Background Integrating clinical findings with neuroradiological changes is a crucial skill in neurology, particularly for diagnosis. Multiple Sclerosis (MS) lesions in the brainstem are rarely asymptomatic, leading to unique and often localised clinical syndromes. MS lesions exhibit a characteristic perivenular distribution, which in the brainstem is imprinted by the consistent topography of the penetrating veins. Objective This review provides an integrative perspective on the anatomical patterns of MS lesions in the brainstem (midbrain, pons, and medulla). It correlates specific clinical syndromes with radiological appearances, aiding in both diagnosis and functional localisation. Methods We searched the available literature using keywords related to the three brainstem sections (midbrain, pons, medulla) and eloquent anatomical locations (medial longitudinal fasciculus, cerebellar peduncle, nerve fascicle, aqueduct, area postrema), aiming to correlate specific radiological patterns of MS lesions with their consistent clinical syndromes as reported in the literature. Summary of Key Findings Brainstem MS lesions often cause irritative symptoms rather than full functional loss. Unlike other conditions, visible MS lesions on MRI rarely disappear and usually remain as silent lesions following an acute event. The consistent venous architecture creates specific radiological patterns that link to distinct clinical presentations. In contrast, inflammatory disorders like NMOSD and MOGAD cause more aggressive and extensive dysfunction. Conclusion The visual details of MS brainstem lesions reflect their close relationship to venous anatomy, which can be anticipated even when the central vein sign is not directly visualised. Recognising these specific clinical-radiological syndromes provides a unique and insightful diagnostic tool for MS, underscoring the value of strong functional and radiological-anatomical interpretation skills in clinical neurology.

To study the impact of cladribine tablets (CladT) on B cell function: kappa and lambda free light chain levels (K/L-FLC), immunoglobulin (Ig) G production including B-cell chemoattractant CXCL-13.

Background: Systemic lupus erythematous is a chronic autoimmune disease of unknown etiology. It predominantly presents in women of child-bearing age. The limited research available suggests that men with lupus are diagnosed at an older age compared to women, have a greater burden of end organ disease and a higher mortality. Objectives: To examine the clinical pattern in male lupus patients in a tertiary multi-ethnic lupus centre in East London. Methods: Male lupus patients were identified through review of a pre-existing database of lupus patients and lupus clinic lists at Barts Trust. All patients' electronic notes were reviewed prior to a telephone interview. All the participants fulfilled the ACR 1997 criteria for SLE. Descriptive data analysis was performed for all identified patients. Results: Fifty-one patients were identified. Sample demographics showed that male lupus was more prevalent among Afro-Caribbeans (37%,n=19), followed by Asians (33%,n=17) and then Caucasians (29%,n=15). The median age was 40.5(IQR: 32.5–52.7) years, with the median age at SLE diagnosis 28 years (IQR:23–45). Family history of an AI condition was seen in 25%(n=13), whilst 14%(n=7) had a family history specifically of SLE. Possible etiological triggers prior to diagnosis included a significant stressor such as death or illness of a loved one, financial challenges, marital separation, or challenges during childhood (childcare disruption or negligence) reported in 45%(n=23) patients. Serological evidence of previous infection with EBV, CMV, VZV, parvovirus, or H pylori was found in 76%(n=22). Although all patients were below the state pension age of 66, more than half (53%,n=27) were unemployed. 43%,(n=22) of participants had a smoking history. The majority of males had multiorgan involvement including renal (67%,n=34), cutaneous (55%,n=28), hematological (45%,n=23), musculoskeletal (31%,n=16), cardiac (27%,n=14), pulmonary (20%,n=10), and neurologic or neuropsychiatric (14%,n=7). Renal biopsy was done in 33/34 renal cases and the showed proliferative-class-III/IV in 65%(n=22). Hypertension was a significant comorbidity in 39%(n=20), 47%(n=24) had a concomitant AI condition (autoimmune hepatitis, rheumatoid arthritis, ITP, Evans syndrome, polymyositis, dermatomyositis, anti-synthetase syndrome or APS. Juvenile-onset SLE was diagnosed in 6%(n=3) of the patients. The median age of this group at disease onset was 10 years (IQR:14–16,100% Caucasians). These males all had kidney involvement (nephropathy class-IV/V). Regarding serology, 48 (94%) were positive for ANA at 1:640(44/48) and 1:160(4/48). In 2 patients ANA test was not recorded but they had confirmed renal or cutaneous biopsy findings. Of the 48 ANA positive samples, 19(40%) speckled, 15(31%) homogenous, 4(8%) each for nucleolar and mixed pattern and 6(13%) were not identified. Three quarters (75%,n=38) were positive for ds-DNA. Ro and La antigens were detected in 35%(n=18) and 8%(n=4) of the patients respectively, while anti-Sm and anti-U1RNP were detected in 37%(n=19) and 43%(n=22), respectively. Antiphospholipid antibodies were identified in less than a third(29%,n=15), of which 40%(n=6) presented with thrombotic events, including deep vein thrombosis, pulmonary embolism, stroke or myocardial infarction. Triple antiphospholipid antibodies including aCL, LA, and anti-B2GP1 was detected in 53%(8/15), 20%(3/15) had LA, 15%(2/15) had aCL, and 7%(1/15) had either anti-B2GP1 or aCL/anti-B2GP. Conclusion: SLE has a low prevalence in males, leading to a paucity of data in this cohort. Our dataset demonstrates a higher prevalence in Afro-Caribbean and Asians compared to Caucasians and a young age of onset (median 28 years) with presentation about 10 years earlier than most other reports. The majority were unemployed and reported significant life stressors. Over three-quarters of the patients had evidence of prior infection with herpes virus or parvovirus. Most of the lupus males had multiorgan involvement and over two-thirds had renal involvement, proliferative class-III/IV. There was a high prevalence of dsDNA (75%), ENA (particularly anti-Ro (35%)) and APL (29%). REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests: None declared.

Background: Cladribine is an effective immunotherapy for people with multiple sclerosis (pwMS). Whilst most pwMS do not require re-treatment following standard dosing (two treatment courses), disease activity re-emerges in others. The characteristics of pwMS developing re-emerging disease activity remain incompletely understood. Objectives: To explore whether clinical and/or paraclinical baseline characteristics, including the degree of lymphocyte reduction, drug dose and lesions on magnetic resonance imaging (MRI) are associated with re-emerging disease activity. Design: Service evaluation in pwMS undergoing subcutaneous cladribine (SClad) treatment. Methods: Demographics, clinical, laboratory and MRI data of pwMS receiving two courses of SClad were extracted from health records. To assess associations of predictor variables with re-emerging disease activity, a series of Cox proportional hazards models was fitted (one for each predictor variable). Results: Of n = 264 pwMS 236 received two courses of SClad and were included in the analysis. Median follow-up was 4.5 years (3.9, 5.3) from the first, and 3.5 years (2.9, 4.3) from the last SClad administration. Re-emerging disease activity occurred in 57/236 pwMS (24%); 22/236 received further cladribine doses (SClad or cladribine tablets) at 36.7 months [median; interquartile range (IQR): 31.7, 42.1], and 22/236 other immunotherapies 18.9 months (13.0, 30.2) after their second course of SClad, respectively. Eligibility was based on MRI activity in 29, relapse in 5, both in 13, elevated cerebrospinal fluid neurofilament light chain level in 3, deterioration unrelated to relapse in 4 and other in 3. Only 36/57 of those eligible for additional immunotherapy had received a reduced dose of SClad for their second treatment course. Association was detected between re-emerging disease activity and (i) high baseline MRI activity and (ii) low second dose of SClad. Conclusion: Re-emerging disease activity was associated with baseline MRI activity and low dose second course of SClad.

BackgroundThere is an urgent need for reliable methods to remotely monitor Multiple Sclerosis (MS). Existing assessments, such as Timed 25-Foot Walk (T25FW) and 9-Hole Peg Test (9HPT), are traditionally carried out in person by physicians. The use of self-administered, remote versions of these assessments could improve monitoring and hence care for people with MS (pwMS). This study evaluated the use of remote T25FW (rT25FW) and 9HPT (r9HPT) assessments.Methods pwMS were given comprehensive instructions and equipment for completing rT25FW/r9HPT. We assessed relationships between EDSS scores (through a previously-validated webEDSS) and contem- poraneous rT25FW/r9HPT using Spearman’s rank-order correlation, to evaluate consistency with previous in-person studies.ResultsSeventy-one pwMS completed the webEDSS and r9HPT, and 108 completed the webEDSS and rT25FW. There was a mild-moderate positive correlation between webEDSS and rT25FW (rho=0.40, p<0.0001, 95%CI=0.23–0.55), a finding consistent with previous in-person studies. There was a non-significant weak correlation between webEDSS and r9HPT. Distributions of rT25FW/r9HPT times were positively skewed. 100% of r9HPT times and 93.5% of rT25FW times were within specified limits used in clinical trials.ConclusionThese findings provide pilot evidence to indicate remote monitoring of MS is feasible. These assessments should be further developed to aid remote follow-up of pwMS.ashvin.kuri99@gmail.com

Objective: To report on safety and effectiveness of subcutaneous cladribine (Litak ® ) in multiple sclerosis (MS) patients. Methods: Litak ® was offered to MS-patients irrespective of disease course. Litak ® 10 mg was administered for 3–4 days during week 1. Based on lymphocyte count at week 4, patients received another 0–3 doses at week 5. A second course was administered 11 months later. Follow-up included adverse events, relapses, expanded disability status scale (EDSS), 9-hole-peg and Timed-25-foot-walking tests, no-evidence-of-disease-activity (NEDA), no-evidence-of-progression-or-active-disease (NEPAD), MRI, cerebrospinal fluid (CSF) neurofilament light chain (NfL), and lymphocyte counts. Results: In all, 208 patients received at least one course of treatment. Age at baseline was 44 (17–72) years and EDSS 0–8.5. Cladribine was generally well tolerated. One myocardial infarction, one breast cancer, and three severe skin reactions occurred without long-term sequelae. Two patients died (one pneumonia, one encephalitis). Lymphopenia grade 3 occurred in 5% and grade 4 in 0.5%. In 94 out of 116 pwMS with baseline and follow-up (BaFU) data after two treatment courses, EDSS remained stable or improved. At 18 months, 64% of patients with relapsing MS and BaFU data ( n = 39) had NEDA. At 19 months, 62% of patients with progressive MS and BaFU data ( n = 13) had NEPAD. Of n = 13 patients whose CSF-NfL at baseline was elevated, 77% were normalised within 12 months. Conclusions: Litak ® was well tolerated. Effectiveness in relapsing MS appeared similar to cladribine tablets and was encouraging in progressive MS. Our data suggest cladribine may be safe and effective in MS-patients irrespective of their disease stage.

Background: There is an urgent clinical need for reliable remote monitoring methods in Multiple Sclerosis (MS). We evaluated the use of remotely patient-recorded timed 25-foot walk (rT25FW) and nine-hole peg test (r9HPT). Methods: Seventy-one people with MS completed a previously-validated online EDSS (webEDSS) and r9HPT, and 108 completed the webEDSS and rT25FW. Results: There was a mild-moderate positive correlation between webEDSS and rT25FW, and no significant correlation between webEDSS and r9HPT. Distributions of rT25FW and r9HPT times were positively skewed. Conclusions: Our results provide pilot evidence that remote monitoring of MS is potentially valid but requires refinement before wide-scale implementation. With a median EDSS of 4.5 and EDSS range of 0 - 8.0, at least some patients with ambulatory difficulty are able to complete the assessments.

Vaccination is one of the most effective and cost-efficient methods for protecting people with multiple sclerosis (MS) from infections. However, use of vaccines has often been problematic because of misguided concerns that they may exacerbate the disease and/or that some disease-modifying therapies may influence the immune response to immunisations and/or their safety. People with MS risk higher morbidity and mortality from vaccine-preventable infections. It is, therefore, important to address any patient’s reluctance to accept vaccination and to provide clear guidance for clinicians on which vaccinations to consider proactively. We have reviewed the current literature and provide recommendations regarding vaccines in adults with MS, including specific advice regarding vaccination safety in patients receiving—or going to receive—disease-modifying therapies, vaccination during pregnancy, pretravel counselling and patient education.

Aims: To examine the association between socioeconomic status (SES) and disease -modifying therapy (DMT) prescribing patterns in people with relapsing -remitting multiple sclerosis (pwRRMS). Methods: A cross-sectional analysis was conducted among pwRRMS treated with a DMT in the neuroin- flammation service at The Royal London Hospital (Barts Health NHS Trust). Study data were collected between July and September 2017. SES was determined by patient income and education extracted from the English Index of Multiple Deprivation. Based on their efficacy, DMTs were categorized as moderate efficacy (Glatiramer Acetate and Beta-Interferons), high efficacy (Cladribine, Fingolimod and Dimethyl Fumarate) and very -high efficacy therapies (Natalizumab and Alemtuzumab). Multinomial logistic regressions were performed for uni- variate and multivariate models to assess differences between SES and DMT prescribing patterns. Results: Treatment consisted of moderate efficacy ( n = 76, 12%), high efficacy ( n = 325, 51.3%) and very -high efficacy therapies ( n = 232, 36.7%). Medians for income and education deciles were 4 (IQR 3 -7) and 6 (IQR 4 -8), respectively. After multinomial logistic regression analysis, patient income was not associated with in- creased odds of being treated with high efficacy (OR, 0.92; 95% CI, 0.82 -1.04; p = 0.177) or very -high efficacy DMTs (OR, 0.95; 95% CI, 0.85 -1.06; p = 0.371). Similarly, patient education was not associated with being treated with high efficacy (OR, 0.91; 95% CI, 0.80 -1.03; p = 0.139) or very -high efficacy therapies (OR, 0.92; 95% CI, 0.81 -1.04; p = 0.188). Conclusions: SES was not predictive of DMT prescribing patterns in pwRRMS. Whilst this appears reassuring within this universal health care setting, the same methodology needs to be applied to other MS services for comparison. Data could then be further interrogated to explore potential socioeconomic inequities in DMT prescribing patterns across the UK.

OBJECTIVE:To evaluate the use of CSF neurofilament light chain (NfL) measurements in clinical practice as well as their effect on treatment strategies and outcomes in patients with MS.METHODS:This was an observational cohort study of patients with MS who had a CSF NfL measurement between December 2015 and July 2018 as part of their routine clinical care. Treatment strategies were classified as "No Treatment/No Escalation" (no treatment or no escalation of treatment) or "Treatment/Escalation" (first-line injectable/oral disease-modifying therapies (DMTs), highly active DMTs, or treatment escalation). Change in Expanded Disability Status Scale (EDSS) scores was evaluated after 1-year follow-up.RESULTS:Of 203 patients with MS, 117 (58%) had relapsing-remitting MS. Disease activity was most frequently indicated by elevated CSF NfL (n = 85), followed by clinical (n = 81) and MRI activity (n = 65). CSF NfL measurements were independently associated with clinical (p = 0.02) and MRI activity (p < 0.001). Of those with elevated CSF NfL as the only evidence of disease activity (n = 22), 77% had progressive MS (PMS). In patients with PMS, 17 (20%) had elevated CSF NfL as the sole indicator of disease activity. Elevated CSF NfL resulted more frequently in Treatment/Escalation than normal CSF NfL (p < 0.001). Median EDSS change at follow-up was similar between patients receiving No Treatment/No Escalation and Treatment/Escalation decisions (p = 0.81).CONCLUSIONS:CSF NfL measurements informed treatment strategies, alongside clinical and MRI measures. CSF NfL levels were the only indicator of disease activity in a subset of patients, which was more pronounced in patients with PMS. Elevated CSF NfL was associated with more Treatment/Escalation strategies, which had an impact on EDSS outcomes at 1 year.

The efficacy and safety of ocrelizumab, versus interferon (IFN) β-1a, for the treatment of relapsing multiple sclerosis (RMS) from the identically designed OPERA I (NCT01247324) and OPERA II (NCT01412333) phase III studies has been reported; here we present subgroup analyses of efficacy endpoints from the pooled OPERA I and OPERA II populations.

May 7, 2019April 9, 2019Free AccessCladribine to treat Relapsing and Progressive Multiple Sclerosis - experience in >200 patients (S26.008)Stefania De Trane, Zhifeng Mao, Cesar Alvarez-Gonzalez, Kimberley Allen-Philbey, Ozlem Yildiz, Tom Campion, Ashok Adams, … Show All … , Benjamin Turner, Lucia Bianchi, Monica Marta, Sharmilee Gnanapavan, Maria Espasandin, Joela Methews, Gavin Giovannoni, David Baker, and Klaus Schmierer Show FewerAuthors Info & AffiliationsApril 9, 2019 issue92 (15_supplement)https://doi.org/10.1212/WNL.92.15_supplement.S26.008 Letters to the Editor

Multiple sclerosis (MS) can result in multi-level uro-neurological dysfunction that significantly increases the risk of urinary tract infections (UTIs). UTIs in patients with MS can lead to significant patient morbidity and cost to the National Health Service (NHS). Data collected from the NHS clinical commissioning groups in 2012/2013, and again in 2016/2017, revealed that UTI remains the most common cause of non-elective hospital admission in patients with MS, and that the overall cost of such admissions continued to rise across this period. In order to address this burgeoning problem, we used the evidence-based co-design methodology to collaborate with patients, their families and clinical staff to create a novel and innovative, patient-centred model called NeuroResponse®. We present the multi-faceted NeuroResponse® model and the results of the pilot study in the London Borough of Camden.

Good communication is essential in neurological consultations, yet this is obviously compromised by the absence of a common language. Interpreters can make valuable contributions to improving consultations, but translation has its shortcomings. The consultation dialogue is not always interpreted correctly or accurately, even (or especially) when friends or family are translating. Clinicians should therefore try to ensure that key information has been communicated and understood, perhaps by repetition or asking the patient to say what they have understood. Cultural factors are also important in the patient–physician interaction. Physicians should try to adopt a culturally sensitive approach during consultations, familiarising themselves with cultural norms within the prevalent ethnic minority groups in their area. They should resist directive approaches to save time and try to involve the patient in decision-making. This requires allocating extra time to consultations with patients for whom English is not their first language.

May 8, 2019April 9, 2019Free AccessSevere skin reactions associated with Cladribine treatment in patients with multiple sclerosis (P4.2-022)Maria Mateo-Casas, Saul Reyes, Stefania De Trane, Ozlem Yildiz, Benjamin Turner, Joela Mathews, Gavin Giovannoni, Edel O’toole, and Klaus SchmiererAuthors Info & AffiliationsApril 9, 2019 issue92 (15_supplement)https://doi.org/10.1212/WNL.92.15_supplement.P4.2-022 Letters to the Editor

Objective: To assess ocrelizumab vs interferon beta-1a (IFNβ1a) on 12- and 24-week confirmed disability progression (CDP) in subgroups of the pooled Phase III OPERA I and OPERA II studies (NCT01412333/NCT01247324). Background: Ocrelizumab, a humanized, CD20+ B cell-selective monoclonal antibody, decreased the risk of 12- and 24-week CDP vs IFNβ1a in the overall populations of the individual OPERA studies and in a pooled analysis. Design/Methods: In the OPERA studies, patients received intravenous ocrelizumab 600mg Q24W or subcutaneous IFNβ1a 44μg Q3W for 96 weeks. Time-to-onset of 12- and 24-week CDP was assessed. Between-group hazard ratios and p-values were based on Cox proportional hazards models with study, region and baseline Extended Disability Status Scale (EDSS) score ( Results: Patient characteristics were comparable between treatments and within subgroup strata. The risk reduction (RR; ocrelizumab vs IFNβ1a) for 12-and 24-week CDP in the overall pooled population was 40% (p Conclusions: These subgroup analyses were consistent with the overall pooled population on ocrelizumab reducing the risk of CDP vs IFNβ1a. Study Supported by: Sponsored by F. Hoffmann-La Roche Ltd; Writing and editorial assistance was provided by Health Interactions, USA, and Articulate Science, UK. Disclosure: Dr. Turner has nothing to disclose. Dr. Cree has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Abbvie, Biogen, EMD Serono, GeNEuro, Novartis, Sanofi Genzyme. Dr. Cree has received research support from Acorda, Hoffman La Roche, MedImmune, Novartis, Receptos and Teva. Dr. Lorscheider has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffman-La Roche Ltd. Dr. Montalban has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Actelion, Bayer, Biogen, Celgene, Genzyme, Merck, Novartis, Oryzon, Roche, Sanofi and Teva Pharmaceutical. Dr. Papeix has nothing to disclose. Dr. Buffels has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of F. Hoffman-La Roche Ltd. Dr. Masterman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Genentech Inc. Dr. Han has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Genentech Inc. Dr. Levesque has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech Inc. Dr. Wolinsky has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with has served on advisory boards and data monitoring or steering committees, has held consulting agreements or has received speaker honoraria from AbbVie, Alkermes, Biogen, Bionest, Clene Nanomedicine, EMD Serono, Forward Pharma, MedDay, Pharmaceuticals, Nov. Dr. Wolinsky has received royalty, license fees, or contractual rights payments from royalties for monoclonal antibodies out-licensed to Chemicon International through UTHealth.

Background: Although the aetiology of multiple sclerosis (MS) remains elusive, it is clear that Epstein Barr virus (EBV) and possibly other viruses play a role in the pathogenesis of MS. Laboratory evidence suggests that human endogenous retroviruses (HERVs) could also have a role, but no interventional therapy has determined what will happen if HERVs are suppressed. Recent epidemiological evidence indicates patients with HIV infection have a significantly lower risk of developing MS and that HIV antiretroviral therapies may be coincidentally inhibiting HERVs, or other retroelements, that could be implicated in MS. Objectives: To systematically investigate the effects of an HIV integrase strand inhibitor, raltegravir, on the number of gadolinium (Gd)-enhanced MRI lesions in people with active relapsing MS. Methods: This is a Phase 2a clinical trial where twenty participants were enrolled in a 3 month baseline phase followed by 3 months of treatment with raltegravir 400 mg twice a day. Patients had monthly Gd-enhanced MRI, saliva collection to test for EBV shedding, blood sampling for safety monitoring, virology (including HERVs), measurement of immunological and inflammatory markers; and physical, neurological and quality-of-life assessments. Results: All patients completed the six months trial period.The primary outcome measure of MS disease activity was the number of Gd-enhancing lesions observed, and raltegravir had no significant effect on the rate of development of Gd-enhancing lesions during the treatment phase compared with the baseline phase. Additionally, there was no change in secondary outcomes of either disability or quality-of-life measures that could reasonably be attributed to the intervention. There was a significant positive between HERV-W/MSRV (multiple sclerosis related virus) Gag Flix (Fluorescence index) B cells and the number of Gd-enhanced lesions at any visit (p = 0.029), which was independent of any potential influence of the trial drug administration. Regarding EBV shedding, there was no significant correlation between the amount of EBV shedding and the number of lesions. No change was detected in inflammatory markers (IL-8, IL-1 beta, IL-6, IL-10, TNF, IL-12p70 and HCRP), which were all within normal limits both before and after the intervention. Serum CD163 expression was also unchanged by raltegravir. Conclusions: Raltegravir did not have any impact on MS disease activity. This could be due to the choice of antiretroviral agent used in this study, the need for a combination of agents, as used in treating HIV infection, the short treatment period or dosing regimen, or the lack of a role of HERV expression in MS once the disease is established. Borderline significance for the association between EBV shedding and the total number of lesions, probably driven by new lesion development, may indicate EBV shedding as a marker of inflammatory disease activity. In conclusion, interesting correlations between HERV-W markers, EBV shedding and new MRI lesions, independent from treatment effects, were found.