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• Rituximab can be prescribed as first-line treatment (early treatment) or after disease activity in patients receiving oral immunosuppressants (escalating therapy) in patients with NMOSD. • Early rituximab treatment may reduce disability progression in NMOSD patients. • Cost-effectiveness analysis supports early rituximab treatment for NMOSD patients. Rituximab, an anti-CD20 monoclonal antibody, has shown effectiveness in reducing disease relapses and disability accrual through relapses in patients with neuromyelitis optica spectrum disorders (NMOSD). However, its higher cost compared to oral immunosuppressants raises questions about its cost-effectiveness, particularly in low and middle-income countries. This study aimed to compare the cost-effectiveness of early rituximab treatment versus escalation treatment in NMOSD patients. We conducted a retrospective study of NMOSD patients treated with rituximab in the first five years of disease at a hospital in São Paulo, Brazil, from 2015 to 2019. The Early Group consisted of NMOSD patients who received rituximab as a first-line treatment. The Escalating Therapy Group included patients who were prescribed rituximab after experiencing disease activity while on oral immunosuppressants, primarily azathioprine. An economic model based on Expanded Disability Status Score (EDSS) transitions was used to assess cost-effectiveness. Cost and utility data were derived from previous studies, and sensitivity analyses for different willingness to pay (WTP) thresholds and percentage of patients upscaling from oral immunossupressants to rituximab were performed. : Thirty NMOSD patients were included. In the Early Group, the proportion of patients reaching the highest EDSS states (6.5 or more) decreased over five years compared to baseline. In contrast, the Escalating Therapy Group experienced an increase in this proportion over the same period. Cost-effectiveness was achieved for willingness to pay (WTP) of €20–80,000 in our main analysis, sustained in our sensitivity analysis. : Early treatment with rituximab has the potential to lower healthcare costs and enhance quality of life for NMOSD patients, supporting its early prescription for preventive treatment. [ABSTRACT FROM AUTHOR]

• We performed an updated systematic review and meta-analysis of randomized controlled trials of vitamin D 3 supplementation to evaluate its efficacy on multiple sclerosis related outcomes. • Vitamin D 3 as an add-on therapy to low-efficacy disease modifying drugs does not confer clinical or radiological benefits on timeframes lasting up to 24 months. • Additional studies are needed to explore outcomes over longer follow-up times. Vitamin D deficiency has been linked to a higher risk of multiple sclerosis (MS) and disease progression. However, the efficacy of vitamin D 3 as an adjuvant therapy for MS remains a controversial topic. To perform a systematic review and meta-analysis of randomized controlled trials to assess the impact of adjunct high-dose vitamin D 3 on clinical and radiological outcomes. PubMed, Embase, and Cochrane Library were searched for trials published until December 18th, 2022. Authors independently selected randomized controlled trials involving patients with MS, with an intervention group receiving high dose (≥ 1000 IU/day) cholecalciferol and reporting clinical or radiological outcomes. Authors independently extracted data and assessed the risk of bias using a standardized, pilot-tested form. The meta-analysis was conducted using RStudio for EDSS at the last follow-up, ARR, and new T2 lesion count. We included 9 studies with 867 participants. No significant reduction of EDSS (MD = 0.02, CI 95 % [–0.37; 0.41], p = 0.91), ARR (MD –0.03, CI 95 % [–0.08; 0.02], p = 0.26), or new T2 lesions (MD –0.59, CI 95 % [-1.24;0.07], p = 0.08) was observed at 6–24 months. We found no evidence of publication bias. The findings of this meta-analysis strengthen current evidence that vitamin D 3 supplementation has no significant impact on clinical outcomes in patients with MS. However, the non-significant reduction of new T2 lesions could precede long-term clinical benefits and should be validated in additional studies. [ABSTRACT FROM AUTHOR]

Background Low-education attainment is associated with worse cognitive performance in multiple sclerosis (MS) patients, and possibly with a lower cognitive reserve and/or increased inflammatory activity. Cognitive reserve refers to the capability of a source of intellectual enrichment in attenuating a negative effect of a disease-related factor; while the inflammatory activity is often related to T2-lesion load (T2-LL) increase. Objective To disentangle the effects of cognitive reserve and an increased T2-LL in MS-patients with low-education levels. Methods The study included 136 MS patients and 65 healthy-controls, divided in low-education (12 years or less of school education without obtaining any technical superior degree) and high-education (more than 12 years of school education with technical or superior degree) groups. An extensive battery of neuropsychological tests was applied examining intelligence quotient and six cognitive domains. Test results were z-scored and subjects with z-scores ≤ −1.5 in two or more domains were considered cognitively impaired. To test the factors associated with worse cognitive performance, regression models were applied using average cognition as target; education level, Expanded Disability Status Scale (EDSS), T2-LL, disease duration, age of disease onset, age and gender as predictors. We also tested the correlation between T2-LL and cognition in the groups. To investigate the role of education level as a source of intellectual enrichment/cognitive reserve in different stages of MS, we sub-divided the MS patients in three groups according to the disease duration (less than 5 years, between 5 and 10 years and more than 10 years). Results Worse average cognition was associated with low-education level, higher T2-LL and male gender. A higher frequency of cognitively impaired patients was observed in MS patients with low-education level, in all stages of the disease. In patients with a disease duration shorter than five years, there was a lower correlation between worse average cognition and T2-LL in the high-education level group, compared to the patients with low-education level; in MS patients with longer disease duration, we observed a stronger correlation between lesion burden and cognitive impairment in both groups. Conclusion Education attainment is a source of intellectual enrichment and can enhance the cognitive reserve in MS patients. The protective effect of a high-education level was stronger in patients with less than five years of disease, suggesting a stronger role of cognitive reserve in short-term disease. In long-term disease we observed a greater impact of increased inflammatory activity on cognition. [ABSTRACT FROM AUTHOR]

• We found similar frequency of visual impairment at 6–12 months in patients with ON treated with 5-day or 7-day duration of 1 g/d intravenous methylprednisolone treatment (IVMPT). • Corticosteroids comprise a genomic and non-genomic effect. • The ceiling effect of IVMP treatment may occur because the genomic effect is already in place at five days and, hence, the non-genomic effect does not provide additional benefit. Optic neuritis (ON), a major cause of visual impairment in young adults, is generally associated with rapid visual recovery when treated with intravenous methylprednisolone treatment (IVMPT). However, the optimal duration of such treatment is unknown, ranging from three to seven days in clinical practice. We aimed to compare the visual recovery in patients treated with 5-day or 7-day duration IVMPT. We performed a retrospective cohort study of consecutive patients with ON in São Paulo, Brazil, from 2016 to 2021. We compared the proportion of participants with visual impairment in 5-day and 7-day treatment schedules at discharge, at 1 month and between 6 and 12 months after the diagnosis of ON. The findings were adjusted to age, severity of the visual impairment, co-intervention with plasma exchange, time from symptom onset to IVMPT and the etiology of the ON to mitigate indication bias. We included 73 patients with ON treated with 5 or 7-day duration of 1 g/d intravenous methylprednisolone therapy. Visual impairment at 6–12 months in the 5-day or the 7-day treatment groups was similar (57% x 59%, p > 0.9, Odds Ratio 1.03 [95% CI 0.59–1.84]). The results were similar after adjusting for prognostic variables and when observed at different time points. Visual recovery is similar in patients treated with 5-day and 7-day duration treatments of 1 g/day intravenous methylprednisolone, suggesting a ceiling effect. Limiting the duration of the treatment can reduce hospital stay and costs, without interfering with clinical benefit. [ABSTRACT FROM AUTHOR]

• Disability in NMOSD results from relapsing attacks. • Long-standing NMOSD is usually associated with severe disability. • A small proportion of patients remained fully functional in all systems 15 years after disease onset. • ARR 0.4 was the boundary line above which severe disability occurred. • Good prognosis associated with Caucasians, low ARR, and absent myelitis at disease onset. Neuromyelitis optica spectrum disorders (NMOSD) most commonly cause severe disability which is related to disease attacks. However, some patients retain good neurological function for a long time after disease onset. To determine the frequency, demographic and the clinical features of good outcome NMOSD, and analyze their predictive factors. We selected patients who met the 2015 International Panel for NMOSD diagnostic criteria from seven MS Centers. Assessed data included age at disease onset, sex, race, number of attacks within the first and three years from onset, annualized relapsing rate (ARR), total number of attacks, aquaporin-IgG serum status, presence of cerebrospinal fluid (CSF)-specific oligoclonal bands (OCB) and the Expanded Disability Status Scale (EDSS) score at the last follow-up visit. NMOSD was classified as non-benign if patients developed sustained EDSS score >3.0 during the disease course, or benign if patients had EDSS score ≤3.0 after ≥15 years from disease onset. Patients with EDSS <3.0 and disease duration shorter than 15 years were not qualified for classification. We compared the demographic and clinical characteristics of benign and non-benign NMOSD. Logistic regression analysis identified predictive factors of outcome. There were 16 patients with benign NMOSD (3% of the entire cohort; 4.2% of those qualified for classification; and 4.1% of those who tested positive for aquaporin 4-IgG), and 362 (67.7%) with non-benign NMOSD, whereas 157 (29.3%) did not qualify for classification. All patients with benign NMOSD were female, 75% were Caucasian, 75% tested positive for AQP4-IgG, and 28.6% had CSF-specific OCB. Regression analysis showed that female sex, pediatric onset, and optic neuritis, area postrema syndrome, and brainstem symptoms at disease onset, as well as fewer relapses in the first year and three years from onset, and CSF-specific OCB were more commonly found in benign NMOSD, but the difference did not reach statistical significance. Conversely, non-Caucasian race (OR: 0.29, 95% CI: 0.07–0.99; p = 0.038), myelitis at disease presentation (OR: 0.07, 95% CI: 0.01–0.52; p <0.001), and high ARR (OR: 0.07, 95% CI: 0.01–0.67; p = 0.011) were negative risk factors for benign NMOSD. Benign NMOSD is very rare and occurs more frequently in Caucasians, patients with low ARR, and those who do not have myelitis at disease onset. [ABSTRACT FROM AUTHOR]

• The optimal sequencing of DMDs in MS treatment is unknown. • There are two main strategies: escalating (ESC) and early intensive (EIT) strategy. • Treatment choice depends on effectiveness, safety, and cost. • EIT has a higher efficacy in preventing progression and similar safety profile. • EIT may be cost-effective in 5-year time horizon. The optimal treatment strategy of multiple sclerosis (MS) is a matter of debate. The classical approach is the escalating (ESC) strategy, which consists of starting with low- to moderate-efficacy disease-modifying drugs (DMDs) and upscale to high-efficacy DMDs when noting some evidence of active disease. Another approach, the early intensive (EIT) strategy, is starting with high-efficiency DMDs as first-line therapy. Our goal was to compare effectiveness, safety, and cost of ESC and EIT strategies. We searched MEDLINE, EMBASE and SCOPUS until September 2022, for studies comparing EIT and ESC strategies in adult participants with relapsing-remitting MS and a minimum follow-up of 5 years. We examined the Expanded Disability Severity Scale (EDSS), the proportion of severe adverse events, and cost in a 5-year period. Random-effects meta-analysis summarized the efficacy and safety and an EDSS-based Markov model estimated the cost. Seven studies with 3,467 participants showed a 30% reduction in EDSS worsening in 5 years (RR 0.7; [0.59–0.83]; p < 0.001) in the EIT group vs in the ESC group. Two studies with 1,118 participants suggested a similar safety profile for these strategies (RR 1.92; [0.38–9.72]; p = 0.4324). EIT with natalizumab in extended interval dosing, rituximab, alemtuzumab, and cladribine demonstrated cost-effectiveness in our model. EIT presents higher efficacy in preventing disability progression, a similar safety profile, and can be cost-effective within a 5-year timeline. [ABSTRACT FROM AUTHOR]

• The estimated prevalence of anti-AQP4 antibody positive neuromyelitis optica spectrum disorder (NMOSD) is relatively high in the city of São Paulo. • The estimated prevalence of MOG antibody associated disease (MOGAD) is relatively low in the city of São Paulo. Numerous studies addressed the prevalence of multiple sclerosis, but prevalence studies of NMOSD and, particularly, MOGAD are scarce. We aimed to estimate the prevalence of NMOSD and MOGAD in the city of São Paulo, based on the known prevalence of MS. In this observational study, we determined the total number of patients with central nervous system demyelinating disease on regular follow-up in a university referral center in São Paulo, from May 2019 to May 2021 according to the diagnosis of multiple sclerosis (MS), NMOSD and MOGAD using the current diagnostic criteria for these diseases. We used the MS: NMOSD and MS: MOGAD ratios to estimate the ratio of these diseases in São Paulo, Brazil. We identified 968 patients with MS, 133 patients with AQP4 positive NMOSD, and 28 patients with MOGAD. We found the MS: NMOSD ratio of 7,28 and the MS: MOGAD ratio of 34,57. We estimated a prevalence of 2,1 per 100,000 inhabitants for NMOSD and of 0,4 per 100,000 inhabitants for MOGAD. The prevalence of NMOSD is high in São Paulo, but the prevalence of MOGAD is low when compared with the prevalence found in most of the studies reported to date. [ABSTRACT FROM AUTHOR]

• Half of the patients disclosed new or enlarged brain/spinal cord lesions. • 12.5% of patients presented asymptomatic lesions irrespective of clinical attacks. • 31.2% of patients presented asymptomatic brain lesions associated with attack of other topography. • 74.5% of lesions reduced or remained stable or developed atrophy/cavitation. • The presence of asymptomatic lesions did not change clinical outcome or patient management. Around 5% of all Neuromyelitis Optica Spectrum Disorders (NMOSD) cases start before 18 years of age. Clinical and radiological manifestations of AQP4-IgG positive NMOSD were revised in 2015, and the importance of neuroimaging in the diagnosis is well recognized. Neuroimaging findings in pediatric-onset NMOSD were scarcely described, and longitudinal evaluation of NMOSD lesions was only accessed in a few adult-onset cohorts. This study evaluated brain, spinal cord, and optic nerve MRI of sixteen pediatric-onset AQP4-IgG positive NMOSD through a qualitative evaluation of lesion evolution. Lesions were classified as symptomatic or asymptomatic in acute or chronic phase (> 30 days from last attack) MRI. Seventy MRI scans and 54 subsequent exams were evaluated. Most NMOSD lesions (74.5%) reduced, remained stable, or developed atrophy/cavitation. New brain lesions or enlargement of existing brain lesions were found in two patients (12.5%) without any clinical symptom and in five patients (31.2%) in the course of an attack from other topography (optic neuritis or acute myelitis). One patient (6.3%) presented an asymptomatic spinal cord lesion irrespective of clinical manifestation. No asymptomatic lesion was described in optic nerve MRI. In acute phase exams, longitudinally extensive transverse myelitis (13/19 vs 8/24; p = 0.033), cervical myelitis (15/19 vs 10/24, p = 0.028), lumbar myelitis (5/19 vs 0/24; p = 0.012), and a higher number of segments [median 8 (range 4–17) vs 3.5 (range 1–14); p = 0.003] were affected. Asymptomatic brain and spinal cord lesions can occur in pediatric-onset NMOSD, especially in the course of acute optic neuritis or myelitis. More longitudinal studies are necessary to guide recommendations on neuroimaging frequency in pediatric patients with AQP4-IgG NMOSD. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Brainstem, hypothalamic and cerebral symptoms may occur in neuromyelitis optica spectrum disorders (NMOSD). However, pathologic yawning has not been previously described in NMOSD patients. Patients and methods: Nine AQP4-IgG seropositive NMOSD patients experienced excessive yawning not related to sleep deprivation or fatigue. Results: Patients were female, aged 19–57 years (median, 39 years) at disease onset. Excessive yawning spells were the presenting symptom of the disease in five patients, lasted 2–16 weeks, and usually occurred in association with nausea, vomiting and hiccups. Brain MRI was abnormal in all patients and most frequently showed brainstem and hypothalamic lesions. Conclusion: Pathologic yawning may be a neglected although not a rare symptom in NMOSD. [Copyright &y& Elsevier]

• Pediatric-onset NMOSD is a highly disabling disease associated with reduced quality of life. • Low quality of life was associated with higher EDSS and poor academic performance. • Emotional functioning was the most affected area in the quality of life inventory. Neuromyelitis optica spectrum disorders (NMOSD) is a severe condition associated with high disability and low quality of life (QoL) in adults. Since this evaluation had been rarely perfomed in children, this study aimed to describe QoL in pediatric-onset NMOSD with positive aquaporin4 antibody (AQP4-IgG) patients. This was a cross-section evaluation of patients and parents' proxy QoL from individuals enrolled in a longitudinal cohort of AQP4-IgG positive NMOSD with onset ≤ 18 years of age. Eighteen patients were included, sixteen girls. The mean (SD) age at disease onset was 11.5 (3.6) years. Eleven of patients experienced disability during a mean (SD) of 8.3 (5.3) years of follow-up. NMOSD had impact in QoL in 10 patients, being associated with higher EDSS and poor academic performance at last follow-up. Results from the PedsQL inventory for 13 patients and 10 parents disclosed low QoL specially in emotional functioning. This study indicates impaired quality of life, high disability and high impact of the disease in daily life of adolescents and young adults with pediatric onset NMOSD. [ABSTRACT FROM AUTHOR]

• Drugs can precipitate immune system deregulations and demyelinating syndromes. • Levamisole is a cocaine adulterant that has been associated with tumefactive demyelination. • High-efficacy MS drugs might facilitate progressive multifocal leukoencephalopahty. • Anti-TNFα therapy might increase the risk of CNS inflammatory adverse events. • Immune check-point inhibitors can precipitate demyelination, which has to be differentiated from metastatic lesions. Some drugs and medications can precipitate immune system deregulations, which might be confused with recurrent demyelinating diseases, such as multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMO), exacerbations of an existing disease, neoplastic lesions or other conditions. In this narrative review we describe some of the most relevant drugs and medications associated with iatrogenic demyelination. The anthelminthic agent levamisole is a frequent cocaine adulterant and can precipitate an exacerbated immune response attacking the central nervous system (CNS). High-efficacy multiple sclerosis (MS) drugs might induce a selective CNS immunosuppression, making it susceptible for opportunistic infections that course with demyelination, such as progressive multifocal leukoencephalopathy. Sometimes, the interruption of a high-efficacy drug to treat MS can induce a rapid CNS reentry of lymphocytes, exacerbating demyelinating processes and triggering rebound syndromes. Furthermore, selective cytokines inhibition, such as anti-TNFα agents, might induce an imbalance between cell death and proliferation inducing a paradoxical increase of CNS tumor necrosis factor (TNF), affecting the activity of lymphocytes, microglia and macrophages, triggering aberrant inflammation and demyelination. Immune checkpoint inhibitors are a new class of antineoplastic drugs that enhance the immune response against tumor cells by an upregulation of T-cell activity. However, this hyperactivation of the immune system might be associated with induction of unwanted autoimmune responses. In this paper we review the risk factors, the possible pathological mechanisms and the magnetic resonance imaging (MRI) findings of these drug-related demyelinating syndromes. [ABSTRACT FROM AUTHOR]

• Neurologists tend to overestimate physical aspects of the disease, such as its consequences on patients' autonomy and future planning. • Emotional and mental health are more essential aspects of the disease in patients' perception. • Patients with PPMS complain more about ambulation issues, imbalance and falls, when compared to other disease phenotypes. • There are major differences in the opinions of neurologists and patients on their participation in the disease's management and on orientations given during medical appointments. : Basic steps in the management of patients with Multiple Sclerosis (MS), such as good patient understanding of the disease and active participation in its management are extremely important, as they directly influence treatment adherence and success. Therefore, this study aimed to evaluate the perception of MS patients and neurologists pertaining to the most common disease symptoms, disabilities that impact on quality of life, and patient concerns and difficulties during medical visits, as information that can be used to improve the doctor-patient relationship. : A cross-sectional study involving two groups: the first composed of neurologists and the second of patients. Participants of the first group were selected by a Steering Committee (15 predetermined neurologists representing each region of Brazil and specialized in MS and neuroimmunological disorders, who also assumed the role of creating the survey and questionnaire). Participants of the second group were selected following dissemination of a questionnaire on the AME's social networks (Amigos Múltiplos pela Esclerose , a non-governmental organization to support patients with MS). Questions about sociodemographic data, disease impact on quality of life, symptoms perception, and concerns and issues regarding disease care were put to both groups. : A total of 317 patients and 182 neurologists answered the questionnaires. Significant divergences were found between the perceptions of patients and neurologists in relation to orientation and information given during medical appointments, and also regarding patient participation in treatment and therapy choice. Considering the topic assessing impact on quality of life, more than 70% of neurologists perceived that autonomy to work and travel, and future planning were aspects that most affected patient lives, however, almost 50% of patients reported that disease monitoring did not affect their life in any way. Analysis of data regarding MS symptoms revealed neurologists to consider physical symptoms, such as ambulation issues, imbalance, falls and urinary incontinence, to be those most interfering with patient quality of life, whereas patients considered non-physical symptoms, such as fatigue, pain, cognitive and memory problems to be more significant. Patients with primary progressive MS complained more about ambulation issues, imbalance and falls (p<0.05), when compared to patients with other disease phenotypes. : Significant differences in disease perception were found in this study. While neurologists tended to overestimate the consequences and symptoms of the disease, for most patients, the disease impact on activities did not appear to be as significant, with more complaints regarding non-physical symptoms. Although neurologists described involving patients in treatment decisions and providing them with appropriate orientation during medical appointments, the opposite was reported by patients. These results may help to improve treatment adherence and disease outcomes by redefining the doctor-patient relationship. [ABSTRACT FROM AUTHOR]

• Largest study of rituximab in MOG-IgG-associated disorder, includes both adults and children. • Rituximab reduced relapse rates in MOG-IgG-associated disorder by 37%. • Compared to similar studies in AQP4-IgG-associated NMOSD, the efficacy seems lower. • Some patients relapsed despite apparent circulating B-cell depletion. To assess the effect of anti-CD20 B-cell depletion with rituximab (RTX) on relapse rates in myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD). Retrospective review of RTX-treated MOGAD patients from 29 centres in 13 countries. The primary outcome measure was change in relapse rate after starting rituximab (Poisson regression model). Data on 121 patients were analysed, including 30 (24.8%) children. Twenty/121 (16.5%) were treated after one attack, of whom 14/20 (70.0%) remained relapse-free after median (IQR) 11.2 (6.3–14.1) months. The remainder (101/121, 83.5%) were treated after two or more attacks, of whom 53/101 (52.5%) remained relapse-free after median 12.1 (6.3–24.9) months. In this 'relapsing group', relapse rate declined by 37% (95%CI=19–52%, p <0.001) overall, 63% (95%CI=35–79%, p = 0.001) when RTX was used first line (n = 47), and 26% (95%CI=2–44%, p = 0.038) when used after other steroid-sparing immunotherapies (n = 54). Predicted 1-year and 2-year relapse-free survival was 79% and 55% for first-line RTX therapy, and 38% and 18% for second-/third-line therapy. Circulating CD19+ B -cells were suppressed to <1% of total circulating lymphocyte population at the time of 45/57 (78.9%) relapses. RTX reduced relapse rates in MOGAD. However, many patients continued to relapse despite apparent B-cell depletion. Prospective controlled studies are needed to validate these results. [ABSTRACT FROM AUTHOR]