Combination of serum markers with optical coherence tomography angiography for evaluating neuromyelitis optica spectrum disorders and multiple sclerosis.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS), autoimmune inflammatory diseases of the central nervous system, affect the optic nerve and brain. A lumbar puncture to obtain biomarkers is highly invasive. Serum biomarkers and optical coherence tomography angiography (OCTA) are more accessible and less expensive than magnetic resonance imaging and provide reliable, reproducible measures of neuroaxonal damage. This study investigated the association between serum neurofilament light chain (sNfL), serum glial fibrillary acidic protein (sGFAP), and OCTA metrics. Serum sNfL and sGFAP levels, OCTA values, and clinical characteristics were compared among 91 patients with NMOSD, 81 patients with MS, and 34 healthy controls (HCs) at baseline and 1-year follow-up. RESULTS: sNfL and sGFAP levels were higher while the sGFAP/sNfL quotients were significantly lower in NMOSD and MS patients than those in HCs. At baseline, the average thicknesses of the peripapillary retinal nerve fibre layer (pRNFL) and macular ganglion cell-inner plexiform layer (mGC-IPL) were significantly smaller in NMOSD and MS patients than those in HCs (pRNFL: MS 92.0 [80.2; 101] µm, NMOSD 80.0 [59.0; 95.8] µm, vs HC 99.0 [92.0; 104] µm, p < 0.001; mGC-IPL: MS 74.5 [64.2; 81.0] µm, NMOSD 68.0 [56.0; 81.0] µm, vs HC 83.5 [78.0; 88.0] µm, p < 0.001). The vessel density (VD) and perfusion density (PD) were increased in MS patients without optic neuritis compared to HCs (VD: MS 16.7 [15.6; 17.9] HC 15.3 [13.4; 16.9], p = 0.008; PD: MS 0.41 [0.38; 0.43], HC 0.37 [0.32; 0.41], p = 0.017). In NMOSD patients without optic neuritis, sNfL was significantly associated with PD at baseline (r = 0.329, q = 0.041). The baseline and follow-up values of the sNfL level and average pRNFL and mGC-IPL thicknesses in MS patients showed significant differences. NMOSD patients showed significant differences between baseline and follow-up sNfL and sGFAP levels but not OCTA metrics. CONCLUSION: Changes in retinal microvasculature might occur earlier than those in retinal structure and may therefore serve as a promising diagnostic marker for early NMOSD. The combination of serum markers and OCTA metrics could be used to evaluate and differentiate between MS and NMOSD.

The MOG antibody non-P42 epitope is predictive of a relapsing course in MOG antibody-associated disease.

BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG) IgG seropositivity is a prerequisite for MOG antibody-associated disease (MOGAD) diagnosis. While a significant proportion of patients experience a relapsing disease, there is currently no biomarker predictive of disease course. We aim to determine whether MOG-IgG epitopes can predict a relapsing course in MOGAD patients. METHODS: MOG-IgG-seropositive confirmed adult MOGAD patients were included (n=202). Serum MOG-IgG and epitope binding were determined by validated flow cytometry live cell-based assays. Associations between epitopes, disease course, clinical phenotype, Expanded Disability Status Scale and Visual Functional System Score at onset and last review were evaluated. RESULTS: Of 202 MOGAD patients, 150 (74%) patients had MOG-IgG that recognised the immunodominant proline42 (P42) epitope and 115 (57%) recognised histidine103/serine104 (H103/S104). Fifty-two (26%) patients had non-P42 MOG-IgG and showed an increased risk of a relapsing course (HR 1.7; 95% CI 1.15 to 2.60, p=0.009). Relapse-freedom was shorter in patients with non-P42 MOG-IgG (p=0.0079). Non-P42 MOG-IgG epitope status remained unchanged from onset throughout the disease course and was a strong predictor of a relapsing course in patients with unilateral optic neuritis (HR 2.7, 95% CI 1.06 to 6.98, p=0.038), with high specificity (95%, 95% CI 77% to 100%) and positive predictive value (85%, 95% CI 45% to 98%). CONCLUSIONS: Non-P42 MOG-IgG predicts a relapsing course in a significant subgroup of MOGAD patients. Patients with unilateral optic neuritis, the most frequent MOGAD phenotype, can reliably be tested at onset, regardless of age and sex. Early detection and specialised management in these patients could minimise disability and improve long-term outcomes.

Cutaneous presentation of cryptococcal infection with subclinical central nervous system involvement secondary to fingolimod therapy.

Fingolimod is a multiple sclerosis disease-modifying therapy which sequestrates lymphocytes in the lymph nodes, thereby reducing peripheral blood lymphocytes. Cryptococcal infection is an important adverse effect which should be recognised. We report a case of cutaneous and central nervous system infection who presented with isolated cutaneous symptoms in the absence of neurological or systemic manifestations.

Comparison Between Dimethyl Fumarate, Fingolimod, and Ocrelizumab After Natalizumab Cessation.

Importance: Natalizumab cessation is associated with a risk of rebound disease activity. It is important to identify the optimal switch disease-modifying therapy strategy after natalizumab to limit the risk of severe relapses. Objectives: To compare the effectiveness and persistence of dimethyl fumarate, fingolimod, and ocrelizumab among patients with relapsing-remitting multiple sclerosis (RRMS) who discontinued natalizumab. Design, Setting, and Participants: In this observational cohort study, patient data were collected from the MSBase registry between June 15, 2010, and July 6, 2021. The median follow-up was 2.7 years. This was a multicenter study that included patients with RRMS who had used natalizumab for 6 months or longer and then were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months after natalizumab discontinuation. Patients without baseline data were excluded from the analysis. Data were analyzed from May 24, 2022, to January 9, 2023. Exposures: Dimethyl fumarate, fingolimod, and ocrelizumab. Main Outcomes and Measures: Primary outcomes were annualized relapse rate (ARR) and time to first relapse. Secondary outcomes were confirmed disability accumulation, disability improvement, and subsequent treatment discontinuation, with the comparisons for the first 2 limited to fingolimod and ocrelizumab due to the small number of patients taking dimethyl fumarate. The associations were analyzed after balancing covariates using an inverse probability of treatment weighting method. Results: Among 66 840 patients with RRMS, 1744 had used natalizumab for 6 months or longer and were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months of natalizumab discontinuation. After excluding 358 patients without baseline data, a total of 1386 patients (mean [SD] age, 41.3 [10.6] years; 990 female [71%]) switched to dimethyl fumarate (138 [9.9%]), fingolimod (823 [59.4%]), or ocrelizumab (425 [30.7%]) after natalizumab. The ARR for each medication was as follows: ocrelizumab, 0.06 (95% CI, 0.04-0.08); fingolimod, 0.26 (95% CI, 0.12-0.48); and dimethyl fumarate, 0.27 (95% CI, 0.12-0.56). The ARR ratio of fingolimod to ocrelizumab was 4.33 (95% CI, 3.12-6.01) and of dimethyl fumarate to ocrelizumab was 4.50 (95% CI, 2.89-7.03). Compared with ocrelizumab, the hazard ratio (HR) of time to first relapse was 4.02 (95% CI, 2.83-5.70) for fingolimod and 3.70 (95% CI, 2.35-5.84) for dimethyl fumarate. The HR of treatment discontinuation was 2.57 (95% CI, 1.74-3.80) for fingolimod and 4.26 (95% CI, 2.65-6.84) for dimethyl fumarate. Fingolimod use was associated with a 49% higher risk for disability accumulation compared with ocrelizumab. There was no significant difference in disability improvement rates between fingolimod and ocrelizumab. Conclusion and Relevance: Study results show that among patients with RRMS who switched from natalizumab to dimethyl fumarate, fingolimod, or ocrelizumab, ocrelizumab use was associated with the lowest ARR and discontinuation rates, and the longest time to first relapse.

Cerebrospinal Fluid Chloride Is Associated with Disease Activity of Relapsing-Remitting Multiple Sclerosis: A Retrospective Cohort Study.

BACKGROUND: Blood-brain barrier dysfunction in active multiple sclerosis (MS) lesions leads to pathological changes in the cerebrospinal fluid (CSF). This study aimed to investigate the possible association between routine CSF findings, especially CSF chloride, at the time of the first lumbar puncture and the relapse risk and disability progression of relapsing-remitting MS (RRMS). METHODS: This retrospective study included 77 patients with RRMS at the MS Center of our institution from January 2012 to December 2020. The Anderson and Gill (AG) model and Spearman correlation analysis were used to explore predictors of relapse and disability during follow-up. RESULTS: In the multivariate AG model, patients with elevated CSF chloride level (hazard ratio [HR], 1.1; 95% confidence interval [CI]: 1.06-1.22; p = 0.001) had a high risk of MS relapse. Using median values of CSF chloride (123.2 mmol/L) as a cut-off, patients with CSF chloride level ≥ 123.2 mmol/L had a 120% increased relapse risk compared with those with CSF chloride level < 123.2 mmol/L (HR = 2.20; 95% CI: 1.19-4.05; p = 0.012). CONCLUSIONS: Elevated CSF chloride levels might be a biologically unfavorable predictive factor for disease relapse in RRMS.

Healthcare complexities during community crises: Recommendation for access to healthcare for Australians with multiple sclerosis.

BACKGROUND: In 2019 and 2020, over 17 million hectares of Australia burned, and half of the Australian population was affected by toxic bushfire smoke. Then in 2020, restrictions designed to curtail the spread of COVID-19 resulted in significant changes to healthcare access. There is no Australian emergency management standard for persons with disabilities, including those with multiple sclerosis (MS). Persons with MS often require multidisciplinary and complex care, with continuity of treatment essential to prevent disease progression. OBJECTIVE: To identify limitations in access to healthcare from the perspective of persons with MS as well as MS care providers during recent crises and make recommendations for policy to improve MS healthcare access during a crisis. METHOD: In mid-2020, we undertook online surveys and interviews with persons with MS, their carers, healthcare professionals and staff of MS service providers (i.e., care providers). We used descriptive analysis for quantitative, and a general inductive approach for qualitative data. RESULTS: One-hundred and thirteen persons with MS and a total of 63 MS care providers, who were close carers, healthcare professionals and service providers provided survey responses. For participants with MS, limited access to general practitioners and medical tests were of the most significant concern during the bushfires and the pandemic. In contrast, during the pandemic accessing physiotherapy was another top concern. Twenty-nine people participated in in-depth interviews, revealing that reduced healthcare access during the bushfire and the pandemic caused concern. The use of telehealth received both positive and negative reviews. All participants indicated a need for preparation and planning for healthcare access before a crisis. Persons with MS recommended centralised information sources, prioritised access to healthcare and increased levels of MS nurses and other allied healthcare. Care providers recommended centralised information sources, more nursing and mental health care access, and increased opportunities for multidisciplinary telehealth delivery. CONCLUSIONS: We recommend the involvement of the MS community in creating and designing disaster preparation plans, which should cater to a range of disaster types, to improve disaster preparedness in a community that is vulnerable to increasingly common community crises.

The impact of the Australian Black Summer Bushfires and the COVID-19 pandemic on wellbeing in persons with multiple sclerosis; preparation for future and ongoing crises.

PURPOSE: The Australian multiple sclerosis (MS) community experienced two recent major crises, widespread bushfires and the COVID 19 pandemic. We aimed to understand the needs of persons with MS during times of crisis. MATERIALS AND METHODS: A consumer-directed mixed-method study. We included an online survey, semi-structured interviews, and a workshop with persons with MS, carers, healthcare professionals, and disability advocates. Data were collected via: (1) 176 people completing online surveys to identify crisis concerns and communications, (2) 29 people completing online interviews on bushfire and pandemic impact, and (3) 13 people participating in a crises-priorities workshop. Descriptive data were calculated for survey response, and a general inductive analytical approach was taken with interview and workshop responses. RESULTS: The most significant concerns were bushfire smoke exposure and disease-modifying-medication and susceptibility to COVID-19 (66% and 63% mean concern score, respectively). Interviews indicated crises experiences from the bushfires, and the pandemic overlapped respective of changes in mood and symptom stability. For bushfires, a need for future preparations, and for the pandemic, the benefits of social restrictions, disclosing personal health information and increased care burden were important. CONCLUSIONS: Multiple crises challenged the MS community but offered lessons for healthcare in future crises. Continued progress in centralised crisis information, with considered use of telehealth and rural healthcare support, is needed.Implications for rehabilitationThe MS community showed high concerns for the effect of toxic smoke from the 2019/2020 Australian bushfires and, separately, for the disease-modifying-medication and susceptibility to COVID-19.The MS community placed priority on a crisis management plan for individuals.Reduced social activity due to restrictions was beneficial for MS symptom self-awareness and may help overall fatigue management.Healthcare system preparation must prepare to alleviate increased carer workload at times of crisis.

Clinical and genetic analysis of familial neuromyelitis optica spectrum disorder in Chinese: associated with ubiquitin-specific peptidase USP18 gene variants.

BACKGROUND: Familial clustering of neuromyelitis optica spectrum disorder (NMOSD) was present in Chinese. This study was to investigate the clinical characteristics and genetic background of familial NMOSD. METHODS: Through questionnaires in four medical centres in 2016-2020, we identified 10 families with NMOSD aggregation. The statistical differences of clinical characteristics between familial and sporadic NMOSD (22 cases and 459 cases) were summarised. The whole-exome sequencing (WES) for seven families (13 cases and 13 controls) was analysed, compared with our previous WES data for sporadic NMOSD (228 cases and 1 400 controls). The family-based and population-based association and linkage analysis were conducted to identify the pathogenetic genes, the variant impacts were predicted. RESULTS: The familial occurrence was 0.87% in Chinese. Familial patients had higher expanded disability status scale score than sporadic patients (p=0.03). The single-nucleotide polymorphism (SNP) rs2252257 in the promoter and enhancer of ubiquitin-specific peptidase USP18 was linked to familial NMOSD (p=7.8E-05, logarithm of the odds (LOD)=3.1), SNPs rs361553, rs2252257 and rs5746523 were related to sporadic NMOSD (p=1.29E-10, 3.45E-07 and 2.01E-09, respectively). Patients with the SNP rs361553 T/T genotype had higher recurrence rate than C/T or C/C genotype (1.22±0.85 vs 0.69±0.57 and 0.81±0.65, p=0.003 and 0.001, respectively). SNPs rs361553 and rs2252257 altered USP18 expression in brain and nerve tissues. CONCLUSION: Most clinical characteristics of familial NMOSD were indistinguishable from sporadic NMOSD except for the worst episodes severity. USP18 with impaired intronic regulatory function contributed to the pathogenesis of NMOSD.

Comparing the effectiveness, safety and tolerability of interventions for depressive symptoms in people with multiple sclerosis: a systematic review and network meta-analysis protocol.

BACKGROUND: Comorbid depression is prevalent in people with multiple sclerosis (MS). Depression is commonly untreated or undertreated, thus, there is a need for effective and safe interventions and current guidelines recommend psychological and pharmaceutical interventions for people with MS. However, research suggests that other interventions, such as exercise, could also be effective. The comparative efficacy and safety of intervention modalities have not been quantified.We plan to conduct a systematic review and network meta-analysis to compare efficacy and safety of psychological, pharmaceutical, physical and magnetic stimulation interventions for depression in people with MS. METHODS AND ANALYSIS: We will search EMBASE, Medline, Cochrane CENTRAL, APA PsycINFO, Web of Science, CINAHL and PEDro from inception to 31 December 2021. Search terms will stem from three concepts: MS, depression and randomised controlled trials. Included studies will be randomised controlled trials, where participants are people with MS randomised to receive one of the aforementioned intervention types, and depression or depressive symptoms is the primary outcome, only outcome or secondary outcome with an a priori power calculation. Screening, data extraction and risk of bias assessment (using the Risk of Bias 2 tool) will be conducted independently by two reviewers. If possible, we will synthesise the evidence by fitting a frequentist network meta-analysis model with multivariate random effects, or a pairwise random-effects meta-analysis model. For each model, efficacy will be measured using a standardised mean difference, and safety using an OR. We plan to provide summary measures including forest plots, a geometry of the network, surface under the cumulative ranking curve, and a league table, and perform subgroup analyses. Otherwise, a narrative review will be provided. ETHICS AND DISSEMINATION: Ethics is not required for a systematic review and network meta-analysis. Results will be published in a peer reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42020209803.

Immunosuppressant and neuromyelitis optica spectrum disorder: optimal treatment duration and risk of discontinuation.

BACKGROUND AND PURPOSE: Preventing relapse by immunosuppressants (ISs) is critical for the prognosis of neuromyelitis optica spectrum disorder (NMOSD); however, the optimal duration of IS treatment is still under discussion. The objective was to explore the optimal duration of IS treatment and the risk of IS discontinuation for NMOSD. METHOD: This cohort study was conducted at a major neurological center that housed the largest NMOSD database in South China. Eligible participants were patients with NMOSD undergoing IS treatment. The main outcome measures were changes in relapse risk based on IS treatment duration, clinical outcomes and predictors of relapse following IS discontinuation. RESULTS: In total, 343 patients were included in this study. The duration of IS treatment was strongly associated with a decrease in relapse risk (hazard ratio [HR] 0.53, p < 0.001). Continuous IS treatment resulted in decreased relapse HRs within 5 years of receiving IS medication, with a mild rebound starting at 5 years. Rituximab reduced the risk of NMOSD relapse to approximately zero within 3 years. The rate of relapse after IS withdrawal was high (77.5%). As opposed to other ISs, a delayed relapse following rituximab withdrawal was observed in this study. Longitudinal extensive transverse myelitis (HR = 2.023, p = 0.006) was associated with a higher risk of relapse after IS discontinuation. CONCLUSIONS: Long-term IS medication for NMOSD is generally suitable. Patients with longitudinal extensive transverse myelitis had a higher risk of relapse after IS discontinuation. Future studies should explore individualized strategies of rituximab maintenance treatment.

Circulating Memory B Cells in Early Multiple Sclerosis Exhibit Increased IgA+ Cells, Globally Decreased BAFF-R Expression and an EBV-Related IgM+ Cell Signature.

Multiple sclerosis (MS) is an immune-mediated inflammatory disease of the central nervous system that results in demyelination of axons, inefficient signal transmission and reduced muscular mobility. Recent findings suggest that B cells play a significant role in disease development and pathology. To further explore this, B cell profiles in peripheral blood from 28 treatment-naive patients with early MS were assessed using flow cytometry and compared to 17 healthy controls. Conventional and algorithm-based analysis revealed a significant increase in MS patients of IgA+ memory B cells (MBC) including CD27+, CD27- and Tbet+ subsets. Screening circulating B cells for markers associated with B cell function revealed a significantly decreased expression of the B cell activation factor receptor (BAFF-R) in MS patients compared to controls. In healthy controls, BAFF-R expression was inversely associated with abundance of differentiated MBC but this was not observed in MS. Instead in MS patients, decreased BAFF-R expression correlated with increased production of proinflammatory TNF following B cell stimulation. Finally, we demonstrated that reactivation of Epstein Barr Virus (EBV) in MS patients was associated with several phenotypic changes amongst MBCs, particularly increased expression of HLA-DR molecules and markers of a T-bet+ differentiation pathway in IgM+ MBCs. Together, these data suggest that the B cell compartment is dysregulated in MS regarding aberrant MBC homeostasis, driven by reduced BAFF-R expression and EBV reactivation. This study adds further insights into the contribution of B cells to the pathological mechanisms of MS, as well as the complex role of BAFF/BAFF-R signalling in MS.

Pregnancy outcome following exposure to ocrelizumab in multiple sclerosis.

Background: Ocrelizumab is a monoclonal antibody targeting CD20-expressing B cells used in the treatment of multiple sclerosis (MS). Currently, there is limited safety data in pregnancy. Objectives: To report the pregnancy outcome following exposure to ocrelizumab in MS. Methods: We retrospectively identified 14 pregnancies of 12 MS patients who had been exposed to ocrelizumab within 6 months prior to conception or during pregnancy from a specialty clinic in Western Australia. Results: 13 of 14 pregnancies resulted in live births. One pregnancy was electively terminated following detection of a chromosomal defect. One pregnancy was complicated with placental insufficiency and the infant developed hyaline membrane disease which was complicated by sepsis. There were no observed major congenital anomalies, preterm births, stillbirths or low birthweight. We did not observe any serious maternal infections. All patients were relapse-free despite a mean ocrelizumab-free interval of 65.1 weeks. Conclusions: We did not identify any major safety signals among the patients who received ocrelizumab prior to conception or during the first trimester of pregnancy. Our patients appeared to have a stable disease course despite a prolonged period of treatment interruption during pregnancy.

Gut Microbiome and Bile Acid Metabolism Induced the Activation of CXCR5+ CD4+ T Follicular Helper Cells to Participate in Neuromyelitis Optica Spectrum Disorder Recurrence.

From the perspective of the role of T follicular helper (Tfh) cells in the destruction of tolerance in disease progression, more attention has been paid to their role in autoimmunity. To address the role of Tfh cells in neuromyelitis optica spectrum disorder (NMOSD) recurrence, serum C-X-C motif ligand 13 (CXCL13) levels reflect the effects of the Tfh cells on B-cell-mediated humoral immunity. We evaluated the immunobiology of the CXCR5+CD4+ Tfh cells in 46 patients with NMOSD, including 37 patients with NMOSD with an annual recurrence rate (ARR) of<1 and 9 patients with NMOSD with an ARR of ≥1. Herein, we reported several key observations. First, there was a lower frequency of circulating Tfh cells in patients with an ARR of<1 than in those with an ARR of ≥1 (P< 0.05). Second, the serum CXCL13 levels were downregulated in individuals with an ARR<1 (P< 0.05), processing the ability to promote Tfh maturation and chemotaxis. Third, the level of the primary bile acid, glycoursodeoxycholic acid (GUDCA), was higher in patients with NMOSD with an ARR of<1 than in those with NMOSD with an ARR of ≥1, which was positively correlated with CXCL13. Lastly, the frequency of the Tfh precursor cells decreased in the spleen of keyhole limpet haemocyanin-stimulated animals following GUDCA intervention. These findings significantly broaden our understanding of Tfh cells and CXCL13 in NMOSD. Our data also reveal the potential mechanism of intestinal microbiota and metabolites involved in NMOSD recurrence.

Response to treatment in NMOSD: the Australasian experience.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is associated with significant morbidity and mortality. Several therapies have been recommended for NMOSD and more recently clinical trials have demonstrated efficacy for three monoclonal antibody therapies. We present a retrospective observational study of treatment response in NMOSD. METHODS: This was a retrospective, unblinded, observational study of treatment efficacy for rituximab and traditional immunosuppressive therapy in patients with AQP4 antibody positive NMOSD. Treatment efficacy was assessed using annualised relapse rates (ARR), time to first relapse and expanded disability status scale (EDSS) scores. RESULTS: Complete relapse and treatment data were available for 43/68 (63%) of AQP4 antibody positive NMOSD cases covering 74 episodes of treatment. In a time to first relapse analysis rituximab showed a risk ratio of 0.23 (95% CI 0.08 - 0.65) when compared with no treatment and there was a non-significant reduction in ARR of 35% compared to pre-treatment. ß-interferon (p = 0.0002) and cyclophosphamide (p = 0.0034) were associated with an increased ARR compared to pre-treatment. Rituximab (median 4.0 [range 0.0 - 7.0]; p = 0.042) and traditional immunosuppressive therapy (median 4.0 [range 0.0 - 8.0]; p = 0.016) were associated with a lower final EDSS compared to ß-interferon (median 6.0 [range 4.0 - 7.5]). CONCLUSIONS: These data provide additional support for the use of rituximab in preference to traditional immunosuppressive agents and MS disease modifying therapies as first line treatment of NMOSD.

Posterior reversible encephalopathy syndrome (PRES): diagnosis and management.

Posterior reversible encephalopathy syndrome (PRES) may present with diverse clinical symptoms including visual disturbance, headache, seizures and impaired consciousness. MRI shows oedema, usually involving the posterior subcortical regions. Triggering factors include hypertension, pre-eclampsia/eclampsia, renal failure, cytotoxic agents and autoimmune conditions. The mechanism underlying PRES is not certain, but endothelial dysfunction is implicated. Treatment is supportive and involves correcting the underlying cause and managing associated complications, such as seizures. Although most patients recover, PRES is not always reversible and may be associated with considerable morbidity and even mortality.

Changes in serum neurofilament light chain levels following narrowband ultraviolet B phototherapy in clinically isolated syndrome.

OBJECTIVE: To determine whether serum neurofilament light chain (sNfL) levels are suppressed in patients with the clinically isolated syndrome (CIS) following narrowband ultraviolet B phototherapy (UVB-PT). METHODS: sNfL levels were measured using a sensitive single-molecule array assay at baseline and up to 12 months in 17 patients with CIS, 10 of whom received UVB-PT, and were compared with healthy control (HC) and early relapsing remitting multiple sclerosis (RRMS) group. sNfL levels were correlated with magnetic resonance imaging total lesion volume (LV) determined using icobrain version 4.4.1 and with clinical outcomes. RESULTS: Baseline median sNfL levels were significantly higher in the CIS (20.6 pg/mL, interquartile range [IQR] 13.7-161.4) and RRMS groups (36.6 pg/ml [IQR] 16.2-212.2) than in HC (10.7 pg/ml [IQR] 4.9-21.5) (p = .012 and p = .0002, respectively), and were strongly correlated with T2 and T1 LV at 12 months (r = .800; p = .014 and r = .833; p = .008, respectively) in the CIS group. Analysis of changes in sNfL levels over time in the CIS group showed a significant cumulative suppressive effect of UVB-PT in the first 3 months (UVB-PT -10.6% vs non-UVB-PT +58.3%; p = .04) following which the levels in the two groups converged and continued to fall. CONCLUSIONS: Our findings provide the basis for further studies to determine the utility of sNfL levels as a marker of neuro-axonal damage in CIS and early MS and for assessing the efficacy of new therapeutic interventions such as UVB-PT.

Central Nervous System Demyelination Related to Tumour Necrosis Factor Alpha Inhibitor.

BACKGROUND: An association between tumour necrosis factor alpha (TNF-α) inhibitors exposure and central nervous system (CNS) demyelinating disorders has been postulated but is poorly understood. OBJECTIVES: Describe the clinical spectrum and progress of a cohort of patients who developed demyelinating disorder following exposure to TNF-α inhibitor. METHODS: Retrospective chart review of patients who presented to a single neurologist in Western Australia between May 2003 and July 2020. RESULTS: 7 patients (6 females and 1 male) were identified. Mean age was 49.1 years. Mean follow-up time was 2.9 years. Mean interval between commencement of TNF-α inhibitor and onset of demyelinating event was 3 years. The spectrum of demyelinating events included transverse myelitis (N = 3), acute brainstem syndrome (N = 1) and optic neuritis (N = 1). 2 patients had an atypical presentation but had MRI findings which unequivocally showed demyelinating changes. 2 patients had a monophasic event while the other 5 patients were diagnosed to have multiple sclerosis. All symptomatic patients with multiple sclerosis were started on disease modifying therapy and remained relapse free during follow-up. CONCLUSION: Exposure to TNF-α inhibitor appears to increase the risk of demyelinating event. Whether TNFα inhibition directly results in CNS demyelination or trigger demyelination in susceptible individuals requires further research.

Serum NfL associated with anti-NMDA receptor encephalitis.

INTRODUCTION: Neurofilament light chains (NfL) have been reported as potential markers for neuronal-axonal injury in neuroinflammatory diseases. In the current study, we describe serum NfL levels as a prognostic marker for anti-N-methyl-D-aspartate receptor encephalitis (NMDARE). METHODS: Serum levels of NfL of 64 patients with anti-NMDARE and 84 healthy controls were measured by Simoa. The anti-NMDAR Encephalitis One-Year Functional Status (NEOS) score, Modified Rankin Scale (mRS) scores, and clinical and cerebrospinal fluid parameters were evaluated in patients with anti-NMDARE. Meanwhile, we performed a receiver-operator characteristic analysis to assess the power of the serum NFL in predicting the 1-year functional status. RESULTS: Serum NfL levels were significantly elevated in patients with anti-NMDARE compared to healthy controls (p < 0.001, padjusted < 0.001), especially in patients with severe impairments (mRS > 3 vs ≤ 3, p = 0.035) or with limited response to treatment (vs. favorable outcome, p = 0.011). Serum NFL was positively associated with the initial admission mRS (r = 0.23, p = 0.072) and 1-year mRS (r = 0.29, p = 0.018). The AUC of serum NfL and NEOS score for 1-year poor functional status was 0.697 (95% CI 0.527-0.866, p = 0.011), 0.753 (95% CI 0.616-0.890, p = 0.001), respectively. Furthermore, AUC of the combination of serum NfL and NEOS was 0.815 (95% CI 0.680-0.950, p < 0.001). CONCLUSION: Our findings show that serum NfL levels evaluated in anti-NMDAR encephalitis may be a good predictor of the risk of 1-year poor functional status.

Prediction of multiple sclerosis outcomes when switching to ocrelizumab.

BACKGROUND: Increasingly, people with relapsing-remitting multiple sclerosis (RRMS) are switched to highly effective disease-modifying therapies (DMTs) such as ocrelizumab. OBJECTIVE: To determine predictors of relapse and disability progression when switching from another DMT to ocrelizumab. METHODS: Patients with RRMS who switched to ocrelizumab were identified from the MSBase Registry and grouped by prior disease-modifying therapy (pDMT; interferon-ß/glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod or natalizumab) and washout duration (<1 month, 1-2 months or 2-6 months). Survival analyses including multivariable Cox proportional hazard regression models were used to identify predictors of on-ocrelizumab relapse within 1 year, and 6-month confirmed disability progression (CDP). RESULTS: After adjustment, relapse hazard when switching from fingolimod was greater than other pDMTs, but only in the first 3 months of ocrelizumab therapy (hazard ratio (HR) = 3.98, 95% confidence interval (CI) = 1.57-11.11, p = 0.004). The adjusted hazard for CDP was significantly higher with longer washout (2-6 m compared to <1 m: HR = 9.57, 95% CI = 1.92-47.64, p = 0.006). CONCLUSION: The risk of disability worsening during switch to ocrelizumab is reduced by short treatment gaps. Patients who cease fingolimod are at heightened relapse risk in the first 3 months on ocrelizumab. Prospective evaluation of strategies such as washout reduction may help optimise this switch.

NMOSD and MS prevalence in the Indigenous populations of Australia and New Zealand.

BACKGROUND: We studied the prevalence of neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) in Indigenous populations of Australia and New Zealand with the aim of assessing potential differences. METHODS: Cases of possible NMOSD and MS were collected from Australia and New Zealand. Clinical details, MR imaging, and serologic results were used to apply 2015 IPND diagnostic criteria for NMOSD and 2010 McDonald criteria for MS. Frequencies of self-determined ethnic ancestry were calculated for confirmed NMOSD, suspected NMOSD, and MS. Prevalence rates for NMOSD and MS according to ancestry were compared. RESULTS: There were 75 cases with NMOSD, 89 with suspected NMSOD, and 101 with MS. NMOSD cases were more likely to have Asian, Indigenous, or Other ancestry compared to suspected NMOSD or MS. There were no differences in the clinical phenotype of NMOSD seen in Indigenous compared to European ancestry populations. Per 100,000, the prevalence estimate for NMOSD in people with Maori ancestry was 1.50 (95% CI 0.52-2.49) which was similar to those with Asian ancestry 1.57 (95% CI 1.15-1.98). NMOSD prevalence in Australian Aboriginal and Torres Strait Islander populations was 0.38 (95% CI 0.00-0.80) per 100,000. CONCLUSION: The prevalence of NMOSD in the Maori population is similar to South East Asian countries, reflecting their historical origins. The prevalence of MS in this group is intermediate between those with South East Asian and European ancestry living in New Zealand. Both NMOSD and particularly MS appear to be uncommon in the Indigenous populations of Australia.