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.

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.

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.

Serum neurofilament light chain in adult and pediatric patients with myelin oligodendrocyte glycoprotein antibody-associated disease: Correlation with relapses and seizures.

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) causes major disability as a consequence of recurrent demyelinating events and neuronal loss. Biomarkers identifying different phenotypes of recurrence or tissue damage might be useful to guide individualized therapy. Herein, we evaluated serum neurofilament light chain (sNfL) as a potential biomarker in both adult and pediatric MOGAD patients. Forty-nine patients with MOGAD (37 adults, 12 children) and 71 healthy controls (HCs) (56 adults, 15 children) were enrolled prospectively from September 2019 to April 2021 at the Third Affiliated Hospital of Sun Yat-sen University and the Children's Hospital, Zhejiang University School of Medicine. sNfL levels were determined using ultrasensitive single-molecule array assay and correlated with clinical parameters. The sNfL levels in MOGAD adults in a relapsed state (median: 31.0 pg/ml) were higher than those in a remission state (8.1 pg/ml, p = 0.001) and in HC adults (10.3 pg/ml, p = 0.004). Similar results were observed in children (relapse: 46.8 pg/ml vs. remission: 13.1 pg/ml, p = 0.001; and vs. HCs: 8.2 pg/ml, p = 0.007) sNfL levels were correlated with recent relapses within 60 days (multivariate: ß = 2.02, p = 0.003), seizures (multivariate: ß = 2.50, p = 0.021) and brain lesions on magnetic resonance imaging (MRI) of a recent relapse (multivariate: ß = 1.72, p = 0.012). Our study showed that sNfL levels are beneficial for identifying recent relapses and seizures and suggest that adult and pediatric MOGAD patients had similar sNfL levels.

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.

Prediction of multiple sclerosis outcomes when switching to ocrelizumab.

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

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.

Serum NfL associated with anti-NMDA receptor encephalitis.

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

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.

Serum neurofilament light chain and glial fibrillary acidic protein in AQP4-IgG-seropositive neuromyelitis optica spectrum disorders and multiple sclerosis: A cohort study.

We investigated the serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) levels in a cohort of Chinese patients with neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) in relation to clinical disease course and treatment. sNfL and sGFAP levels were determined by ultrasensitive single molecule array (Simoa) assay in patients with NMOSD (n = 102) and MS (n = 98) and healthy controls (HCs; n = 84). Notably, 13 patients with NMOSD and 27 patients with MS were enrolled in the 1-year follow-up cohort. Levels were compared with data such as clinical course, disease duration, Expanded Disability Status Scale (EDSS) score, and lesions on MRI. Higher levels of sNfL and sGFAP were found in subjects with NMOSD and MS than in HCs (sNfL, median 12.11, 17.5 vs. 8.88 pg/ml, p < .05; sGFAP, median 130.2, 160.4 vs. 80.01 pg/ml, p < .05). Moreover, sNfL levels were higher in the relapse phase of MS than in the relapse phase of NMOSD (30.02 vs. 14.57 pg/ml, p < .05); sGFAP levels were higher in the remission phase of MS than in the remission phase of NMOSD (159.8 vs. 124.5 pg/ml, p < .01). A higher sGFAP/sNfL quotient at relapse differentiated NMOSD from MS. Multivariate analyses indicated that sGFAP levels were associated with the EDSS score in NMOSD (p < .05). At the 1-year follow-up, sNfL and sGFAP levels were both decreased in NMOSD patients in remission, while only sNfL levels were decreased in MS patients in remission. sGFAP and sNfL are potential blood biomarkers for diagnosing and monitoring NMOSD and MS.

Use of Twitter in Neurology: Boon or Bane?

Twitter is a free, open access social media platform that is widely used in medicine by physicians, scientists, and patients. It provides an opportunity for advocacy, education, and collaboration. However, it is likely not utilized to its full advantage by many disciplines in medicine, and pitfalls exist in its use. In particular, there has not been a review of Twitter use and its applications in the field of neurology. This review seeks to provide an understanding of the current use of Twitter in the field of neurology to assist neurologists in engaging with this potentially powerful application to support their work.

Myelin oligodendrocyte glycoprotein-associated disorders are associated with HLA subtypes in a Chinese paediatric-onset cohort.

OBJECTIVE: Myelin oligodendrocyte glycoprotein-associated disorders (MOGADs) are a rare new neurological autoimmune disease with unclear pathogenesis. Since a linkage of the disease to the human leucocyte antigen (HLA) has not been shown, we here investigated whether MOGAD is associated with the HLA locus. METHODS: HLA genotypes of 95 patients with MOGADs, assessed between 2016 and 2018 from three academic centres, were compared with 481 healthy Chinese Han individuals. Patients with MOGADs included 51 paediatric-onset and 44 adult-onset cases. All patients were seropositive for IgG targeting the myelin oligodendrocyte glycoprotein (MOG). RESULTS: Paediatric-onset MOGAD was associated with the DQB1*05:02-DRB1*16:02 alleles (OR=2.43; OR=3.28) or haplotype (OR=2.84) of HLA class II genes. The prevalence of these genotypes in patients with paediatric-onset MOGAD was significantly higher than healthy controls (padj=0.0154; padj=0.0221; padj=0.0331). By contrast, adult-onset MOGAD was not associated with any HLA genotype. Clinically, patients with the DQB1*05:02-DRB1*16:02 haplotype exhibited significantly higher expanded disability status scale scores at onset (p=0.004) and were more likely to undergo a disease relapse (p=0.030). HLA-peptide binding prediction algorithms and computational docking analysis provided supporting evidence for the close relationship between the MOG peptide subunit and DQB1*05:02 allele. In vitro results indicated that site-specific mutations of the predicted target sequence reduced the antigen-antibody binding, especially in the paediatric-onset group with DQB1*05:02 allele. CONCLUSIONS: This study demonstrates a possible association between specific HLA class II alleles and paediatric-onset MOGAD, providing evidence for the conjecture that different aetiology and pathogenesis likely underlie paediatric-onset and adult-onset cases of MOGAD.

Redefining the Multiple Sclerosis Severity Score (MSSS): The effect of sex and onset phenotype.

BACKGROUND: The Multiple Sclerosis Severity Score (MSSS) is a widely used measure of the disability progression rate. However, the global MSSS may not be the best basis for comparison between all patient groups. OBJECTIVE: We evaluated sex-specific and onset phenotype-specific MSSS matrices to determine if they were more effective than the global MSSS as a basis for comparison within these subsets. METHODS: Using a large international dataset of multiple sclerosis (MS) patient records and the original MSSS algorithm, we constructed global, sex-specific and onset phenotype-specific MSSS matrices. We compared matrices using permutation analysis. RESULTS: Our final dataset included 30,203 MS cases, with 28.9% males and 6.5% progressive-onset cases. Our global MSSS matrix did not differ from previously published data (p > 0.05). The progressive-onset-specific matrix differed significantly from the relapsing-onset-specific matrix (p < 0.001), with lower MSSS attributed to cases with the same Expanded Disability Status Score (EDSS) and disease duration. When evaluated with a simulation, using an onset-specific MSSS improved statistical power in mixed cohorts. There were no significant differences by sex. CONCLUSION: The differences in the disability accrual rate between progressive- and relapsing-onset MS have a significant effect on MSSS. An onset-specific MSSS should be used when comparing the rate of disability progression among progressive-onset cases and for mixed cohorts.

Dimethyl fumarate-associated transient bone marrow oedema syndrome.

BACKGROUND: Dimethyl fumarate (DMF) is a commonly used and effective treatment for relapsing and remitting multiple sclerosis. Its use results in impairment of the transcription factor nuclear factor erythroid-derived 2 (E2)-related factor (Nrf2), which is involved in both immunomodulation and bone health. DMF has not previously been reported to cause bone marrow complications, though other fumarates including tenofovir have. The mechanism of fumarate-associated bone toxicity remains unclear with altered osteoblastic gene expression and function suggested. METHODS: We present a case of a 54-year-old female with relapsing remitting multiple sclerosis (RRMS) treated for 30 months with DMF who developed relapsing atraumatic lower limb bone pain. RESULTS: Serial imaging revealed multifocal areas of bone marrow oedema and trabecular fractures. The patient was diagnosed with transient bone marrow oedema syndrome. Management consisted of cessation of therapy and treatment with the pro-osteobalstic agent denosumab. CONCLUSION: In this instance of DMF-associated bone marrow oedema, cessation of DMF and treatment with denosumab resulted in symptomatic improvement. DMF therapy may potentially result in bone marrow oedema due to inhibition of common upstream signalling pathways, including the Nrf2 signalling pathway.

Warts and all: Fingolimod and unusual HPV-associated lesions.

BACKGROUND: Fingolimod is used to reduce relapse rates in relapsing-remitting multiple sclerosis (MS). It is a sphingosine 1-phosphate (S1P) analogue having antagonistic effects on S1P receptors. Its immunosuppressive effect is due to reduced circulating lymphocyte numbers, and it may also be associated with impaired intrinsic cancer surveillance. Fingolimod side effects include increased rates and severity of viral infections particularly varicella zoster. METHODS: We present five cases of chronic and treatment refractory warts associated with fingolimod therapy. RESULTS: Each of the five cases presenting with chronic warts while receiving fingolimod therapy had prolonged periods of lymphopenia and improvements were seen following dose reduction or cessation of fingolimod. CONCLUSION: Cutaneous warts are associated with human papilloma virus (HPV) infection, suggesting an increased risk of other HPV-driven conditions such as cervical cancer following fingolimod administration. HPV viruses are responsible for approximately 90% of cervical cancers as well as a significant portion of anogenital cancers and have a high prevalence in sexually active adults. Given the reduced immune response to viral infections and potential impaired cancer surveillance in those receiving fingolimod, HPV vaccination and frequent assessment for the development of HPV-associated malignancies are recommended.

Relapsing optic neuritis and meningoencephalitis in a child: case report of delayed diagnosis of MOG-IgG syndrome.

BACKGROUND: Recurrent optic neuritis (ON) was previously thought to be associated with multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). Meningoencephalitis has recently been suggested to be a clinical finding typical of myelin oligodendrocyte glycoprotein (MOG) encephalomyelitis. We report a Chinese patient with recurrent ON at disease initiation, who had a delayed diagnosis of MOG-IgG syndrome, until recurrent meningoencephalitis appeared and serum MOG-IgG was detected. CASE PRESENTATION: From the age of 7 years, an AQP4-IgG negative female patient had 10 disease recurrences, including 4 episodes of recurrent ON, 4 episodes of fever and meningoencephalitis, and 2 episodes of ON as well as meningoencephalitis. She was initially diagnosed as recurrent ON and treated with glucocorticoids followed by gradual tapering when ON reoccurred. Later, she was diagnosed as central nervous system infection when fever and meningoencephalitis appeared, and antiviral drugs and glucocorticoids were used. However, when she returned to our department for follow-up on July 2017, the results of serum demyelinating autoimmune antibody revealed positive MOG-IgG (titer 1:320 by an in-house, cell-based assay using live cells transfected with full-length human MOG). A diagnosis of MOG-IgG syndrome was established. CONCLUSIONS: Testing for MOG-IgG in atypical MS and NMOSD patients, and patients with meningoencephalitis with a history of relapsing demyelinating symptoms is warranted.

Cladribine versus fingolimod, natalizumab and interferon ß for multiple sclerosis.

OBJECTIVE: This propensity score-matched analysis from MSBase compared the effectiveness of cladribine with interferon ß, fingolimod or natalizumab. METHODS: We identified all patients with relapse-onset multiple sclerosis, exposure to the study therapies and ⩾1-year on-treatment follow-up from MSBase. Three pairwise propensity score-matched analyses compared treatment outcomes over 1 year. The outcomes were hazards of first relapse, disability accumulation and disability improvement events. Sensitivity analyses were completed. RESULTS: The cohorts consisted of 37 (cladribine), 1940 (interferon), 1892 (fingolimod) and 1410 patients (natalizumab). The probability of experiencing a relapse on cladribine was lower than on interferon ( p = 0.05), similar to fingolimod ( p = 0.31) and higher than on natalizumab ( p = 0.042). The probability of disability accumulation on cladribine was similar to interferon ( p = 0.37) and fingolimod ( p = 0.089) but greater than natalizumab ( p = 0.021). The probability of disability improvement was higher on cladribine than interferon ( p = 0.00017), fingolimod ( p = 0.0025) or natalizumab ( p = 0.00099). Sensitivity analyses largely confirmed the above results. CONCLUSION: Cladribine is an effective therapy for relapse-onset multiple sclerosis. Its effect on relapses is comparable to fingolimod and its effect on disability accrual is comparable to interferon ß and fingolimod. Cladribine may potentially associate with superior recovery from disability relative to interferon, fingolimod and natalizumab.

Brain Immunohistopathology in a Patient with Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy.

BACKGROUND: Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a novel meningoencephalomyelitis. However, the pathogenesis of this disease is unclear. We therefore examined a brain biopsy from a patient with autoimmune GFAP astrocytopathy by immunohistopathology. METHODS: We examined brain biopsy sections from a patient with autoimmune GFAP astrocytopathy using hematoxylin and eosin (HE) and Luxol fast blue (LFB) staining, and immunostaining with antibodies for CD4, CD8, CD3, CD20, CD68, CD138, Neu-N, GFAP, myelin oligodendrocyte glycoprotein (MOG), and aquaporin-4 (AQP4). RESULTS: HE staining revealed extensive inflammatory cells (marked lymphocytes) around brain vessels, and LFB showed no signs of demyelination or axon loss. Immunohistochemical analysis showed CD3+ and CD4+ T cells cuffing around brain vessels, accompanied by CD8+ T cells, CD20+ B cells, and CD138+ plasma cells, while some macrophages (CD68+) were scattered throughout the brain parenchyma. There was no loss of AQP4 or MOG expression in this patient, while GFAP was abundantly expressed. CONCLUSIONS: These findings suggest that inflammatory cells, including T cells, B cells, plasma cells, and macrophages, are involved in autoimmune GFAP astrocytopathy. Demyelination and astrocyte loss may not necessarily occur in this disease.

Evolving Identification of Blood Cells Associated with Clinically Isolated Syndrome: Importance of Time since Clinical Presentation and Diagnostic MRI.

It is not clear how the profile of immune cells in peripheral blood differs between patients with clinically isolated syndrome (CIS) and healthy controls (HC). This study aimed to identify a CIS peripheral blood signature that may provide clues for potential immunomodulatory approaches early in disease. Peripheral blood mononuclear cells (PBMCs) were collected from 18 people with CIS, 19 HC and 13 individuals with other demyelinating conditions (ODC) including multiple sclerosis (MS). Individuals with CIS separated into two groups, namely those with early (≤14 days post-diagnostic magnetic resonance imaging (MRI); n = 6) and late (≥27 days; n = 12) blood sampling. Transitional B cells were increased in the blood of CIS patients independently of when blood was taken. However, there were two time-dependent effects found in the late CIS group relative to HC, including decreased CD56bright NK cells, which correlated significantly with time since MRI, and increased CD141+ myeloid dendritic cell (mDC2) frequencies. Higher CD1c+ B cells and lower non-classical monocyte frequencies were characteristic of more recent demyelinating disease activity (ODC and early CIS). Analysing cell populations by time since symptoms (subjective) and diagnostic MRI (objective) may contribute to understanding CIS.

The low EOMES/TBX21 molecular phenotype in multiple sclerosis reflects CD56+ cell dysregulation and is affected by immunomodulatory therapies.

Multiple Sclerosis (MS) is an autoimmune disease treated by therapies targeting peripheral blood cells. We previously identified that expression of two MS-risk genes, the transcription factors EOMES and TBX21 (ET), was low in blood from MS and stable over time. Here we replicated the low ET expression in a new MS cohort (p<0.0007 for EOMES, p<0.028 for TBX21) and demonstrate longitudinal stability (p<10(-4)) and high heritability (h(2)=0.48 for EOMES) for this molecular phenotype. Genes whose expression correlated with ET, especially those controlling cell migration, further defined the phenotype. CD56+ cells and other subsets expressed lower levels of Eomes or T-bet protein and/or were under-represented in MS. EOMES and TBX21 risk SNP genotypes, and serum EBNA-1 titres were not correlated with ET expression, but HLA-DRB1*1501 genotype was. ET expression was normalised to healthy control levels with natalizumab, and was highly variable for glatiramer acetate, fingolimod, interferon-beta, dimethyl fumarate.