This scientific commentary refers to ‘Human herpesvirus 6A and axonal injury before the clinical onset of multiple sclerosis’ by Grut et al. (https://doi.org/10.1093/brain/awad374).

Inflammatory injury to the spinal cord causes a well-recognized clinical syndrome. Patients typically develop bilateral weakness, usually involving the legs, although the arms may also become affected, in association with a pattern of sensory changes that suggests a spinal cord dermatomal level. Bowel and bladder impairment is also common in many patients. Recognition of the clinical pattern of spinal cord injury should lead clinicians to perform imaging studies to evaluate for compressive etiologies. MRI of the spine is particularly useful in helping visualize intraparenchymal lesions and when these lesions enhance following contrast administration a diagnosis of myelitis is made. Cerebrospinal fluid analysis can also confirm a diagnosis of myelitis when a leukocytosis is present. There are many causes of non-compressive spinal cord injury including infectious, parainfectious, toxic, nutritional, vascular, systemic as well as idiopathic inflammatory etiologies. This review focuses on inflammatory spinal cord injury and its relationships with multiple sclerosis, neuromyelitis optica, acute disseminated encephalomyelitis and systemic collagen vascular and paraneoplastic diseases.

Familial aggregation and the studies of twins indicate that heredity contributes to multiple sclerosis (MS) risk. Immunologic studies of leukocyte antigens subsequently followed by gene-mapping techniques identified the primary MS susceptibility locus to be within the major histocompatibility complex (MHC). The primary risk allele is HLA-DRB1*15, although other alleles of this gene also influence MS susceptibility. Other genes within the MHC also contribute to MS susceptibility. Genome-wide association studies have identified over 50 additional common variants of genes across the genome. Estimates suggest that there may be as many as 200 genes involved in MS susceptibility. In addition to these common polymorphisms, studies have identified several rare risk alleles in some families. Interestingly, the majority of the genes identified have known immunologic functions and many contribute to the risk of inheriting other autoimmune diseases. Genetic variants in the vitamin D metabolic pathway have also been identified. That vitamin D contributes to MS susceptibility as both an environmental as well as genetic risk factor underscores the importance of this metabolic pathway in disease pathogenesis. Current efforts are focused on understanding how the myriad of genetic risk alleles interact within networks to influence MS risk at family level as well as within populations.

Multiple sclerosis (MS) patients are classified as either having relapsing onset or progressive onset disease, also known as primary progressive MS (PPMS). Relative to relapsing onset patients, PPMS patients are older at disease onset, are equally likely to be men or women, and have more rapid accumulation of disability that does not respond well to treatments used in relapsing onset MS. Although estimates vary, 5-15% of all MS patients have a PPMS disease course. Genetic variance is a proposed determinant of MS disease course. If distinct genes associated with PPMS were identified study of these genes might lead to an understanding of the biology underlying disease progression and neural degeneration that are the hallmarks of PPMS. These genes and their biological pathways might also represent therapeutic targets. This chapter systematically reviews the PPMS genetic literature. Despite the intuitively appealing notion that differences between PPMS and relapsing onset MS are due to genetics, definite differences associated with these phenotypes at the major histocompatibility complex or elsewhere in the genome have not been found. Recent large-scale genome wide screens identified multiple genes associated with MS susceptibility outside the MHC. The genetic variants identified thus far make only weak individual contributions to MS susceptibility. If the genetic effects that contribute to the differences between PPMS and relapsing MS are similar in magnitude to those that distinguish MS from healthy controls then, given the relative scarcity of the PPMS phenotype, very large datasets will be needed to identify PPMS associated genes. International collaborative efforts could provide the means to identify such genes. Alternately, it is possible that factors other than genetics underlie the differences between these clinical phenotypes.

Rapid advances are occurring in multiple sclerosis disease modifying therapies. Recent therapeutic advances include modifications to improve tolerability of existing products (e.g. interferon beta and glatiramer acetate), development of novel anti-neuroinflammatory medications (e.g. fingolimod, teriflunomide and dimethyl fumarate, daclizumab, alemtuzumab, ocrelizumab) and investigation of treatments in progressive MS (e.g. natalizumab, mastinib, natalizumab, siponimod). The impact of vitamin D supplementation on the disease course in relapsing MS patients is also being studied in several clinical trials. This article reviews the current state of the field with a forward look to the next phase of MS research that could focus on strategies to promote remyelination and provide neuronal protection.

Multiple sclerosis (MS) is an autoimmune demyelinating and neurodegenerative disease of the central nervous system, and the leading cause of nontraumatic neurological disability in young adults. Effective management requires a multifaceted approach to control acute attacks, manage progressive worsening, and remediate bothersome or disabling symptoms associated with this illness. Remarkable advances in treatment of all forms of MS, and especially for relapsing disease, have favorably changed the long-term outlook for many patients. There also has been a conceptual shift in understanding the immune pathology of MS, away from a purely T-cell-mediated model to recognition that B cells have a key role in pathogenesis. The emergence of higher-efficacy drugs requiring less frequent administration have made these preferred options in terms of tolerability and adherence. Many experts now recommend use of these as first-line treatment for many patients with early disease, before permanent disability is evident.

Objective: Aquaporin 4 (AQP4)-specific autoantibodies in neuromyelitis optica (NMO) are immunoglobulin (Ig)G1, a T cell-dependent Ig subclass, indicating that AQP4-specific T cells participate in NMO pathogenesis. Our goal was to identify and characterize

Selective depletion of CD20⁺ B cells by anti-CD20 monoclonal antibodies as monotherapy in multiple sclerosis (MS) profoundly suppresses acute inflammatory disease activity and signifies an important advance in the treatment of relapsing-remitting MS. Ocrelizumab, a humanized anti-CD20 monoclonal antibody, is also the first proven therapy to lessen disability progression in primary progressive MS-a breakthrough for patients with a disease that had no proven therapy. Ocrelizumab is generally well tolerated, with the most common adverse events experienced being infusion reactions and infections. In ocrelizumab trials in MS a numerical imbalance in the risk of malignancies was observed. In this article, we review advances in anti-CD20 B-cell-depleting biological therapies for MS, including ocrelizumab, rituximab, and ofatumumab.