Resource publications for this Seminar were identified through searches of PubMed and MEDLINE, and references from selected articles, using “multiple sclerosis” as search terms relevant to each, and a filter for publication date (up to Dec 31, 2017). Studies chosen for this Seminar describe the most recent advances in research, were published in high-impact, peer-reviewed journals, and showed results based on satisfactory numbers of study participants, covering a relevant population. Only
SeminarMultiple sclerosis
Introduction
Multiple sclerosis is a complex condition but some of the fundamental questions relating to causation and susceptibility have been answered. It predominantly affects individuals in their early adult life, and has a huge impact functionally, financially, and on quality of life. Costs are considerable and rise with increasing disability.1
This Seminar will focus on major developments in our understanding of the development and management of multiple sclerosis. There is an improved understanding of the genetic (eg, HLA DRB1*15:01), environmental (eg, vitamin D), and lifestyle (eg, cigarette smoking) factors that contribute to the development of the disease, with environmental, rather than genetic, factors playing a bigger part in susceptibility. Both the innate and adaptive immune systems, with their effector cells (eg, microglia, activated macrophages, B and T lymphocytes), are known to influence the pathogenesis of multiple sclerosis, and the discovery that B cells are major contributors to the disease has led to new treatment targets.
The increase in the number of disease-modifying treatments available for the most common form of the condition, relapsing remitting multiple sclerosis, is another major development;2 however, this advance is in contrast to the paucity of effective treatments for the progressive forms of the condition. Treatment guidelines that place the patient at the centre of the decision-making process have been developed to improve management of multiple sclerosis. The emergence of effective treatments has created an impetus to diagnose as early as possible. Diagnostic criteria in patients with clinically isolated syndrome have been revised to put more emphasis on exclusion of disorders that mimic multiple sclerosis, and the introduction of cerebrospinal fluid (CSF) findings. The use of disease-modifying treatments might have contributed to the improved longevity in multiple sclerosis,3 and reduced rates of worsening and evolution to secondary progressive multiple sclerosis when compared with early natural history cohorts.4 The plethora of new agents poses challenges in selecting the right drug for the right person at the right time, and so current research aims to provide the evidence and tools for personalised medicine in multiple sclerosis.5 Finally, when considering the overall management of the disease, there is increasing awareness of the effect of age on the pathophysiology and clinical manifestations of the condition.6 The aim of this Seminar is to provide clinicians and researchers with a comprehensive review of the latest developments and discoveries in multiple sclerosis research, by emphasising those that have an implication for care and an impact on patient management and treatment.
Section snippets
Epidemiology
With a prevalence of 50–300 per 100 000 people, about 2·3 million people are estimated to live with multiple sclerosis globally (figure 1),7 although this is likely to be an underestimate given the relative lack of data from large populations including India and China. The global distribution of multiple sclerosis generally increases with increasing distance from the equator, although there are exceptions.7 In addition, while the disease is common in regions populated by people from northern
Causes
Environmental, genetic, and epigenetic factors have a causal role in multiple sclerosis and potentially interact with modifiable risk factors.16 Current research is focused on the identification of new risk factors and the extent to which they contribute to multiple sclerosis aetiology.
From immune responses to pathology
Genetic and pathological studies37, 38 point towards the adaptive immune system, which consists of T cells and B cells, as a key player in the pathogenesis of multiple sclerosis. Inflammation in multiple sclerosis only affects the central nervous system (CNS), strongly suggesting that T cells and B cells are selectively recruited by specific target antigens (probably autoantigens) that are only expressed in the CNS. Although several candidate antigens have been proposed, none has been confirmed.
From pathology to clinical features
Early multiple sclerosis is usually characterised by acute episodes of neurological deficits known as relapses, that depend on both the location of the CNS region affected by the acute inflammatory demyelinating lesions and the extent of the inflammatory process. For example, the development of an acute inflammatory lesion in the optic nerve leads to optic neuritis, which is characterised by visual impairment and pain on eye movements. Here we use optic neuritis as a model to illustrate the
Tissue repair, plasticity, and clinical recovery
Clinical deficits caused by acute inflammatory demyelination could be reversible via restoration of nerve conduction. The restored nerve conduction is more continuous than saltatory, and is achieved because the demyelinated axonal membrane shows several changes following demyelination, such as an increase in sodium channels. In addition, remyelination leads to new myelinated internodes, although these are shorter and thinner than normal.56 These changes lead to increased energy demand, which in
Diagnosis
The diagnosis of multiple sclerosis is based on the integration of clinical, imaging, and laboratory findings. Clinical expertise is necessary to demonstrate evidence of dissemination in time and space and, importantly, to exclude other neurological conditions. MRI can provide this evidence and assist in excluding other conditions, allowing earlier diagnosis with increased certainty with successive versions of the diagnostic criteria.60 The diagnostic criteria, known as the McDonald Criteria,61
Phenotype
The overwhelming majority of patients who develop multiple sclerosis begin with a single episode, termed a clinically isolated syndrome, that involves the optic nerve, brainstem, or spinal cord, and resolves over time. The concept of a clinically isolated syndrome is now well established66 and is being incorporated into the WHO International Classification of Diseases, version 11. Most patients who have experienced a clinically isolated syndrome and have an abnormal MRI scan will have a second
Predicting clinical course
Age, sex, spinal cord lesions, and extent of brain abnormalities on MRI are predictors of outcome across all phenotypes of multiple sclerosis. 34% of patients with radiologically isolated syndrome develop a first acute clinical event consistent with clinically isolated syndrome or multiple sclerosis within 5 years;76 risk factors for developing a first symptomatic event include male sex, younger age at the time of radiologically isolated syndrome diagnosis (<37 years), and presence of spinal
Disease-modifying treatments
Several disease-modifying treatments have been discovered and approved for patients with relapsing remitting multiple sclerosis and clinically isolated syndrome (table 3, figure 3). In general, treatments target neuroinflammation and could have an indirect effect on neurodegeneration; however, their efficacy for reducing the development of brain atrophy in clinical trials has been moderate at best. Only one disease-modifying treatment (ocrelizumab) has been shown to slow progression in patients
Management
Active management, centring on the person with multiple sclerosis, is advocated at all stages of the condition to minimise disease impact, maximise quality of life, and espouse a philosophy of wellness.126 Addressing the array of multiple sclerosis symptoms is a critical component of management (table 4). While drug treatments are available for some symptoms, the evidence base is poor and well designed trials with adequate numbers are the exception, though studies of fampridine provide a useful
Future directions
The therapeutic developments seen in multiple sclerosis are unequalled in any area of neurology. The priorities now are to get the greatest benefit for individual patients from the available armamentarium and to ensure equity of access globally. The greatest outstanding challenges are to clarify mechanisms of neurodegeneration and improve trial outcomes to facilitate the development of much needed treatments for progressive multiple sclerosis. Reparative agents are likely to be used in
Search strategy and selection criteria
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