Is there a prodrome to NMOSD? An investigation of neurologic symptoms preceding the first NMOSD attack.

BACKGROUND: It is unknown whether people with aquaporin-4 antibody positive (AQP4-IgG+) neuromyelitis optica spectrum disorder (NMOSD) experience a prodrome, although a few cases report AQP4 + serology up to 16 years before the first attack. OBJECTIVES: To evaluate whether individuals with AQP4-IgG + NMOSD have prodromal neurologic symptoms preceding the first attack. METHODS: We reviewed medical records of participants meeting the 2015 diagnostic criteria for AQP4-IgG + NMOSD from four demyelinating disease centres in the Canadian NMOSD cohort study CANOPTICS. We searched for neurologic symptoms occurring at least 30 days before the first attack. RESULTS: Of 116 participants with NMOSD, 17 (14.7%) had prodromal neurologic symptoms. The median age was 48 years (range 25-83) at first attack; 16 (94.1%) were female. Participants presented with numbness/tingling (n = 9), neuropathic pain (n = 5), visual disturbance (n = 4), tonic spasms (n = 2), Lhermitte sign (n = 2), severe headache (n = 2), incoordination (n = 2), weakness (n = 1), psychosis (n = 1) or seizure (n = 1). Of eight who underwent magnetic resonance imaging (MRI) brain, orbits and/or spinal cord, five had T2 lesions. Within 1.5-245 months (median 14) from the onset of prodromal neurologic symptoms, participants experienced their first NMOSD attack. CONCLUSIONS: One in seven people with NMOSD experienced neurologic symptoms before their first attack. Further investigation of a possible NMOSD prodrome is warranted.

Investigation of health care use and a possible prodrome before the first attack in NMOSD and MOGAD.

BACKGROUND: Prodromal phases are well recognized in many inflammatory and neurodegenerative diseases, including multiple sclerosis. We evaluated the possibility of a prodrome in aquaporin-4 antibody positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD) using health administrative data. METHODS: We investigated individuals with AQP4 + NMOSD and MOGAD, confirmed by medical chart review, in Ontario, Canada. Each NMOSD and MOGAD participant was matched 1:5 to general population controls by sex, birth year, immigrant status, and region. Total outpatient visits and hospitalizations were compared in the 5 years preceding the incident attack in multivariable negative binomial models. RESULTS: We identified 96 people with AQP4 + NMOSD, matched to 479 controls, and 61 people with MOGAD, matched to 303 controls. In the 5 years preceding the incident attack, health care use was elevated for outpatient visits and hospitalizations for the NMOSD cohort (adjusted rate ratio (aRR): 1.47; 95% confidence interval (CI): 1.25-1.73; aRR: 1.67; 95% CI: 1.19-2.36, respectively) but not for MOGAD. Rate ratios steadily increased in NMOSD for outpatient visits in the 2 years preceding the incident attack. CONCLUSION: Our findings support a prodromal phase preceding clinical onset of AQP4 + NMOSD. Earlier recognition and management of NMOSD patients may be possible.

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.

CNS demyelination after initiating the tyrosine kinase inhibitor imatinib: A report of two cases.

The tyrosine kinase inhibitor, imatinib, used to treat certain malignancies, is in clinical trials as a potential treatment for multiple sclerosis and acute stroke. This is the first report of cases of multifocal central nervous system (CNS) demyelination following exposure to imatinib. One case was severe with bilateral optic neuritis and transverse myelitis that was AQP4 IgG and myelin oligodendrocyte glycoprotein (MOG) IgG negative and improved after plasma exchange and withdrawal of imatinib. The second case involved a unilateral optic neuritis with magnetic resonance imaging (MRI) brain confirming other demyelinating lesions. Although the mechanism is unknown, demyelination on imatinib could be related to activation of previously normal T-cells.

Diet quality and risk of multiple sclerosis in two cohorts of US women.

OBJECTIVE: To determine the association between measures of overall diet quality (dietary indices/patterns) and risk of multiple sclerosis (MS). METHODS: Over 185,000 women in the Nurses' Health Study (NHS) and Nurses' Health Study II (NHSII) completed semiquantitative food frequency questionnaires every 4 years. There were 480 MS incident cases. Diet quality was assessed using the Alternative Healthy Eating Index-2010 (AHEI-2010), Alternate Mediterranean Diet (aMED) index, and Dietary Approaches to Stop Hypertension (DASH) index. Principal component analysis was used to determine major dietary patterns. We calculated the hazard ratio (HR) of MS with Cox multivariate models adjusted for age, latitude of residence at age 15, body mass index at age 18, supplemental vitamin D intake, and cigarette smoking. RESULTS: None of the dietary indices, AHEI-2010, aMED, or DASH, at baseline was statistically significantly related to the risk of MS. The principal component analysis identified "Western" and "prudent" dietary patterns, neither of which was associated with MS risk (HR, top vs bottom quintile: Western, 0.81 (p = 0.31) and prudent, 0.96 (p = 0.94)). When the analysis was repeated using cumulative average dietary pattern scores, the results were unchanged. CONCLUSION: There was no evidence of an association between overall diet quality and risk of developing MS among women.

An observational comparison of natalizumab vs. fingolimod using JCV serology to determine therapy.

BACKGROUND: The lack of prospective trial data comparing certain multiple sclerosis (MS) therapies could be addressed with observational research. OBJECTIVE: The objective of this paper is to investigate outcomes of natalizumab versus fingolimod treatment in an MS cohort using a novel method of patient selection. METHODS: We reviewed entries from our clinic's database for all relapsing-remitting MS patients started on fingolimod and natalizumab where JCV serology was used to determine treatment. We analyzed each group for time to first relapse and in a second analysis, time to first relapse or gadolinium-enhancing lesion. RESULTS: Sixty-nine patients on natalizumab and 36 on fingolimod met our inclusion criteria and had adequate follow-up for analysis. The baseline clinical characteristics at the time of treatment switch were similar. With a mean follow-up of 1.5 years for both treatment groups, there was a trend favoring natalizumab in time to first relapse, although this was not statistically significant (2.20 (0.87, 5.55) p = 0.095). There was a significant difference in the secondary outcome, time to relapse or gadolinium-enhancing lesion (2.31 (1.03, 5.17) p = 0.041), favoring natalizumab. Adjusted analyses favored natalizumab for both outcomes (p < 0.05). CONCLUSION: This work employed an observational study design where treatment allocation by JCV serology allowed for treatment groups with well-balanced characteristics.

A case report of cavernous sinus syndrome in a patient with Takayasu's arteritis.

Neurologists must entertain a broad differential diagnosis when considering a patient with cavernous sinus syndrome, including neoplasm, trauma, vascular causes, inflammatory processes, and infections. We report the case of a 37-year-old woman initially diagnosed with cavernous sinus syndrome, where subsequent investigations revealed findings of Takayasu's arteritis, a large vessel vasculitis. The patient also tested positive for perinuclear antineutrophil cytoplasmic antibodies, suggesting the possibility of a vasculitic spectrum disorder although no clinical features of Wegener's granulomatosis were present. Criteria for Takayasu's arteritis and its protean neurologic manifestations are reviewed. This case highlights the spectrum of vasculitic conditions that may be associated with cavernous sinus inflammation.

Myelin oligodendrocyte glycoprotein antibody titers by fixed cell-based assay: positive predictive value and impact of sample collection timing.

Introduction: In January 2023, our laboratory began performing serum myelin oligodendrocyte glycoprotein antibody (anti-MOG) titers by fixed cell-based assay (CBA). As a quality assurance (QA) assessment, we evaluated titer positive predictive value (PPV) as well as impact of sample collection timing on titers. Methods: Among patients who underwent antibody titers to distinguish between low-positive (<1:100) and clear-positive (≥1:100) anti-MOG, records were reviewed to classify results as true-positive (TP) or false-positive (FP) and facilitate PPV calculation. Timing of sample collection relative to administration of immunotherapy and symptom onset was determined for TP results. Results: Overall PPV of anti-MOG was 70/85 (82%). The PPV of low-positive anti-MOG was significantly lower than clear-positive anti-MOG (72% vs. 95%, p = 0.009). The difference in PPV between low-positive and clear-positive anti-MOG was significant among adults tested, but not children. Among patients with TP anti-MOG, the proportion who received immunotherapy prior to sample collection was significantly higher and median time from symptom onset to sample collection was significantly longer for low-positive compared to clear-positive results. Conclusion: Overall PPV of anti-MOG testing by fixed CBA was reasonably high. The PPV of low-positive anti-MOG was significantly lower than clear-positive anti-MOG. This was driven by the significantly lower PPV of low-positive anti-MOG in adults, possibly reflecting the lower prevalence of MOG antibody-associated disease among adults tested. Timing of sample collection relative to administration of immunotherapy and symptom onset may substantially impact titers, indicating that testing should ideally be performed prior to immunotherapy and close to time of attack.

Proportion of Life Spent in Canada and the Incidence of Multiple Sclerosis in Permanent Immigrants.

BACKGROUND AND OBJECTIVES: While immigrants to high-income countries have a lower risk of multiple sclerosis (MS) compared with host populations, it is unknown whether this lower risk among immigrants increases over time. Our objective was to evaluate the association between proportion of life spent in Canada and the hazard of incident MS in Canadian immigrants. METHODS: We conducted a population-based retrospective cohort study in Ontario, using linked health administrative databases. We followed immigrants, who arrived in Ontario between 1985 and 2003, from January 1, 2003, to December 31, 2016, to record incident MS using a validated algorithm based on hospital admission or outpatient visits. We derived proportion of life spent in Canada based on age at arrival and time since immigration obtained from linked immigration records. We used multivariable proportional hazard models, adjusting for demographics and comorbidities, to evaluate the association between proportion of life in Canada and the incidence of MS, where proportion of life was modelled using restricted cubic spline terms. We further evaluated the role of age at migration (15 or younger vs older than 15 years), sex, and immigration class in sensitivity analyses. RESULTS: We included 1.5 million immigrants (49.9% female, mean age 35.9 [SD 14.2] years) who had spent a median of 20% (Q1-Q3 10%-30%) of their life in Canada. During a mean follow-up of 13.9 years (SD 1.0), 934 (0.44/100,000 person-years) were diagnosed with MS. Compared with the median, a higher risk of MS was observed at higher values of proportion of life spent (e.g., hazard ratio [70% vs 20% proportion of life] 1.38; 1.07-1.78). This association did not vary by sex (p(sex × proportion of life) = 0.70) or immigration class (p(immigration class × proportion of life) = 0.13). The results did not vary by age at migration but were statistically significant only at higher values of proportion of life for immigrants aged 15 years or younger at arrival. DISCUSSION: The risk of incident MS in immigrants varied with the proportion of life spent in Canada, suggesting an acculturation effect on MS risk. Further work is required to understand environmental and sociocultural factors driving the observed association.

Predicting time to serologic diagnosis of AQP4+ NMOSD based on clinical factors and social determinants of health.

BACKGROUND: Early serologic diagnosis and initiation of targeted therapy are associated with better outcomes in aquaporin-4 IgG positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD). OBJECTIVE: To determine predictors of time to serologic diagnosis of AQP4+ NMOSD. METHODS: In CANOPTICS, a multi-centre, Canadian cohort study of NMOSD, we retrospectively evaluated time from the first clinical attack to first positive AQP4-IgG serology. We used a multivariable negative binomial regression model to evaluate possible predictors of time to diagnosis. RESULTS: We identified 129 participants with AQP4+ NMOSD from 7 centres. Diagnostic delay of >1 month was observed in 82 (63.6 %). Asian compared to European (White) ethnicity (IRR:0.40, 95 % CI:0.21-0.78), female sex (IRR:0.56, 95 % CI:0.32-0.99), later calendar year (IRR:0.84, 95 % CI:0.81-0.86), and hospitalization for the first attack (IRR:0.35, 95 % CI:0.20-0.62) were associated with shorter times to serologic diagnosis. We did not observe any overall effect of Afro-Caribbean ethnicity, but in exploratory analyses, Afro-Caribbean individuals with low income had longer times to diagnosis. CONCLUSION: More than 60 % of patients with NMOSD experienced delays to AQP4-IgG serologic diagnosis in this cohort. Given evidence of more adverse long-term outcomes in Afro-Caribbean individuals with NMOSD, intersectional effects of ethnicity and social determinants of health merit further study.

A Canadian case control study investigating demographic and environmental factors associated with MOGAD.

BACKGROUND: Little is known about demographic and environmental factors associated with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). OBJECTIVE: To investigate factors associated with MOGAD using a case-control design and validated questionnaire from the Environmental Risk Factors in Multiple Sclerosis Study (EnvIMS). METHODS: We enrolled patients with positive MOG antibody serology and diagnosis of MOGAD at six Canadian centres. MOGAD participants completed the EnvIMS questionnaire, and were compared to unaffected controls from the Canadian arm of EnvIMS. We calculated crude and adjusted odds ratios (OR) using logistic regression models and Firth's procedure for rare events. RESULTS: We enrolled 39 MOGAD participants with mean (SD) age 45.0 (14.4) years, 28 (71.8 %) women, 25 (64.1 %) White, 26 (66.7 %) residents of Ontario, and mean BMI 28.6 (7.1). They were compared to 956 controls. Using multivariable logistic regression, larger body size at age 10 years (OR: 3.57, 95 % CI:1.23 - 10.33) and non-White ethnicity (OR:3.81, 95 % CI:1.93-7.54) were associated with higher odds of MOGAD. Among Ontario residents, current BMI ≥30 was associated with higher odds of MOGAD (OR:2.79, 95 % CI:1.03-7.53). CONCLUSION: Our findings are hypothesis-generating due to the sample size, but suggest that obesity and ethnicity should be explored as potential risk factors for MOGAD in other settings.

Chronic Cognitive Impairment in AQP4+ NMOSD With Improvement in Cognition on Eculizumab: A Report of Two Cases.

Cognitive impairment may be associated with aquaporin-4 antibody positive (AQP4+) NMOSD, particularly where there is prominent cerebral, corpus callosum, or thalamic involvement. It is unclear to what extent this phenomenon may be treatable after months to years. We describe two cases of AQP4+ NMOSD with cognitive impairment persisting over more than 6 months, where cognition improved after eculizumab was initiated. In the first case, a 51-year-old woman presented with a 2-month history of cognitive decline and ataxia, and diffuse involvement of the corpus callosum on MRI. AQP4 antibody testing returned positive. Cognitive impairment persisted on therapy with mycophenolate, then rituximab. She was switched to eculizumab from rituximab 18 months after disease onset because of breakthrough optic neuritis; memory and cognitive function improved on eculizumab. In the second case, a 26-year-old woman initially presented with visual, auditory and tactile hallucinations, and impairment in activities of daily living, and was given a diagnosis of schizophrenia. Nine months later she was hospitalized for increasing confusion. MRI showed leukoencephalopathy and diffuse involvement of the corpus callosum with multiple enhancing callosal lesions. AQP4 antibody testing was positive and CSF testing for other antibodies of autoimmune encephalitis was negative. She had some improvement in cognition with high dose corticosteroids but remained significantly impaired. On follow-up, her repeat MRI showed a small new right inferomedial frontal enhancing lesion although she did not complain of any new cognitive issues, her MOCA score was 21/30, and she was started on eculizumab. Two months after eculizumab initiation she and her family reported cognitive improvement and MOCA score was 25/30. Common features of these two cases included extensive callosal involvement and an element of ongoing gadolinium enhancement on MRI. Our experience suggests the possibility that cognitive impairment may be amenable to immunotherapy in certain cases of NMOSD.

A window into the future? MRI for evaluation of neuromyelitis optica spectrum disorder throughout the disease course.

Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing, inflammatory disease of the central nervous system marked by relapses often associated with poor recovery and long-term disability. Magnetic resonance imaging (MRI) is recognized as an important tool for timely diagnosis of NMOSD as, in combination with serologic testing, it aids in distinguishing NMOSD from possible mimics. Although the role of MRI for disease monitoring after diagnosis is not as well established, MRI may provide important prognostic information and help differentiate between relapses and pseudorelapses. Increasing evidence of subclinical disease activity and the emergence of newly approved, highly effective immunotherapies for NMOSD adjure us to re-evaluate MRI as a tool to guide optimal treatment selection and escalation throughout the disease course. In this article we review the role of MRI in NMOSD diagnosis, prognostication, disease monitoring, and treatment selection.

Increasing use of disease modifying drugs for MS in Canada.

BACKGROUND/OBJECTIVES: The course of multiple sclerosis may be slowed by use of the disease modifying drugs (DMDs): subcutaneous or intramuscular interferon beta-1a, interferon beta-1b, glatiramer acetate, and natalizumab. We set out to compare utilization of these drugs in the Canadian provinces from 2002-2007. METHODS: Using a retrospective cohort analysis, we reviewed population data from International Medical Statistics (IMS) Health between November 2001 and October 2007. RESULTS: The total annual number of DMD prescriptions increased from 3.9, in 2002, to 5.1, in 2007, per 1,000 Canadians. The total annual cost of prescriptions rose from $187 million to $287 million. Of the four provinces responsible for the majority of prescriptions--Alberta, BC, Ontario, and Quebec--Quebec had the highest average annual prescription rate (7 per 1,000 population) and BC had the lowest rate (3.3 per 1,000 population). Subcutaneous interferon beta-1a was the most commonly used drug whereas glatiramer acetate showed the greatest growth in use from 2002 to 2007. CONCLUSIONS: Disease modifying drugs prescription rates and costs increased by more than 30% between 2002 and 2007. There was wide variation in DMD prescription rates and relative drug preferences across the provinces.

Health service utilization in immigrants with multiple sclerosis.

BACKGROUND: Access to neurology specialty care can influence outcomes in individuals with multiple sclerosis (MS), but may vary based on patient sociodemographic characteristics, including immigration status. OBJECTIVE: To compare health services utilization in the year of MS diagnosis, one year before diagnosis and two years after diagnosis in immigrants versus long-term residents in Ontario, Canada. METHODS: We identified incident cases of MS among adults aged 20-65 years by applying a validated algorithm to health administrative data in Ontario, Canada, a region with universal health insurance and comprehensive coverage. We separately assessed hospitalizations, emergency department (ED) visits, outpatient neurology visits, other outpatient specialty visits, and primary care visits. We compared rates of health service use in immigrants versus long-term residents using negative binomial regression models with generalized estimating equations adjusted for age, sex, socioeconomic status, urban/rural residence, MS diagnosis calendar year, and comorbidity burden. RESULTS: From 2003 to 2014, there were 13,028 incident MS cases in Ontario, of whom 1,070 (8.2%) were immigrants. As compared to long-term residents, rates of hospitalization were similar (Adjusted rate ratio (ARR) 0.86; 95% CI: 0.73-1.01) in immigrants the year before MS diagnosis, but outpatient neurology visits (ARR 0.93; 95% CI: 0.87-0.99) were slightly less frequent. However, immigrants had higher rates of hospitalization during the diagnosis year (ARR 1.20, 95% CI: 1.04-1.39), and had greater use of outpatient neurology (ARR 1.17, 95% CI: 1.12-1.23) but fewer ED visits (ARR 0.86; 95% CI: 0.78-0.96). In the first post-diagnosis year, immigrants continued to have greater numbers of outpatient neurology visits (ARR 1.16; 95% CI: 1.10-1.23), but had fewer hospitalizations (ARR 0.79; 95% CI: 0.67-0.94). CONCLUSIONS: Overall, our findings were reassuring concerning health services access for immigrants with MS in Ontario, a publicly funded health care system. However, immigrants were more likely to be hospitalized despite greater use of outpatient neurology care in the year of MS diagnosis. Reasons for this may include more severe disease presentation or lack of social support among immigrants and warrant further investigation.

MS risk in immigrants in the McDonald era: A population-based study in Ontario, Canada.

OBJECTIVE: To determine risk factors for multiple sclerosis (MS) in immigrants and to compare MS risk in immigrants and long-term residents in Ontario, Canada. METHODS: We applied a validated algorithm to linked, population-based immigration and health claims data to identify incident cases of MS in immigrants and long-term residents between 1994 and 2016. We conducted 2 multivariable Cox proportional hazards regression analyses: 1 analysis limited to the immigrant cohort assessing potential risk factors for developing MS, and 1 analysis comparing MS risk between immigrants and matched long-term residents (1:3 match). RESULTS: We identified 2,304,302 immigrants for the immigrant-only analysis, of whom 1,526 (0.066%) developed MS. Risk was greatest in those <15 years old at landing (referent <15 years; 16-30 years: hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.63-0.85; 31-45 years: HR 0.55, 95% CI 0.47-0.64). Immigrants from the Middle East (HR 1.22, 95% CI 1.06-1.40) were at greater MS risk than immigrants from Western nations; all other regions had lower risk (p < 0.0001). The matched analysis included 2,207,751 immigrants and 6,362,169 long-term residents. Immigrants were less likely to develop MS than long-term residents (p < 0.0001), although this lower risk was attenuated with longer residence in Canada. CONCLUSIONS: MS incidence in immigrants to Ontario, Canada, varied widely by region of origin, with greatest risk seen in those from the Middle East. Longer residence in Canada was associated with increased risk, even with migration in adulthood, suggesting that environmental exposures into adulthood contribute to MS risk.