assess the structural and functional integrity of the SC have been evaluated in investigational settings. These techniques have collectively demonstrated usefulness in providing insight into microstructural and functional changes relevant to disability in MS. With further development, these techniques may be useful in clinical trial settings as biomarkers of neurodegeneration and protection, and in day-to-day clinical practice.

Autologous and allogeneic stem-cell transplantation for transformed follicular lymphoma: a report of the Canadian blood and marrow transplant group.

PURPOSE: To determine whether autologous (auto) or allogeneic (allo) stem-cell transplantation (SCT) improves outcome in patients with transformed follicular lymphoma compared with rituximab-containing chemotherapy alone. PATIENTS AND METHODS: This was a multicenter cohort study of patients with follicular lymphoma and subsequent biopsy-proven aggressive histology transformation. Patient, treatment, and outcome data were collected from each transplantation center and combined for analysis. A separate control group was composed of patients with transformation treated with rituximab-containing chemotherapy but not SCT. The primary end point was overall survival (OS) after transformation. RESULTS: One hundred seventy-two patients were identified: 22 (13%) treated with alloSCT, 97 (56%) with autoSCT, and 53 (31%) with rituximab-containing chemotherapy. Five-year OS after transformation was 46% for patients treated with alloSCT, 65% with autoSCT, and 61% with rituximab-containing chemotherapy (P = .24). Five-year progression-free survival (PFS) after transformation was 46% for those treated with alloSCT, 55% with autoSCT, and 40% with rituximab-containing chemotherapy (P = .12). In multivariate analysis, patients treated with autoSCT had improved OS compared with those who received rituximab-containing chemotherapy (hazard ratio [HR], 0.13; 95% CI, 0.05 to 0.34; P < .001). On the other hand, there was no OS difference between those treated with alloSCT and rituximab-containing chemotherapy (HR, 0.44; 95% CI, 0.16 to 1.24; P = .12). OS and PFS after SCT were similar between those treated with autoSCT and alloSCT. Five-year transplantation-related mortality was 23% for those treated with alloSCT and 5% for autoSCT. CONCLUSION: Patients undergoing autoSCT had better outcomes than those treated with rituximab-containing chemotherapy alone. AlloSCT did not improve outcome compared with rituximab-containing chemotherapy and was associated with clinically significant toxicity.