Patterns and utility of myelin oligodendrocyte glycoprotein (MOG) antibody testing in cerebrospinal fluid.

BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is an idiopathic central nervous system (CNS) demyelinating disease gaining recognition with wider availability of cell-based assay (CBA) testing and recently published diagnostic criteria. However, uncertainty remains regarding the interpretation of antibody titers, particularly cerebrospinal fluid (CSF) MOG antibody titers. METHODS: All MOG IgG CBA results performed by the provincial MitogenDx laboratory in Alberta from July 2017 to July 2023 were retrieved. Chart review was performed in patients with both serum and CSF testing and ≥ 1 positive MOG antibody result. Demographics, antibody titers, clinical and imaging features, treatment, and diagnosis were analyzed based on serum/CSF status. RESULTS: Among 4494 MOG CBA assays, there were 413 CSF samples in 402 patients, and 268 patients had at least one associated serum sample. Mean time between CSF and serum testing was 20.9 days (range 0-870 days), most with testing within 30 days. Five of the 268 patients had serum positive/CSF positive MOG antibodies, 4 with acute disseminated encephalomyelitis and 1 with longitudinally extensive transverse myelitis. Twenty-three patients had serum positive/CSF negative MOG and 13/23 with optic neuritis. CSF MOG antibody positive patients were younger, and more likely to remain MOG seropositive versus CSF negative patients. No seronegative patient had MOG antibodies in CSF. CONCLUSIONS: In province-wide testing, CSF MOG antibodies were rare, only in MOG seropositive patients and none with optic neuritis. Our study does not support a clear role for CSF MOG antibody testing in the majority of patients, although further study is required.

A Clinical Approach to Existing and Emerging Therapeutics in Neuromyelitis Optica Spectrum Disorder.

PURPOSE OF REVIEW: Neuromyelitis optica spectrum disorder (NMOSD) is a rare but highly disabling disease of the central nervous system. Unlike multiple sclerosis, disability in NMOSD occurs secondary to relapses that, not uncommonly, lead to blindness, paralysis, and death. Recently, newer, targeted immunotherapies have been trialed and are now in the treatment arsenal. We have endeavoured to evaluate the current state of NMOSD therapeutics. RECENT FINDINGS: This review provides a pragmatic evaluation of recent clinical trials and post-marketing data for rituximab, inebilizumab, satralizumab, eculizumab, and ravalizumab, contrasted to older agents. We also review contemporary issues such as treatment in the context of SARS-CoV2 infection and pregnancy. There has been a dramatic shift in NMOSD morbidity and mortality with earlier and improved disease recognition, diagnostic accuracy, and the advent of more effective, targeted therapies. Choosing a maintenance therapy remains nuanced depending on patient factors and accessibility. With over 100 putative agents in trials, disease-free survival is now a realistic goal for NMOSD patients.

A national case-control study investigating demographic and environmental factors associated with NMOSD.

BACKGROUND: Risk factors for aquaporin-4 (AQP4+) antibody neuromyelitis optica spectrum disorder (NMOSD) are not well-established. OBJECTIVE: To investigate demographic and environmental factors associated with NMOSD using a validated questionnaire and case-control design. METHODS: We enrolled patients with AQP4 + NMOSD through six Canadian Multiple Sclerosis Clinics. Participants completed the validated Environmental Risk Factors in Multiple Sclerosis Study (EnvIMS) questionnaire. Their responses were compared to those of 956 unaffected controls from the Canadian arm of EnvIMS. We calculated odds ratios (ORs) for the association between each variable and NMOSD using logistic regression and Firth's procedure for rare events. RESULTS: In 122 participants (87.7% female) with NMOSD, odds of NMOSD in East Asian and Black participants were ⩾8 times that observed in White participants. Birthplace outside Canada was associated with an increased risk of NMOSD (OR = 5.5, 95% confidence interval (CI) = 3.6-8.3) as were concomitant autoimmune diseases (OR = 2.7, 95% CI = 1.4-5.0). No association was observed with reproductive history or age at menarche. CONCLUSION: In this case-control study, risk of NMOSD in East Asian and Black versus White individuals was greater than that observed in many previous studies. Despite the preponderance of affected women, we did not observe any association with hormonal factors such as reproductive history or age at menarche.

A Quality Assessment of Aquaporin-4 & Myelin Oligodendrocyte Glycoprotein Antibody Testing.

BACKGROUND: Accurate anti-aquaporin-4 (AQP4) and anti-myelin oligodendrocyte glycoprotein (MOG) autoantibody assays are needed to effectively diagnose neuromyelitis optica spectrum disorder and MOG antibody-associated disease. A proportion of patients at our centre have been tested for anti-AQP4 and anti-MOG autoantibodies locally, followed by an outsourced test as part of real-world practice. Outsourced testing is costly and of unproven utility. We conducted a quality improvement project to determine the value of outsourced testing for anti-AQP4 and anti-MOG autoantibodies. METHODS: All patients seen by Calgary neurological services who underwent cell-based testing for anti-AQP4 and/or anti-MOG autoantibodies at both MitogenDx (Calgary, AB) and Mayo Clinic Laboratories (Rochester, MN, USA) between 2016 and 2020 were identified from a provincial database. The interlaboratory concordance was calculated by pairing within-subject results collected no more than 365 days apart. Retrospective chart review was done for subjects with discordant results to determine features associated with discordance and use of outsourced testing. RESULTS: Fifty-seven anti-AQP4 and 46 anti-MOG test pairs from January 2016 to July 2020 were analyzed. Concordant tests pairs comprised 54/57 (94.7%, 95%CI 88.9-100.0%) anti-AQP4 and 41/46 (89.1%, 95%CI 80.1-98.1%) anti-MOG results. Discordant anti-AQP4 pairs included two local weak positives (negative when outsourced) and one local negative (positive when outsourced). Discordant anti-MOG pairs were all due to local weak positives (negative when outsourced). CONCLUSION: Interlaboratory discordant results for cell-based testing of anti-AQP4 autoantibodies were rare. Local anti-MOG weak positive results were associated with discordance, highlighting the need for cautious interpretation based on the clinical context. Our findings may reduce redundant outsourced testing.

Discussing the potential for progression with patients newly diagnosed with multiple sclerosis: When, how, and why?

Despite convergent evidence that upwards of 50% of patients with MS transition from a relapsing to progressive phase within 20 years of disease onset, and the recent acknowledgement of the commonality of progression independent of relapses, there remains no consensus regarding the nature and timing of a discussion about the possibility of a secondary progressive phase with relapsing-remitting MS patients. Some neurologists prefer to conduct this at the inaugural visit to provide more information about disease behaviour and potential planning that might entail, while others may defer any discussion about this phase, as there is no clear consensus for it and it can be a sensitive topic, with concern that too early a discussion could worsen anxiety and discourage or delay decisions regarding disease modifying treatments. Furthermore, it is unknown at onset which patients will transition to a progressive phenotype. This review and opinion paper will outline some of the opportunities and challenges associated with such a disclosure, and attempt to provide a balanced, patient-centred approach to address this delicate topic.

Contemporary management challenges in seropositive NMOSD.

Neuromyelitis optica spectrum disorders (NMOSD) is an inflammatory disorder of the central nervous system that presents unique management challenges. Neurologic disability in NMOSD is directly linked to acute attacks, therefore, relapse prevention is an overarching goal of care. To this end, identifying effective biomarkers that predict relapse onset and severity is of critical importance. As treatment becomes more precision-based and patient-centred, clinicians will need to be familiar with managing circumstances of particular vulnerability for patients with NMOSD, including infection, pregnancy, and the post-partum phase. The discovery of the pathogenic aquaporin-4 Immunoglobulin G (AQP4 IgG) autoantibody almost 20 years ago ultimately distinguished NMOSD as an autoimmune astrocytopathy and helped spearhead recent therapeutic advancements. Targeted therapies, including eculizumab, satralizumab, and inebilizumab, approved for use in aquaporin-4 immunoglobulin G (AQP4 IgG) seropositive patients with NMOSD will likely improve outcomes, but there are formidable costs involved. Importantly, seronegative patients continue to have limited therapeutic options. Moving forward, areas of research exploration should include relapse prevention, restorative therapies, and initiatives that promote equitable access to approved therapies for all people living with NMOSD.

Longitudinally extensive transverse myelitis with positive aquaporin-4 IgG associated with dengue infection: a case report and systematic review of cases.

BACKGROUND: Neuromyelitis Optica Spectrum Disorder can be associated with parainfectious and post-infectious triggers. Dengue virus infection is one of the most common arbovirus infections in the world, and may present with neurological manifestations. OBJECTIVES: We present a case of DENV-associated with LETM and positive aquaporin-4 IgG, and a systematic review of published cases. METHODS: Medline (Ovid) and PubMed were search through June 2021, for case reports, series and observational studies that described patients with DENV-associated LETM and/or NMOSD. RESULTS: An adolescent girl who had recently immigrated from a Dengue-endemic region presented with a LETM with high positive AQP4-IgG titer and seropositive DENV IgM/IgG antibodies. She responded well to steroids and subsequently started maintenance rituximab for her NMOSD diagnosis. LITERATURE REVIEW: 22 publications describing 27 patients met inclusion criteria. In addition to this case, three published cases met current criteria for NMOSD with serological evidence of acute DENV infection. CONCLUSIONS: It is unknown whether there is a pathophysiological association between DENV infection and NMOSD. Regardless, if an immune-mediated event is suspected, particularly NMOSD, appropriate immunotherapy should be considered early. Decision regarding long term immunotherapy may depend on index of suspicion of true NMOSD, and this is where AQP4-IgG status and follow-up is helpful.

A pilot trial of autologous hematopoietic stem cell transplant in neuromyelitis optic spectrum disorder.

BACKGROUND: Autologous hematopoietic stem cell transplantation (AHSCT) has become a standard treatment in multiple sclerosis. The role of AHSCT for neuromyelitis optica spectrum disorder (NMO/NMOSD) is unclear. We studied AHSCT in NMO/NMOSD patients who have failed conventional immunosuppressive therapy. METHODS: Eligible patients received AHSCT with cyclophosphamide, rabbit antithymocyte globulin, and rituximab and followed for ≥ five years. The primary outcome was relapse-free status at year three. Additional outcomes included relapse status at year five, relapse rate, EDSS, MRI activity, and overall survival. RESULTS: Between 2010-2016, three patients were enrolled. One patient has had no evidence of disease activity over 10 years, one had improvement in relapse rate and EDSS but did have a breakthrough clinically and radiologically requiring rituximab at year five, and the third died at year 3.5 due to uncontrollable NMOSD relapses and accumulation of marked disability. CONCLUSION: In our trial, AHSCT appeared safe, and moderately effective with two of three patients showing improvement in disease activity and disability. Future studies should be undertaken to determine the ideal AHSCT conditioning and the characteristics of patients likely to enter long-term remission.

Efficacy of Allogeneic Hematopoietic Cell Transplantation for Autoimmune Diseases.

Allogeneic hematopoietic cell transplantation (HCT) may be efficacious for autoimmune diseases (AIDs), but its efficacy for individual AIDs is unknown. Factors influencing the likelihood of relapse for each AID are also unknown. This study aimed to determine the likelihood of relapse for each common AID and to generate hypotheses about factors influencing the likelihood of relapse. We reviewed charts of adult patients with nonhematologic AIDs who had undergone HCT in Alberta (n = 21) and patients described in the literature (n = 67). We used stringent inclusion criteria to minimize the inclusion of patients whose AID may have been cured before transplantation. We also used stringent definitions of AID relapse and remission. AID relapsed in 2 of 9 patients (22%) with lupus, in 4 of 12 (33%) with rheumatoid arthritis (RA), in 0 of 4 (0%) with systemic sclerosis (SSc), in 3 of 16 (19%) with psoriasis, in 1 of 12 (8%) with Behçet's disease (BD), in 1 of 15 (7%) with Crohn's disease (CD), in 0 of 5 (0%) with ulcerative colitis (UC), in 4 of 8 (50%) with multiple sclerosis (MS), and in 3 of 3 (100%) with type 1 diabetes mellitus (T1DM). Among highly informative patients (followed for >1 year after discontinuation of immunosuppressive therapy if no relapse, or donor AID status known if relapse), relapse occurred in 0 of 3 patients with lupus, in 2 of 7 with RA, in 0 of 2 with SSc, in 3 of 6 with psoriasis, in 0 of 3 with BD, in 0 of 10 with CD, in 0 of 3 with UC, in 2 of 3 with MS, and in 2 of 2 with T1DM. There appeared to be no associations between AID relapse and low intensity of pretransplantation chemoradiotherapy, multiple lines of AID therapy (surrogate for AID refractoriness) except perhaps for lupus, absence of serotherapy for graft-versus-host disease (GVHD) prophylaxis, lack of GVHD except perhaps for lupus, or incomplete donor chimerism. Even though remission commonly occurs after HCT in lupus, RA, SSc, psoriasis, BD, CD, and UC, HCT is efficacious for only a subset of patients. The efficacy appears to be unrelated to pretransplantation therapy, GVHD, or chimerism. Large studies are needed to determine the characteristics of patients likely to benefit from HCT for each AID.

Choosing Wisely Neurology: Recommendations for the Canadian Neurological Society.

BACKGROUND: Choosing Wisely Canada (CWC) is a national branch of a global campaign advocating for fewer unnecessary tests and for optimizing patient care. Professional societies representing physicians, pharmacists, and nurses participate by generating lists of recommendations meant to reduce patient harm and resource mismanagement in healthcare. The Canadian Neurological Society (CNS) plays an important role in advocating for quality patient care demonstrated by deriving specific recommendations. This process is described. METHOD: The CNS Choosing Wisely task force adapted 10 recommendations for Canadian neurology practice. These were approved by the CNS board, and subsequently ranked by CNS members. RESULTS: Ten recommendations were brought forward and ranked in a survey completed by CNS members. Survey ranking is presented. The top five recommendations were selected and optimized, resulting in seven key recommendations. CONCLUSION: The recommendations set forth by the CNS will help with resource stewardship and patient safety in the delivery of neurological care by healthcare providers in Canada.

Area postrema syndrome: A short history of a pearl in demyelinating diseases.

In this topical review, we discuss the history of the area postrema syndrome, with special attention given to early studies aimed at identifying the area postrema and its function, possible early cases of the syndrome and its current relevance in neuroimmunology and demyelinating diseases. In 1896, Retzius named a structure in the posterior medulla oblongata as the area postrema. The work of Borison in the middle of the 20th century led to the elucidation of its function as a "vomiting center." The historical medical literature is filled with excellent examples that could be described as "area postrema syndrome." While severe and bilateral optic neuritis and transverse myelitis still constitute the classic components of neuromyelitis optica spectrum disorder (NMOSD), intractable vomiting and hiccups due to area postrema involvement is now recognized as essentially pathognomonic, indeed a shiny pearl in neuroimmunology and demyelinating diseases.

Neuromyelitis optica spectrum disorder presenting with concurrent autoimmune diseases.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune syndrome characterized by optic nerve and spinal cord inflammation. In recent years, there has been increasing awareness of NMOSD presenting concurrently with other autoimmune diseases, including myasthenia gravis (MG), systemic lupus erythematosus (SLE), Sjögren's syndrome, and sarcoidosis, among others. Whether these diseases coexist in patients due to shared susceptibility to multiple autoimmune conditions as a result of a genetic tendency toward humoral autoimmunity, or whether systemic rheumatologic diseases facilitate some aspect of NMOSD pathogenesis remains an open question. Here, we describe two cases of NMOSD presenting with concurrent autoimmune disease, and highlight the clinical features and diagnostic challenges of each case. Our first patient had aquaporin-4 antibody-positive NMOSD with concurrent hypothyroidism, SLE, and muscle specific kinase antibody-positive MG. Our second patient had seronegative NMOSD with concurrent acetylcholine receptor antibody-positive MG. Practitioners should be aware of the potential for patients to present with a combination of NMOSD and one or more concurrent autoimmune diseases to ensure timely diagnosis and appropriate treatment.

Retinal imaging with optical coherence tomography: a biomarker in multiple sclerosis?

Multiple sclerosis (MS) is a progressive neurological disorder characterized by both inflammatory and degenerative components that affect genetically susceptible individuals. Currently, the cause of MS remains unclear, and there is no known cure. Commonly used therapies tend to target inflammatory aspects of MS, but may not halt disease progression, which may be governed by the slow, subclinical accumulation of injury to neuroaxonal structures in the central nervous system (CNS). A recognized challenge in the field of MS relates to the need for better methods of detecting, quantifying, and ameliorating the effects of subclinical disease. Simply stated, better biomarkers are required. To this end, optical coherence tomography (OCT) provides highly reliable, reproducible measures of axonal damage and neuronal loss in MS patients. OCT-detected decrements in retinal nerve fiber layer thickness and ganglion-cell layer-inner plexiform layer thickness, which represent markers of axonal damage and neuronal injury, respectively, have been shown to correlate with worse visual outcomes, increased clinical disability, and magnetic resonance imaging-measured burden of disease in MS patients. Recent reports have also suggested that OCT-measured microcystic macular edema and associated thickening of the retinal inner nuclear layer represent markers of active CNS inflammatory activity. Using the visual system as a putative clinical model in MS, OCT measures of neuroaxonal structure can be correlated with functional outcomes to help us elucidate mechanisms of CNS injury and repair. In this review, we evaluate evidence from the published literature and ongoing clinical trials that support the emerging role of OCT in diagnosing, staging, and determining response to therapy in MS patients.

The Shifting Landscape of Disease-Modifying Therapies for Relapsing Multiple Sclerosis.

BACKGROUND: Multiple sclerosis (MS) is the most common nontraumatic neurological disorder of young adults, and roughly 85% of patients present with the relapsing form of the disease. Over the past 2 decades, the treatment arsenal for relapsing MS has expanded and evolved from mildly effective and relatively benign injectable agents to potent cell-depleting monoclonal agents. The latter have the potential to achieve disease remission coupled with risk of moderate to severe adverse events with which all MS care providers will need to acquaint themselves. METHODS: This review is based on a detailed assessment of MS pivotal trials, extension studies, and expert reviews of the agents discussed. RESULTS/CONCLUSIONS: The following review should aid those practitioners directly and indirectly involved in the care of MS patients in understanding the benefits and risks associated with the medications they prescribe.

The prevalence of anxiety and associated factors in persons with multiple sclerosis.

BACKGROUND: The prevalence of anxiety and its association with sociodemographic and clinical factors is not well characterized in those with multiple sclerosis (MS). We aimed to estimate the prevalence and examine associated factors of anxiety in persons with MS. METHODS: A cross-sectional analysis was conducted utilizing data from 244 participants from the Neurological Disease and Depression study. Anxiety was assessed using the Hospital Anxiety and Depression Scale (HADS). Descriptive statistics and multiple logistic regression was used to examine anxiety and associated factors. RESULTS: Nearly 30.0% of participants had anxiety according to the HADS. The most prevalent symptom of anxiety was "worrying thoughts" (26.6%). After adjustment for various confounders, depression (OR: 7.31 95% CI 3.29-16.26) was found to be associated with higher odds of anxiety, while lower odds of anxiety were associated with higher education (OR: 0.51, 95% CI 0.28-0.94). Furthermore, anxiety was strongly associated with decreased quality of life. CONCLUSION: Anxiety represents a substantial burden for those with MS and is associated with a variety of adverse outcomes including decreased quality of life. Our results further emphasize the importance of understanding the impact of anxiety in this population.

Refractory Longitudinally Extensive Transverse Myelitis Responsive to Cyclophosphamide.

Severe longitudinally extensive transverse myelitis (LETM) can cause quadriplegia, marked sensory dysfunction, and respiratory failure. Some patients are unresponsive to conventional immune therapy. We report two cases of severe immune-mediated LETM requiring intensive care admission that failed to respond to high-dose corticosteroids, plasma exchange, intravenous immunoglobulin, and rituximab. Disease cessation and significant recovery was achieved after cyclophosphamide induction. In patients with severe acute immune-mediated LETM who fail to respond to corticosteroids and plasma exchange, cyclophosphamide induction should be considered. This agent and regimen provides a robust immunosuppressive response and can be induced rapidly. Cyclophosphamide effects and supportive evidence are discussed.