Intimate partner violence and multiple sclerosis.

People with MS may be at heightened risk of intimate partner violence (IPV) compared to the general population; however, little is known about the prevalence of IPV among people with MS or its effects on MS-specific clinical outcomes. Additionally, while MS clinicians often discuss family planning with patients, many clinicians may have received little training in detecting and responding to IPV. Moreover, no studies have investigated how to implement IPV case-finding and resource provision in the MS clinical setting. Overall, there are several scholarly, educational, and implementation-related gaps in IPV-associated care for people with MS. This article aims to summarize the available literature on IPV in people with MS, identify future research questions, and aid MS clinicians in safely addressing IPV while awaiting vital MS-specific knowledge.

Acute central nervous system inflammation following COVID-19 vaccination: An observational cohort study.

BACKGROUND: Reports suggest a potential association between coronavirus disease 2019 (COVID-19) vaccines and acute central nervous system (CNS) inflammation. OBJECTIVE: The main objective of this study is to describe features of acute CNS inflammation following COVID-19 vaccination. METHODS: A retrospective observational cohort study was performed at the BARLO MS Centre in Toronto, Canada. Clinicians reported acute CNS inflammatory events within 60 days after a COVID-19 vaccine from March 2021 to August 2022. Clinical characteristics were evaluated. RESULTS: Thirty-eight patients (median age 39 (range: 20-82) years; 60.5% female) presented within 0-55 (median 15) days of a receiving a COVID-19 vaccine and were diagnosed with relapsing remitting multiple sclerosis (MS) (n = 16), post-vaccine transverse myelitis (n = 7), clinically isolated syndrome (n = 5), MS relapse (n = 4), tumefactive demyelination (n = 2), myelin oligodendrocyte glycoprotein antibody disease (n = 1), neuromyelitis optica spectrum disorder (n = 1), chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (n = 1) and primary autoimmune cerebellar ataxia (n = 1). Twenty-two received acute treatment and 21 started disease-modifying therapy. Sixteen received subsequent COVID-19 vaccination, of which 87.5% had no new or worsening neurological symptoms. CONCLUSION: To our knowledge, this is the largest study describing acute CNS inflammation after COVID-19 vaccination. We could not determine whether the number of inflammatory events was higher than expected.

Risk factors for peripartum depression in women with multiple sclerosis.

BACKGROUND: Peripartum depression (PPD) is underexplored in multiple sclerosis (MS). OBJECTIVE: To evaluate prevalence of and risk factors for PPD in women with MS. METHODS: Retrospective single-center analysis of women with MS with a live birth. Prevalence of PPD was estimated with logistic regression with generalized estimating equations (GEE). GEE evaluated predictors of PPD (e.g. age, marital status, parity, pre-pregnancy depression/anxiety, antidepressant discontinuation, sleep disturbance, breastfeeding, relapses, gadolinium-enhancing lesions, and disability). Factors significant in univariable analyses were included in multivariable analysis. RESULTS: We identified 143 live births in 111 women (mean age 33.1 ± 4.7 years). PPD was found in 18/143 pregnancies (12.6%, 95% CI = 7.3-17.8). Factors associated with PPD included older age (OR 1.16, 95% CI = 1.03-1.32 for 1-year increase), primiparity (OR 4.02, CI = 1.14-14.23), pre-pregnancy depression (OR 3.70, CI = 1.27-10.01), sleep disturbance (OR 3.23, CI = 1.17-8.91), and breastfeeding difficulty (OR 3.58, CI = 1.27-10.08). Maternal age (OR 1.17, CI = 1.02-1.34), primiparity (OR 8.10, CI = 1.38-47.40), and pre-pregnancy depression (OR 3.89, CI = 1.04-14.60) remained significant in multivariable analyses. Relapses, MRI activity, and disability were not associated with PPD. CONCLUSION: The prevalence of PPD in MS appeared similar to the general population, but was likely underestimated due to lack of screening. PPD can affect MS self-management and offspring development, and prospective studies are needed.

Real-World Effectiveness of Initial Disease-Modifying Therapies in Pediatric Multiple Sclerosis.

OBJECTIVE: To assess real-world effectiveness of initial treatment with newer compared to injectable disease-modifying therapies (DMTs) on disease activity in pediatric multiple sclerosis (MS) and clinically isolated syndrome (CIS). METHODS: This is a cohort study of children with MS/CIS followed at 12 clinics in the US Network of Pediatric MS Centers, who received initial therapy with newer (fingolimod, dimethyl fumarate, teriflunomide, natalizumab, rituximab, ocrelizumab) or injectable (interferon-ß, glatiramer acetate) DMTs. Propensity scores (PSs) were computed, including preidentified confounders. Relapse rate while on initial DMT was modeled with negative binomial regression, adjusted for PS-quintile. Time to new/enlarging T2-hyperintense and gadolinium-enhancing lesions on brain magnetic resonance imaging were modeled with midpoint survival analyses, adjusted for PS-quintile. RESULTS: A total of 741 children began therapy before 18 years, 197 with newer and 544 with injectable DMTs. Those started on newer DMTs were older (15.2 vs injectable 14.4 years, p = 0.001) and less likely to have a monofocal presentation. In PS-quintile-adjusted analysis, those on newer DMTs had a lower relapse rate than those on injectables (rate ratio = 0.45, 95% confidence interval (CI) = 0.29-0.70, p < 0.001; rate difference = 0.27, 95% CI = 0.14-0.40, p = 0.004). One would need to treat with newer rather than injectable DMTs for 3.7 person-years to prevent 1 relapse. Those started on newer DMTs had a lower rate of new/enlarging T2 (hazard ratio [HR] = 0.51, 95% CI = 0.36-0.72, p < 0.001) and gadolinium-enhancing lesions (HR = 0.38, 95% CI = 0.23-0.63, p < 0.001) than those on injectables. INTERPRETATION: Initial treatment of pediatric MS/CIS with newer DMTs led to better disease activity control compared to injectables, supporting greater effectiveness of newer therapies. Long-term safety data for newer DMTs are required. ANN NEUROL 2020 ANN NEUROL 2020;88:42-55.

Rituximab in patients with pediatric multiple sclerosis and other demyelinating disorders of the CNS: Practical considerations.

Anti-CD20 therapies have established efficacy in the treatment of immune-mediated neurological and non-neurological diseases. Rituximab, one of the first B-cell-directed therapies, is relatively inexpensive compared to newer anti-CD20 molecules, is available in many countries, and has been used off-label in pediatric patients with neuroimmune conditions. The objective of this paper is to describe the experience with rituximab in pediatric multiple sclerosis and other inflammatory immune-mediated disorders of the central nervous system (CNS), and to define a protocol for its use in clinical practice, in particular addressing doses, interval of administration, duration of treatment, and tests to perform at baseline and during follow-up.

Telomere Length Is Associated with Disability Progression in Multiple Sclerosis.

OBJECTIVE: To assess whether biological aging as measured by leukocyte telomere length (LTL) is associated with clinical disability and brain volume loss in multiple sclerosis (MS). METHODS: Adults with MS/clinically isolated syndrome in the University of California, San Francisco EPIC cohort study were included. LTL was measured on DNA samples by quantitative polymerase chain reaction and expressed as telomere to somatic DNA (T/S) ratio. Expanded Disability Status Scale (EDSS) and 3-dimensional T1-weighted brain magnetic resonance imaging were performed at baseline and follow-up. Associations of baseline LTL with cross-sectional and longitudinal outcomes were assessed using simple and mixed effects linear regression models. A subset (n = 46) had LTL measured over time, and we assessed the association of LTL change with EDSS change with mixed effects models. RESULTS: Included were 356 women and 160 men (mean age = 43 years, median disease duration = 6 years, median EDSS = 1.5 [range = 0-7], mean T/S ratio = 0.97 [standard deviation = 0.18]). In baseline analyses adjusted for age, disease duration, and sex, for every 0.2 lower LTL, EDSS was 0.27 higher (95% confidence interval [CI] = 0.13-0.42, p < 0.001) and brain volume was 7.4mm3 lower (95% CI = 0.10-14.7, p = 0.047). In longitudinal adjusted analyses, those with lower baseline LTL had higher EDSS and lower brain volumes over time. In adjusted analysis of the subset, LTL change was associated with EDSS change over 10 years; for every 0.2 LTL decrease, EDSS was 0.34 higher (95% CI = 0.08-0.61, p = 0.012). INTERPRETATION: Shorter telomere length was associated with disability independent of chronological age, suggesting that biological aging may contribute to neurological injury in MS. Targeting aging-related mechanisms is a potential therapeutic strategy against MS progression. ANN NEUROL 2019;86:671-682.

Recurrent Alternate-Sided Homonymous Hemianopia Due to Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-Like Episodes (MELAS): A Case Report.

Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) can rarely cause alternate-sided homonymous hemianopia due to stroke-like episodes involving the occipital lobes, as reported in three previously published cases. The authors report an interesting case of a 16-year-old presenting with myoclonic epilepsy due to MELAS with the rare ND3 mitochondrial mutation T10191C, with recurrent alternate-sided homonymous hemianopia. Visual field and corresponding magnetic resonance imaging (MRI) findings are presented. To the authors' knowledge, this is the first report of recurrent alternate-sided homonymous hemianopia in MELAS with documented visual field and MRI findings with resolution between each episode.

Quality of Life, Cognition and Mood in Adults with Pediatric Multiple Sclerosis.

BACKGROUND: Pediatric onset multiple sclerosis (MS) negatively affects cognitive function, mood and health related quality of life (HRQOL). We aimed to explore the cognitive, psychological and HRQOL impacts of pediatric MS on young adults and to explore the relationships between disability, disease duration, cognition, mood and HRQOL in this hypotheses generating study. METHODS: Thirty-four young adults with pediatric onset MS at St. Michael's Hospital in Toronto were included in this cross-sectional study (mean age 21.3 years, 56% female). Participants completed assessments of physical disability (Expanded Disability Status Scale (EDSS)), cognitive function (Symbol Digit Modalities Test (SDMT)), mood (Beck Depression Inventory II (BDI-II)), and HRQOL (Short Form Health Survey (SF-36v2)). Findings were compared to age- and gender- matched normative data. RESULTS: Individuals with pediatric MS performed worse on the SDMT compared to normative data, with 53% demonstrating cognitive impairment. There was no difference in BDI-II scores from normative data, but 21% showed at least mild depression. There was a non-significant impairment in physical HRQOL compared to normative data. Decreased physical HRQOL was related to disability (EDSS), while mental HRQOL was related to depression (BDI-II). CONCLUSIONS: Young adults with pediatric MS have reduced cognitive function. Non-significant reductions in HRQOL may be partly attributed to physical disability and depression. These factors should be addressed in the care of adults with pediatric MS. Further studies including control groups and longitudinal design are needed to confirm these findings.

Identifying individuals with multiple sclerosis in an electronic medical record.

BACKGROUND: The increasing use of electronic medical records (EMRs) presents an opportunity to efficiently evaluate and improve quality of care for individuals with MS. OBJECTIVES: We aimed to establish an algorithm to identify individuals with MS within EMRs. METHODS: We used a sample of 73,003 adult patients from 83 primary care physicians in Ontario using the Electronic Medical Record Administrative data Linked Database (EMRALD). A reference standard of 247 individuals with MS was identified through chart abstraction. The accuracy of identifying individuals with MS in an EMR was assessed using information in the cumulative patient profile (CPP), prescriptions and physician billing codes. RESULTS: An algorithm identifying MS in the CPP performed well with 91.5% sensitivity, 100% specificity, 98.7% PPV and 100% NPV. The addition of prescriptions for MS-specific medications and physician billing code 340 used four times within any 12-month timeframe slightly improved the sensitivity to 92.3% with a PPV of 97.9%. CONCLUSIONS: Data within an EMR can be used to accurately identify patients with MS. This study has positive implications for clinicians, researchers and policy makers as it provides the potential to identify cohorts of MS patients in the primary care setting to examine quality of care.

Ageing and multiple sclerosis.

The factor that is most relevant and strongly associated with the clinical course of multiple sclerosis is chronological age. Very young patients exclusively have relapsing remitting disease, whereas those with later onset disease face a more rapid development of permanent disability. For people with progressive multiple sclerosis, the poor response to current disease modifying therapies might be related to ageing in the immune system and CNS. Ageing is also associated with increased risks of side-effects caused by some multiple sclerosis therapies. Both somatic and reproductive ageing processes might contribute to development of progressive multiple sclerosis. Understanding the role of ageing in immune and neural cell function in patients with multiple sclerosis might be key to halting non-relapse-related progression. The growing literature on potential therapies that target senescent cells and ageing processes might provide effective strategies for remyelination and neuroprotection.

Family planning considerations in people with multiple sclerosis.

Multiple sclerosis is often diagnosed in patients who are planning on having children. Although multiple sclerosis does not negatively influence most pregnancy outcomes, less is known regarding the effects of fetal exposure to novel disease-modifying therapies (DMTs). The withdrawal of some DMTs during pregnancy can modify the natural history of multiple sclerosis, resulting in a substantial risk of pregnancy-related relapse and disability. Drug labels are typically restrictive and favour fetal safety over maternal safety. Emerging data reporting outcomes in neonates exposed to DMTs in utero and through breastfeeding will allow for more careful and individualised treatment decisions. This emerging research is particularly important to guide decision making in women with high disease activity or who are treated with DMTs associated with risk of discontinuation rebound. As increasing data are generated in this field, periodic updates will be required to provide the most up to date guidance on how best to achieve multiple sclerosis stability during pregnancy and post partum, balanced with fetal and newborn safety.

Anti-CD20 monoclonal antibody therapy in postpartum women with neurological conditions.

OBJECTIVE: Postpartum, patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) have increased risk for disease activity. Anti-CD20 IgG1 monoclonal antibodies (mAb) are increasingly used as disease-modifying therapies (DMTs). Patients may wish to both breastfeed and resume DMT postpartum. This study aimed to determine the transfer of anti-CD20 IgG1 mAbs, ocrelizumab, and rituximab (OCR/RTX), into mature breastmilk and describe maternal and infant outcomes. METHODS: Fifty-seven cis-women receiving OCR/RTX after 59 pregnancies and their infants were enrolled and followed up to 12M postpartum or 90 days post-infusion. Breastmilk was collected pre-infusion and serially up to 90 days and assayed for mAb concentration. Medical records and patients' questionnaire responses were obtained to assess neurologic, breastfeeding, and infant development outcomes. RESULTS: The median average concentration of mAb in breastmilk was low (OCR: 0.08 µg/mL, range 0.05-0.4; RTX: 0.03 µg/mL, range 0.005-0.3). Concentration peaked 1-7 days post-infusion in most (77%) and was nearly undetectable after 90 days. Median average relative infant dose was <1% (OCR: 0.1%, range 0.07-0.7; RTX: 0.04%, range 0.005-0.3). Forty-three participants continued to breastfeed post-infusion. At 8-12 months, the proportion of infants' growth between the 3rd and 97th World Health Organization percentiles did not differ for breastfed (36/40) and non-breastfed (14/16, p > 0.05) infants; neither did the proportion with normal development (breastfed: 37/41, non-breastfed: 11/13; p > 0.05). After postpartum infusion, two mothers experienced a clinical relapse. INTERPRETATION: These confirm minimal transfer of mAb into breastmilk. Anti-CD20 mAb therapy stabilizes MS activity before conception to the postpartum period, and postpartum treatments appears to be safe and well-tolerated for both mother and infant.

Clinical characteristics and outcomes of multiple sclerosis patients with COVID-19 in Toronto, Canada.

OBJECTIVE: To report clinical characteristics and outcomes of people with multiple sclerosis (PwMS) who developed COVID-19 infection in Toronto, Canada. METHODS: Descriptive, retrospective, single-center study that included all known PwMS at the St. Michael's Hospital MS Clinic who had PCR-confirmed COVID-19 infection between March 2020 and May 2021. RESULTS: Of 7000 PwMS in our clinic, 80 (1.1%) tested positive for SARS-CoV-2. Fifty-four (67.5%) were on disease-modifying therapy (DMT) without over-representation of any single treatment. Seventy-one patients (88.8%) had mild symptoms, but nine (11.3%) were hospitalized and one 70-year-old male patient not on treatment died. Of those hospitalized, one-third were treated with ocrelizumab. CONCLUSION: In Toronto, PwMS did not appear to have higher prevalence of COVID-19 infection compared to the general population, but disease severity may be affected by DMT use. Our findings add to the accumulating global data regarding COVID-19 infection in PwMS.

A hormonal therapy for menopausal women with MS: A phase Ib/IIa randomized controlled trial.

INTRODUCTION: Most women develop MS before menopause. Menopausal hot flashes can worsen MS symptoms, and could be relieved with hormone therapy. Our objective was to evaluate feasibility, tolerability and symptom response of Duavee® (bazedoxifene + conjugated estrogen) in a Phase Ib/IIa double-blind randomized controlled clinical trial. METHODS: We randomized 24 peri/postmenopausal women with MS and symptomatic hot flashes 1:1 to Duavee® versus placebo. Evaluations occurred at baseline and 2 months. RESULTS: Groups were balanced for age (mean 51.2 ± 3.6 years), EDSS [median 3 (IQR:2.5, 4.5)], and MS duration. 21/24 participants completed the study. FEASIBILITY: Enrollment was protracted (34 months), partially due to concerns about hormone therapy safety. TOLERABILITY: treatment group participants reported greater satisfaction and fewer missed doses; one participant (placebo) developed new MRI lesions; liver function testing remained normal for all patients. SYMPTOMS: Hot Flash Related Daily Interference scale at 2 months was lower in treatment vs. placebo group [median (IQR) of 4 (0.5, 14) vs. 9 (0, 33)]. Between-group differences were not statistically significant. CONCLUSION: Despite perceived benefits in MS, estrogens have perceived risks that represent a hurdle to enrollment. With appropriate education and screening of participants, the favorable study retention (87%) and treatment satisfaction observed in the current study support the feasibility of a longer, powered trial to evaluate whether a proven treatment for menopausal symptoms, Duavee®, could also improve MS-related function in menopausal women with MS.

The toronto observational study of natalizumab in multiple sclerosis.

BACKGROUND: Natalizumab is indicated for the treatment of relapsing multiple sclerosis (MS) with insufficient response to first-line disease-modifying therapy (DMT). We studied the efficacy of natalizumab for treatment of MS in a single centre observational design. METHODS: A retrospective observational study of 146 patients [66% female; mean age 37.4; 72% relapsing remitting MS (RRMS), 28% secondary progressive MS (SPMS)] referred for natalizumab treatment at St. Michael's Hospital MS Clinic between 2007 and August 2009. Data included demographic, clinical (Expanded Disability Status Scale (EDSS) and annualized relapse rate (ARR)) and patient self-report measures. RESULTS: The mean duration of treatment was 20 months in those treated with natalizumab and 97% had received prior DMTs. Eighty-three patients (57%) received at least 12 months of natalizumab treatment. In those who received at least 12 months of treatment, baseline ARR and EDSS were 1.6 and 2.7 in RRMS patients versus 1.0 and 5.4 in SPMS with relapses. The ARR decreased with natalizumab treatment to 0.38 (76% reduction, p<0.001) in RRMS versus 0.32 in SPMS patients (68% reduction, p=0.01). There was a treatment associated 11% reduction in EDSS to 2.4 (p=0.04) in RRMS, but no significant change in SPMS. Eighty-five percent of patients reported improved overall quality of life (QOL) and 62% indicated improved energy. CONCLUSIONS: There was a major reduction in relapse rate, stabilization in EDSS and improvement in QOL and energy in some patients on natalizumab, all similar to treatment effects in the pivotal trial.

Treatment of Women with Multiple Sclerosis Planning Pregnancy.

PURPOSE OF REVIEW: We review data available for treatment of multiple sclerosis (MS) before, during, and after pregnancy. We present recent data on disease-modifying therapies (DMT) before/during pregnancy and while breastfeeding, with treatment recommendations. RECENT FINDINGS: Observational data support the safety of injectable DMTs (glatiramer acetate, interferon-beta) for use in pregnancy, while some oral DMTs might be associated with fetal risk. Monoclonal antibodies (mAbs) before pregnancy such as rituximab or natalizumab likely do not pose significant fetal risks, but can cross the placenta with neonatal hematological abnormalities if given in the second trimester or later. Breastfeeding is associated with decreased risk of postpartum relapses. Finally, injectables and mAbs likely have low transfer into breastmilk. SUMMARY: Many women with MS do not require DMTs during pregnancy, although injectables could be continued. For women with highly active MS, cell-depleting therapies could be given before conception, or natalizumab could be continued through pregnancy, with monitoring of the fetus. Women should be encouraged to breastfeed, and those with higher relapse risk could consider injectables or mAbs while breastfeeding. Further data on safety of DMTs around pregnancy are needed. Maximizing function through non-pharmacologic approaches is complementary to DMTs. Special considerations for pregnancy and DMTs during the COVID-19 pandemic are needed.

Clinical and Radiologic Disease Activity in Pregnancy and Postpartum in MS.

OBJECTIVE: To evaluate radiologic and clinical inflammatory activity in women with MS during pregnancy and postpartum. METHODS: We performed a retrospective analysis of prospectively collected clinical and MRI reports for women who became pregnant while followed at the University of California, San Francisco MS Center between 2005 and 2018. Proportion of brain MRIs with new T2-hyperintense or gadolinium enhancing (Gd+) lesions (primary outcome) and annualized relapse rate (ARR; secondary) were compared before and after pregnancy. RESULTS: We identified 155 pregnancies in 119 women (median Expanded Disability Status Scale [EDSS] 2.0). For the 146 live birth pregnancies, prepregnancy ARR was 0.33; ARR decreased during pregnancy, particularly the third trimester (ARR 0.10, p = 0.017) and increased in the 3 months postpartum (ARR 0.61, p = 0.012); and 16% of women experienced a clinically meaningful increase in EDSS. Among 70 pregnancies with paired brain MRIs available, 53% had new T2 and/or Gd+ lesions postpartum compared with 32% prepregnancy (p < 0.001). Postpartum clinical relapses were associated with Gd+ lesions (p < 0.001). However, even for patients without postpartum relapses, surveillance brain MRIs revealed new T2 and/or Gd+ lesions in 31%. Protective effects of exclusive breastfeeding for ≥3 months (odds ratio = 0.3, 95% confidence interval 0.1-0.9) were observed for relapses. CONCLUSIONS: Building on previous reports of increased relapse rate in the first 3 months postpartum, we report a significant association between inflammation on MRI and this clinical activity. We also detected postpartum radiologic activity in the absence of relapses. Both clinical and radiologic reassessment may inform optimal treatment decision-making during the high-risk early postpartum period.

High titers of myelin oligodendrocyte glycoprotein antibody are only observed close to clinical events in pediatrics.

BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG)-IgG is increasingly detected in children with CNS demyelinating diseases. Due to the clinical overlap in children with CNS demyelination with and without MOG-IgG positivity, identifying distinct characteristics would help early diagnosis. OBJECTIVE: To compare the specific features that may help differentiate MOG-IgG positive from negative children with CNS demyelinating diseases. To compare characteristics of patients with high and low MOG-IgG titers. METHODS: Children with CNS demyelinating disorders with onset before 18 years of age who were tested for MOG-IgG at the University of California San Francisco were included. This retrospective study collected the following by chart review: demographic, clinical, MRI, CSF, and treatment data. Serum was tested for MOG-IgG at Mayo Clinic by live cell-based fluorescent activated cell sorting assay with titer ≥1:20 confirming positivity. RESULTS: We assessed 65 Mog-IgG positive and 65 MOG-IgG negative patients. Median (IQR) age of onset was 7.6 (6.6) years for MOG-IgG positive and 13.8 (5.8) years for MOG-IgG negative (p<0.001). The female to male ratio was approximately 1:1 for the MOG-IgG positive group and 3:1 for the negative group (p=0.042). The most common initial diagnosis was demyelinating disease not otherwise specified (52.3%) in the positive group, compared to relapsing-remitting multiple sclerosis (41.5%) in the negative group (p<0.01). Optic nerve involvement (52.3%) was the most common clinical localization at onset for the MOG-IgG positive group, while brainstem/cerebellar (49.2%) localization predominated in the MOG-IgG negative group. The positive group also presented more often with a severe event at disease onset than the negative group (81.5% vs 60.3%; p< 0.002). MOG-IgG positive children had a lower frequency of oligoclonal bands (15.8% vs 57.4%; p<0.001). The frequency of baseline brain and spinal cord MRI abnormalities were similar in both groups; however, MOG-IgG positive patients more often had T2 hyperintense lesions in the optic nerves (26/43 vs 10/41; p<0.001). Disease-modifying medications were used in 64.6% of MOG-IgG positive patients versus 80% of negative children. Of the 32 positive patients with follow-up titers, seven reverted to negative while two who tested negative initially converted to positive. Positive titers greater than 1:160 were only observed within four months of a clinical event (disease onset or relapse). Patients with high and low MOG-IgG titers were comparable in demographic and clinical characteristics. CONCLUSION: Despite some clinical overlap, we report notable demographic, MRI and CSF differences between MOG-IgG positive and negative children with CNS demyelinating disorders at disease onset. High MOG-IgG titers were only observed close to a clinical event.

A pilot study of oxidative pathways in MS fatigue: randomized trial of N-acetyl cysteine.

OBJECTIVE: To assess feasibility, tolerability, and safety of N-acetyl cysteine (NAC) for fatigue in progressive MS. Secondary objectives evaluated changes in fatigue and oxidative pathway biomarkers on NAC versus placebo. METHODS: Individuals with progressive MS with Modified Fatigue Impact Scale (MFIS) > t38 were randomized 2:1 to NAC 1250mg TID or placebo for 4 weeks. The primary outcome was tolerability and safety. The secondary outcome to evaluate efficacy was MFIS change from baseline to week 4 between groups. Exploratory biomarker outcomes included change in blood GSH/GSSG ratio (reduced-to-oxidized glutathione (GSH)) and in vivo relative GSH using 7T MR spectroscopy (MRS) between groups. Fisher exact test was used for categorical and rank sum for continuous outcomes. RESULTS: Fifiteen were randomized (10 NAC, 5 placebo; mean age 56.1 years, 80% female, median EDSS 6.0). At least one adverse event (AE) occurred in 60% on NAC versus 80% on placebo (p = 0.75). There were two AEs attributed to NAC in one patient (abdominal pain and constipation), with 94% adherence to NAC. MFIS decreased in both groups at week 4, with the mean improvement of 11-points on NAC versus 18-points on placebo (p = 0.33). GSH/GSSG ratio decreased on placebo (-0.6) and NAC (-0.1) (p = 0.18). Change in GSH levels to total creatine in anterior and posterior cingulate cortex, insula, caudate, putamen, and thalamus did not differ between groups. INTERPRETATION: NAC was well-tolerated in progressive MS, although reduction in fatigue on NAC was similar to placebo. Antioxidant blood and MRS biomarkers were not significantly altered by NAC, which could be due to dose, route of administration, time of sample collection, short half-life, or lack of effect. REGISTERED: clinicaltrials.gov NCT02804594.

Biosensor vital sign detects multiple sclerosis progression.

OBJECTIVE: To determine whether a small, wearable multisensor device can discriminate between progressive versus relapsing multiple sclerosis (MS) and capture limb progression over a short interval, using finger and foot tap data. METHODS: Patients with MS were followed prospectively during routine clinic visits approximately every 6 months. At each visit, participants performed finger and foot taps wearing the MYO-band, which includes accelerometer, gyroscope, and surface electromyogram sensors. Metrics of within-patient limb progression were created by combining the change in signal waveform features over time. The resulting upper (UE) and lower (LE) extremity metrics' discrimination of progressive versus relapsing MS were evaluated with calculation of AUROC. Comparisons with Expanded Disability Status Scale (EDSS) scores were made with Pearson correlation. RESULTS: Participants included 53 relapsing and 15 progressive MS (72% female, baseline mean age 48 years, median disease duration 11 years, median EDSS 2.5, median 10 months follow-up). The final summary metrics differentiated relapsing from secondary progressive MS with AUROC UE 0.93 and LE 0.96. The metrics were associated with baseline EDSS (UE P = 0.0003, LE P = 0.0007). While most had no change in EDSS during the short follow-up, several had evidence of progression by the multisensor metrics. INTERPRETATION: Within a short follow-up interval, this novel multisensor algorithm distinguished progressive from relapsing MS and captured changes in limb function. Inexpensive, noninvasive and easy to use, this novel outcome is readily adaptable to clinical practice and trials as a MS vital sign. This approach also holds promise to monitor limb dysfunction in other neurological diseases.