Multiple Sclerosis and COVID-19: Health and healthcare access, health information and consumer co-created strategies for future access at times of crisis.

BACKGROUND: Persons with multiple sclerosis (MS) need regular access to medical services for optimal health outcomes. During the COVID-19 crisis, evidence indicated some detrimental health changes in persons with MS. Maintaining access to healthcare providers and healthcare information may minimise detrimental health changes during times of crisis. In Australia, there is limited evidence of consultation with people who have chronic health conditions or disabilities regarding government decisions to restrict healthcare access and in the provision of health guidance during the COVID-19 crisis. Yet, there are good examples of government consultation with other minority populations in Australia, leading to beneficial outcomes. OBJECTIVE: To identify MS community members' (persons with MS carers, advocates, healthcare providers) concerns about the health and healthcare access of persons with MS, during the second year of the COVID-19 pandemic and to collaborate with consumers in the MS community to co-create strategies to improve future access and health information provision at times of crisis. METHOD: We undertook a consumer-co-created mixed-method study in the second year of the COVID-19 pandemic to identify healthcare access needs for MS. We presented results to our stakeholder group to identify support needs during crises. Persons with MS and care providers in the MS community completed an online survey and online interviews, and the stakeholder group participated in a stakeholder workshop. RESULTS: Forty-four people participated in surveys, 33 completed interviews, and seven stakeholders participated in the stakeholder workshops. Three themes were identified from the surveys and interviews: health concerns, accessing healthcare services and communication sources. Healthcare providers (76.9 % of persons with MS and 77.8 % of care providers) and websites specific to the pandemic (76.9 % of persons with MS and 83.3 % of care providers) were identified by most survey respondents as preferred information sources during the COVID-19 crisis. Consultation with stakeholders resulted in the co-creation of strategies directed at communication, health, and lifestyle, as well as policies and protocols to address the needs of the MS community during crises. CONCLUSION: We listened to persons with MS and care providers to identify strategies to support health-communication, -access, and -lifestyle during crises. Consumer-created strategies are directed at national and local health advocacy organisations and governments. They are relevant for the coordinated healthcare planning of persons with chronic health conditions and disabilities during crises, such as those experienced by persons with MS.

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.

Clinical and imaging features of patients with late-onset myelin oligodendrocyte glycoprotein antibody-associated disease.

BACKGROUND: There is an age-dependent change in the clinical phenotype of Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). However, the clinical features of late-onset MOGAD have not been well described. METHODS: Clinical data of 110 MOGAD patients, including 21 late-onset patients with onset age greater than or equal to 50 years old were retrospectively analyzed. RESULTS: Compared to pediatric- and younger adult-onset ones, late-onset MOGAD patients experienced milder disease onset (p < 0.001), more monophasic course (p < 0.001), fewer relapses (p = 0.007), less cerebrospinal fluid leukocytosis (p = 0.021), less longitudinally extensive transverse myelitis (onset p = 0.026, whole course p = 0.028), fewer lesions in basal ganglia (whole course p = 0.012), thalamus (whole course p = 0.040) and cerebellum (whole course p = 0.028). However, they had more cerebral symptoms (p = 0.021 onset and whole course), more lesions in white matter (onset p = 0.005, whole course p < 0.001) and periventricular area (onset p = 0.026), along with longer and delayed therapeutic intervention (p < 0.001). The main differences in clinical characteristics between late-onset patients with and without these brain involvements might be comorbidities. CONCLUSIONS: Late-onset MOGAD are more likely to experience delayed diagnosis. Brain involvement may be modulated by comorbidities of the elderly, which alter the clinical manifestations of late-onset MOGAD.

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.

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.

The risk of secondary progressive multiple sclerosis is geographically determined but modifiable.

Geographical variations in the incidence and prevalence of multiple sclerosis have been reported globally. Latitude as a surrogate for exposure to ultraviolet radiation but also other lifestyle and environmental factors are regarded as drivers of this variation. No previous studies evaluated geographical variation in the risk of secondary progressive multiple sclerosis, an advanced form of multiple sclerosis that is characterized by steady accrual of irreversible disability. We evaluated differences in the risk of secondary progressive multiple sclerosis in relation to latitude and country of residence, modified by high-to-moderate efficacy immunotherapy in a geographically diverse cohort of patients with relapsing-remitting multiple sclerosis. The study included relapsing-remitting multiple sclerosis patients from the global MSBase registry with at least one recorded assessment of disability. Secondary progressive multiple sclerosis was identified as per clinician diagnosis. Sensitivity analyses used the operationalized definition of secondary progressive multiple sclerosis and the Swedish decision tree algorithm. A proportional hazards model was used to estimate the cumulative risk of secondary progressive multiple sclerosis by country of residence (latitude), adjusted for sex, age at disease onset, time from onset to relapsing-remitting phase, disability (Multiple Sclerosis Severity Score) and relapse activity at study inclusion, national multiple sclerosis prevalence, government health expenditure, and proportion of time treated with high-to-moderate efficacy disease-modifying therapy. Geographical variation in time from relapsing-remitting phase to secondary progressive phase of multiple sclerosis was modelled through a proportional hazards model with spatially correlated frailties. We included 51 126 patients (72% female) from 27 countries. The median survival time from relapsing-remitting phase to secondary progressive multiple sclerosis among all patients was 39 (95% confidence interval: 37 to 43) years. Higher latitude [median hazard ratio = 1.21, 95% credible interval (1.16, 1.26)], higher national multiple sclerosis prevalence [1.07 (1.03, 1.11)], male sex [1.30 (1.22, 1.39)], older age at onset [1.35 (1.30, 1.39)], higher disability [2.40 (2.34, 2.47)] and frequent relapses [1.18 (1.15, 1.21)] at inclusion were associated with increased hazard of secondary progressive multiple sclerosis. Higher proportion of time on high-to-moderate efficacy therapy substantially reduced the hazard of secondary progressive multiple sclerosis [0.76 (0.73, 0.79)] and reduced the effect of latitude [interaction: 0.95 (0.92, 0.99)]. At the country-level, patients in Oman, Tunisia, Iran and Canada had higher risks of secondary progressive multiple sclerosis relative to the other studied regions. Higher latitude of residence is associated with a higher probability of developing secondary progressive multiple sclerosis. High-to-moderate efficacy immunotherapy can mitigate some of this geographically co-determined risk.

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.

Early non-disabling relapses are important predictors of disability accumulation in people with relapsing-remitting multiple sclerosis.

BACKGROUND: The prognostic significance of non-disabling relapses in people with relapsing-remitting multiple sclerosis (RRMS) is unclear. OBJECTIVE: To determine whether early non-disabling relapses predict disability accumulation in RRMS. METHODS: We redefined mild relapses in MSBase as 'non-disabling', and moderate or severe relapses as 'disabling'. We used mixed-effects Cox models to compare 90-day confirmed disability accumulation events in people with exclusively non-disabling relapses within 2 years of RRMS diagnosis to those with no early relapses; and any early disabling relapses. Analyses were stratified by disease-modifying therapy (DMT) efficacy during follow-up. RESULTS: People who experienced non-disabling relapses within 2 years of RRMS diagnosis accumulated more disability than those with no early relapses if they were untreated (n = 285 vs 4717; hazard ratio (HR) = 1.29, 95% confidence interval (CI) = 1.00-1.68) or given platform DMTs (n = 1074 vs 7262; HR = 1.33, 95% CI = 1.15-1.54), but not if given high-efficacy DMTs (n = 572 vs 3534; HR = 0.90, 95% CI = 0.71-1.13) during follow-up. Differences in disability accumulation between those with early non-disabling relapses and those with early disabling relapses were not confirmed statistically. CONCLUSION: This study suggests that early non-disabling relapses are associated with a higher risk of disability accumulation than no early relapses in RRMS. This risk may be mitigated by high-efficacy DMTs. Therefore, non-disabling relapses should be considered when making treatment decisions.

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.

Linear interactions between intraocular, intracranial pressure, and retinal vascular pulse amplitude in the fourier domain.

PURPOSE: To compare the retinal vascular pulsatile characteristics in subjects with normal (ICPn) and high (ICPh) intracranial pressure and quantify the interactions between intraocular pressure, intracranial pressure, and retinal vascular pulse amplitude in the Fourier domain. MATERIALS AND METHODS: Twenty-one subjects were examined using modified photoplethysmography with simultaneous ophthalmodynamometry. A harmonic regression model was fitted to each pixel in the time-series, and used to quantify the retinal vascular pulse wave parameters including the harmonic regression wave amplitude (HRWa). The pulse wave attenuation was measured under different ranges of induced intraocular pressure (IOPi), as a function of distance along the vessel (VDist). Intracranial pressure (ICP) was measured using lumbar puncture. A linear mixed-effects model was used to estimate the correlations between the Yeo-Johnson transformed harmonic regression wave amplitude (HRWa-YJt) with the predictors (IOPi, VDist and ICP). A comparison of the model coefficients was done by calculating the weighted Beta (ßx) coefficients. RESULTS: The median HRWa in the ICPn group was higher in the retinal veins (4.563, interquartile range (IQR) = 3.656) compared to the retinal arteries (3.475, IQR = 2.458), p<0.0001. In contrast, the ICPh group demonstrated a reduction in the median venous HRWa (3.655, IQR = 3.223) and an elevation in the median arterial HRWa (3.616, IQR = 2.715), p<0.0001. Interactions of the pulsation amplitude with ICP showed a significant disordinal interaction and the loss of a main effect of the Fourier sine coefficient (bn1) in the ICPh group, suggesting that this coefficient reflects the retinal vascular response to ICP wave. The linear mixed-effects model (LME) showed the decay in the venous (HRWa-YJt) was almost twice that in the retinal arteries (-0.067±0.002 compared to -0.028±0.0021 respectively, p<0.00001). The overall interaction models had a total explanatory power of (conditional R2) 38.7%, and 42% of which the fixed effects explained 8.8%, and 5.8% of the variance (marginal R2) for the venous and arterial models respectively. A comparison of the damping effect of VDist and ICP showed that ICP had less influence on pulse decay than distance in the retinal arteries (ßICP = -0.21, se = ±0.017 compared to [Formula: see text], se = ±0.019), whereas the mean value was equal for the retinal veins (venous [Formula: see text], se = ±0.015, ßICP = -0.42, se = ±0.019). CONCLUSION: The retinal vascular pulsation characteristics in the ICPh group showed high retinal arterial and low venous pulsation amplitudes. Interactions between retinal vascular pulsation amplitude and ICP suggest that the Fourier sine coefficient bn1 reflects the retinal vascular response to the ICP wave. Although a matrix of regression lines showed high linear characteristics, the low model explanatory power precludes its use as a predictor of ICP. These results may guide future predictive modelling in non-invasive estimation of ICP using modified photoplethysmography.

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.

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.

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.

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.