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BackgroundOngoing controversy exists regarding optimal management of disease modifying therapy (DMT) in older people with multiple sclerosis (pwMS). There is concern that the lower relapse rate, combined with a higher risk of DMT-related infections and side effects, may alter the risk-benefit balance in older pwMS. Given the lack of pwMS above age 60 in randomised controlled trials, the comparative efficacy of high-efficacy DMTs such as ocrelizumab has not been shown in older pwMS. We aimed to evaluate the comparative effectiveness of ocrelizumab, a high-efficacy DMT, versus interferon/glatiramer acetate (IFN/GA) in pwMS over the age of 60.MethodsUsing data from MSBase registry, this multicentre cohort study included pwMS above 60 who switched to or started on ocrelizumab or IFN/GA. We analysed relapse and disability outcomes after balancing covariates using an inverse probability treatment weighting (IPTW) method. Propensity scores were obtained based on age, country, disease duration, sex, baseline Expanded Disability Status Scale, prior relapses (all-time, 12 months and 24 months) and prior DMT exposure (overall number and high-efficacy DMTs). After weighting, all covariates were balanced. Primary outcomes were time to first relapse and annualised relapse rate (ARR). Secondary outcomes were 6-month confirmed disability progression (CDP) and confirmed disability improvement (CDI).ResultsA total of 248 participants received ocrelizumab, while 427 received IFN/GA. The IPTW-weighted ARR for ocrelizumab was 0.01 and 0.08 for IFN/GA. The IPTW-weighted ARR ratio was 0.15 (95% CI 0.06 to 0.33, p<0.001) for ocrelizumab compared with IFN/GA. On IPTW-weighted Cox regression models, HR for time to first relapse was 0.13 (95% CI 0.05 to 0.26, p<0.001). The hazard of first relapse was significantly reduced in ocrelizumab users after 5 months compared with IFN/GA users. However, the two groups did not differ in CDP or CDI over 3.57 years.ConclusionIn older pwMS, ocrelizumab effectively reduced relapses compared with IFN/GA. Overall relapse activity was low. This study adds valuable real-world data for informed DMT decision making with older pwMS. Our study also confirms that there is a treatment benefit in older people with MS, given the existence of a clear differential treatment effect between ocrelizumab and IFN/GA in the over 60 age group.

BackgroundMyelin 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.MethodsMOG-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.ResultsOf 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%).ConclusionsNon-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.

BackgroundTo compare the effectiveness and treatment persistence of ocrelizumab, cladribine and natalizumab in patients with relapsing–remitting multiple sclerosis switching from fingolimod.MethodsUsing data from MSBase registry, this multicentre cohort study included subjects who had used fingolimod for ≥6 months and then switched to ocrelizumab, cladribine or natalizumab within 3 months after fingolimod discontinuation. We analysed relapse and disability outcomes after balancing covariates using an inverse-probability-treatment-weighting method. Propensity scores for the three treatments were obtained using multinomial-logistic regression. Due to the smaller number of cladribine users, comparisons of disability outcomes were limited to natalizumab and ocrelizumab.ResultsOverall, 1045 patients switched to ocrelizumab (n=445), cladribine (n=76) or natalizumab (n=524) after fingolimod. The annualised relapse rate (ARR) for ocrelizumab was 0.07, natalizumab 0.11 and cladribine 0.25. Compared with natalizumab, the ARR ratio (95% confidence interval [CI]) was 0.67 (0.47 to 0.96) for ocrelizumab and 2.31 (1.30 to 4.10) for cladribine; the hazard ratio (95% CI) for time to first relapse was 0.57 (0.40 to 0.83) for ocrelizumab and 1.18 (0.47 to 2.93) for cladribine. Ocrelizumab users had an 89% lower discontinuation rate (95% CI, 0.07 to 0.20) than natalizumab, but also a 51% lower probability of confirmed disability improvement (95% CI, 0.32 to 0.73). There was no difference in disability accumulation.ConclusionAfter fingolimod cessation, ocrelizumab and natalizumab were more effective in reducing relapses than cladribine. Due to the low ARRs in all three treatment groups, additional observation time is required to determine if statistical difference in ARRs results in long-term disability differences.

IntroductionSeizures are a common characteristic of Autoimmune encephalitis (AIE). The use of the electroclinical characteristics to assist in the diagnosis of AIE has been explored1however use of specific electroencephalogram (EEG) changes has not been examined with regards to outcome prediction.MethodsPatients with AIE were recruited retrospectively across 4 hospitals in Victoria. Clinical Data was collected during admission and at final follow-up. EEGs of patients were reviewed using an objective proforma. Associations between EEG biomarkers and clinical outcomes were demonstrated using logistic regression modelling.ResultsWe recruited 88 patients with AIE and available EEGs. Presence of rhythmic delta, superimposed fast activity and an abnormal background were significantly more common in N-methyl-D-aspartame receptor (NMDAR) antibody associated AIE patients (p<0.05). ICU admission was associated with rhythmic delta epileptiform activity (OR 3.25, p=0.046), sharp elements in the EEG abnormality (OR 3.55, p=0.05), and an abnormal background rhythm (OR 3.56, p=0.03). Development of drug resistant epilepsy was associated with prolonged duration of abnormality on EEG (OR 11.99, p=0.013), and sharp elements in the EEG abnormality (OR 7.29, p=0.02).ConclusionWe have identified EEG biomarkers that differentiate NMDAR AIE from other subtypes, and likely represents an objective description of extreme delta brush which has previously been described in NMDAR AIE.2We have also demonstrated biomarkers associated with important outcomes that can be used to help guide treatment and prognosis.ReferencesLimotai C, Denlertchaikul C, Saraya AW, Jirasakuldej S. Predictive values and specificity of electroencephalographic findings in autoimmune encephalitis diagnosis. Epilepsy Behav2018;84:29–36.Veciana M, Becerra JL, Fossas P, Muriana D, Sansa G, Santamarina E, et al. EEG extreme delta brush: An ictal pattern in patients with anti-NMDA receptor encephalitis. Epilepsy Behav2015;49:280–5.

IntroductionMyelin oligodendrocyte glycoprotein (MOG) antibody mediated disease is an autoimmune demyelinating disorder which can resemble multiple sclerosis (MS).1 2Thus, this condition can be misdiagnosed and treated as MS.3We present the clinical trajectory of two cases initially diagnosed as MS, treated with Alemtuzumab followed by clinical and radiological deterioration. Both were subsequently found to have anti MOG antibody in their serum.MethodsThis is a retrospective case study based on a medical record search of neuroimmunology clinics in two teaching hospitals in Victoria. We searched for patients treated with Alemtuzumab who subsequently tested positive for MOG antibody.ResultsWe found two young women who fulfilled the eligibility criteria. One patient presented with dizziness and vertigo, the other with unilateral optic neuritis. Both had supratentorial MRI lesions and were both diagnosed as having MS. Both patients experienced multiple relapses while on treatment for MS. Hence, they were commenced on Alemtuzumab therapy. Unexpectedly, both patients experienced a decline in their clinical status with worsening of expanded disability status scale (EDSS) and an increasing lesion load on MRI brain. Their serum anti MOG antibodies were then found to be positive. Subsequently, patients were treated with rituximab and plasma exchange with a favorable response.ConclusionsThese two cases demonstrate that Alemtuzumab is ineffective and in fact can worsen cases of anti-MOG antibody associated encephalomyelitis. This highlights the importance of anti MOG antibody testing when patients diagnosed with MS do not respond to Alemtuzumab and in those patients presenting with atypical features of MS.ReferencesWeber MS, Derfuss T, Metz I, Bruck W. Defining distinct features of anti-MOG antibody associated central nervous system demyelination. Ther Adv Neurol Disord. 2018;11:1756286418762083.Narayan R, Simpson A, Fritsche K, Salama S, Pardo S, Mealy M, et al. MOG antibody disease: A review of MOG antibody seropositive neuromyelitis optica spectrum disorder. Mult Scler Relat Disord. 2018;25:66–72.Wildemann B, Jarius S, Schwarz A, Diem R, Viehover A, Hahnel S, et al. Failure of alemtuzumab therapy to control MOG encephalomyelitis. Neurology2017;89(2):207–9.

IntroductionLong-term exposure of women with Multiple sclerosis (MS, wwMS) to immunomodulatory or immunosuppressive treatments may increase the risk of cervical dysplasia. However, little is known about cervical dysplasia risk and Human Papillomavirus (HPV)-vaccine coverage in wwMS.MethodsAdult wwMS were recruited from two tertiary MS clinics. To explore the association between MS treatments (DMTs) and abnormal cervical screening tests (CSTs), we linked individual data from MSBase, the Victorian Cervical Screening Registry, and National HPV vaccination program registry (NHPVPR).ResultsTo date, we have recruited 208 wwMS of whom 102 had complete data (vaccination status, cervical screening tests, MSBase data) and no previous history of abnormal CST at MS onset for this interim analysis. The average age was 33.8 (18 to 59 yrs) and most (n=58, 88%) were unvaccinated. 19 wwMS (19%) had an abnormal CST after MS onset (incidence rate 20.6 cases/1000 person-years, 95% confidence interval 12.4–32.1) over average 9.0 years of follow-up. 57 wwMS were treated with lower-efficacy therapies (56%), 73 with a high-efficacy therapy (72%), and 44 were exposed to both. Eight abnormal CSTs were detected before starting high-efficacy therapy (rate 12.6, 95% CI (5.4–24.8)) and 11 were detected after starting high-efficacy therapy (rate 38.6, 95% CI (19.3–69.0), p=0.022.ConclusionWe provide preliminary data that high efficacy DMTs may increase the risk of abnormal CSTs over time. A larger cohort and inclusion of additional cervical dysplasia risk factors are required to fully elucidate risk in wwMS.

IntroductionCladribine tablets (marketed as Mavenclad®) is a new oral therapy, which has recently been listed on the pharmaceuticals benefit scheme (PBS) in Australia for treatment of relapsing MS. The current dosing schedule is for 2 courses given a year apart, which has been shown to be effective for treatment of MS up to 4 years in 75% of patients (based on annualised relapse rate). However, re-initiation of therapy after year 4 has not been studied.MethodsThis will be a multicentre, 6-year, phase IV, low interventional trial. Subjects considered for treatment with cladribine will receive an initial treatment course in year 1 and a continuing treatment course in year 2. After year 3, patients will have the option for re-dosing, if clinically indicated or to switch to another disease modifying therapy. Throughout the duration of the study we will assess blood based biomarkers including lymphocyte subsets, serum neurofilament light chain, DNA methylation and RNA analysis as well as MRI findings (brain volume/lesion load) and cognitive performance.ResultsThis study has been approved by the Hunter New England Local Health District Human Research Ethics Committee. The study is due to commence on March 14th.ConclusionsThis will be the first long-term efficacy trial of cladribine which offers re-initiation of therapy after the initial two courses. We expect this study will be an indication if any of the assessed biomarkers can be used to predict treatment efficacy or the need for re-initiation of Cladribine in MS patients.

IntroductionCladribine Tablets (Mavenclad®) is nucleoside analogue of deoxyadenosine, and an oral treatment for relapsing remitting MS (RRMS). In RRMS clinical trials, Cladribine has been shown to reduce brain atrophy, relapse rates, and new lesions on brain MRI. P2X7R is a purinergic receptor expressed in innate immune cells, and is thought to play a critical role in neuroinflammation. The mechanism of action of Cladribine on peripheral innate immune cells (monocytes), and its effect on P2X7R, is unclear, and forms the basis of this study.MethodsThis will be a Phase IV, multi-centre, 3 year, translational trial. Patients who are starting Cladribine as part of their routine clinical care will consent to take part in the study. Monocyte numbers and activation states will be measured at various times prior and after commencement of therapy. In addition, and in an in vitro setting the effect of Cladribine on P2X7R expression and function will be assessed, as well as measuring various cytokines/chemokines in serum. The laboratory data will also be correlated with clinical data from another long-term Cladribine study, CLOBAS.ResultsThis study has been approved by Alfred Health Human Research Ethics Committee. The study is to commence in April 2019.ConclusionThis study will shed light on whether Cladribine is exerting its beneficial effects via action on peripheral monocytes and alterations of their P2X7Rs. The laboratory and clinical data will be analysed to understand the relationship between innate immune parameters and patient outcome.

IntroductionNeuroimaging and CSF analysis compose essential steps in evaluating patients with autoimmune encephalitis (AE). No study has compared the magnitude and prognostic implications of these findings between different subtypes. Herein we examine cases of AE with neuronal cell surface antibodies, and contrast the results of early investigations.MethodsWe performed medical records search from 2008–2018 in 5 Victorian hospitals. Cases of AE were established in accordance with diagnostic criteria by Graus et al.1Clinical and laboratory data was collected. All neuroimaging was evaluated independently by a neuroradiologist.ResultsWe identified 52 patients with AE with neuronal cell surface antibodies (21 NMDAR, 27 VGKC, 3 AMPAR, 1 GABAb).We found that among patients with anti-LGI1 antibodies the presence of abnormal CSF correlated with increased rates of mortality (50% vs 0%). This effect was largely mediated by CSF lymphocytosis, which was present in 2 patients who both died within 12 months of diagnosis.We found that the development of hippocampal atrophy was more common amongst patients with abnormal MRI findings, but in particular those with changes affecting the medial temporal lobe. This effect was evident both in the cases with anti-VGKC antibodies (60% vs 18%, 75% vs 17%) and the cohort as a whole (56% vs 15%, 83% vs 13%).ConclusionsThis is the first study of its kind in Australia, and identifies some unique correlation between early investigation findings, and the clinical and radiological outcome. A larger cohort is required to determine if these findings are statistically significant.ReferenceGraus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, Cortese I, Dale RC, Gelfand JM, Geschwind M, Glaser CA, Honnorat J, Hoftberger R, Iizuka T, Irani SR, Lancaster E, Leypoldt F, Pruss H, Rae-Grant A, Reindl M, Rosenfeld MR, Rostasy K, Saiz A, Venkatesan A, Vincent A, Wandinger KP, Waters P, Dalmau J. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol2016;15:391–404.