Multiple sclerosis (OMIM 126200) is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability.1 Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals;2,3 and systematic attempts to identify linkage in multiplex families have confirmed that variation within the Major Histocompatibility Complex (MHC) exerts the greatest individual effect on risk.4 Modestly powered Genome-Wide Association Studies (GWAS)5-10 have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects play a key role in disease susceptibility.11 Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the Class I region. Immunologically relevant genes are significantly over-represented amongst those mapping close to the identified loci and particularly implicate T helper cell differentiation in the pathogenesis of multiple sclerosis.

ObjectiveWe characterised the clinical course, treatment and outcomes in 59 patients with relapsing myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination.MethodsWe evaluated clinical phenotypes, annualised relapse rates (ARR) prior and on immunotherapy and Expanded Disability Status Scale (EDSS), in 218 demyelinating episodes from 33 paediatric and 26 adult patients.ResultsThe most common initial presentation in the cohort was optic neuritis (ON) in 54% (bilateral (BON) 32%, unilateral (UON) 22%), followed by acute disseminated encephalomyelitis (ADEM) (20%), which occurred exclusively in children. ON was the dominant phenotype (UON 35%, BON 19%) of all clinical episodes. 109/226 (48%) MRIs had no brain lesions. Patients were steroid responsive, but 70% of episodes treated with oral prednisone relapsed, particularly at doses <10 mg daily or within 2 months of cessation. Immunotherapy, including maintenance prednisone (P=0.0004), intravenous immunoglobulin, rituximab and mycophenolate, all reduced median ARRs on-treatment. Treatment failure rates were lower in patients on maintenance steroids (5%) compared with non-steroidal maintenance immunotherapy (38%) (P=0.016). 58% of patients experienced residual disability (average follow-up 61 months, visual loss in 24%). Patients with ON were less likely to have sustained disability defined by a final EDSS of ≥2 (OR 0.15, P=0.032), while those who had any myelitis were more likely to have sustained residual deficits (OR 3.56, P=0.077).ConclusionRelapsing MOG antibody-associated demyelination is strongly associated with ON across all age groups and ADEM in children. Patients are highly responsive to steroids, but vulnerable to relapse on steroid reduction and cessation.

The emergence of novel coronavirus 2019 (COVID-19) 1 and the subsequent pandemic present a unique challenge to neurologists managing patients with multiple sclerosis (MS) and related neuroinflammatory disorders, such as neuromyelitis spectrum disorder (NMOSD). National professional bodies (e.g., Italian Society of Neurology and Association of British Neurologists) and patient organizations (e.g., National MS Society, MS International Federation, UK MS Society, and MS Australia) have responded rapidly by issuing guidelines for the COVID-19 pandemic, primarily focused on MS disease-modifying therapies (DMTs). In this commentary, we highlight the implications of COVID-19 for people with MS and related disorders, including the risk of respiratory infections, general health advice, and recommendations (from consensus-based guidelines) for immunotherapies, relapse management, and service delivery during the COVID-19 pandemic. Risk of respiratory infectionsWhether people with MS and NMOSD are at an increased risk of COVID-19 infection or at a higher risk of more severe infection is unknown. There are no data available on whether the rate of mild, self-limiting respiratory infections that do not require a medical encounter is increased in people with MS. However, there is increased infection-related health care utilization across all age groups in people with MS compared with the general population. 2 These infections include pneumonia 2,3 (particularly in people with bulbar weakness resulting in aspiration and impaired pulmonary function due to severe quadriparesis) and influenza, 3 but not upper respiratory tract infections. 2 Older age, male sex, worse physical disability, and lower socioeconomic status are associated with increased hospitalization rates in MS. 3 People with MS have a higher risk of intensive care unit admission with infections and higher 1-year mortality after admission than the general population. 4 In addition to the higher background risk of infection-related health care utilization, people with MS treated with the secondgeneration DMTs are exposed to a further increased risk of infections. 5 These factors should be considered when counseling individuals about the risks of COVID-19 infection. General health advicePeople with MS and related disorders should follow World Health Organization (WHO) and national or local health authority guidance on preventive measures to reduce transmission of COVID-19 in the general population. These include social distancing, frequent hand washing with soap and water or an alcohol-based hand rub, and respiratory hygiene. Advice from the WHO is updated regularly (who.int/emergencies/diseases/novel-coronavirus-2019).